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Sample records for acute tissue damage

  1. Temporal relationship of serum markers and tissue damage during acute intestinal ischemia/reperfusion

    PubMed Central

    la Garza, Francisco Javier Guzmán-de; Ibarra-Hernández, Juan Manuel; Cordero-Pérez, Paula; Villegas-Quintero, Pablo; Villarreal-Ovalle, Claudia Ivette; Torres-González, Liliana; Oliva-Sosa, Norma Edith; Alarcón-Galván, Gabriela; Fernández-Garza, Nancy Esthela; Muñoz-Espinosa, Linda Elsa; Cámara-Lemarroy, Carlos Rodrigo; Carrillo-Arriaga, José Gerardo

    2013-01-01

    OBJECTIVE: It is essential to identify a serological marker of injury in order to study the pathophysiology of intestinal ischemia reperfusion. In this work, we studied the evolution of several serological markers after intestinal ischemia reperfusion injury in rats. The markers of non-specific cell damage were aspartate aminotransferase, alanine aminotransaminase, and lactic dehydrogenase, the markers of inflammation were tumor necrosis factor alpha, interleukin-6, and interleukin-1 beta, and the markers of intestinal mucosal damage were intestinal fatty acid binding protein and D-lactate. We used Chiús classification to grade the histopathological damage. METHODS: We studied 35 Wistar rats divided into groups according to reperfusion time. The superior mesenteric artery was clamped for 30 minutes, and blood and biopsies were collected at 1, 3, 6, 12, 24, and 48 hours after reperfusion. We plotted the mean ± standard deviation and compared the baseline and maximum values for each marker using Student's t-test. RESULTS: The maximum values of interleukin-1 beta and lactic dehydrogenase were present before the maximal histopathological damage. The maximum tumor necrosis factor alpha and D-lactate expressions coincided with histopathological damage. Alanine aminotransaminase and aspartate aminotransferase had a maximum expression level that increased following the histopathological damage. The maximum expressions of interluken-6 and intestinal fatty acid binding protein were not significantly different from the Sham treated group. CONCLUSION: For the evaluation of injury secondary to acute intestinal ischemia reperfusion with a 30 minute ischemia period, we recommend performing histopathological grading, quantification of D-lactate, which is synthesized by intestinal bacteria and is considered an indicator of mucosal injury, and quantification of tumor necrosis factor alpha as indicators of acute inflammation three hours after reperfusion. PMID:23917671

  2. Prediction of tissue thermal damage.

    PubMed

    Li, Xin; Zhong, Yongmin; Subic, Aleksandar; Jazar, Reza; Smith, Julian; Gu, Chengfan

    2016-04-29

    This paper presents a method to characterize tissue thermal damage by taking into account the thermal-mechanical effect of soft tissues for thermal ablation. This method integrates the bio-heating conduction and non-rigid motion dynamics to describe thermal-mechanical behaviors of soft tissues and further extends the traditional tissue damage model to characterize thermal-mechanical damage of soft tissues. Simulations and comparison analysis demonstrate that the proposed method can effectively predict tissue thermal damage and it also provides reliable guidelines for control of the thermal ablation procedure. PMID:27163325

  3. Prediction of tissue thermal damage.

    PubMed

    Li, Xin; Zhong, Yongmin; Subic, Aleksandar; Jazar, Reza; Smith, Julian; Gu, Chengfan

    2016-04-29

    This paper presents a method to characterize tissue thermal damage by taking into account the thermal-mechanical effect of soft tissues for thermal ablation. This method integrates the bio-heating conduction and non-rigid motion dynamics to describe thermal-mechanical behaviors of soft tissues and further extends the traditional tissue damage model to characterize thermal-mechanical damage of soft tissues. Simulations and comparison analysis demonstrate that the proposed method can effectively predict tissue thermal damage and it also provides reliable guidelines for control of the thermal ablation procedure.

  4. Tissue-Specific Regulation of p38α-Mediated Inflammation in Con A-Induced Acute Liver Damage.

    PubMed

    Kang, Young Jun; Bang, Bo-Ram; Otsuka, Motoyuki; Otsu, Kinya

    2015-05-15

    Because p38α plays a critical role in inflammation, it has been an attractive target for the development of anti-inflammation therapeutics. However, p38α inhibitors showed side effects, including severe liver toxicity, that often prevailed over the benefits in clinical studies, and the mechanism of toxicity is not clear. In this study, we demonstrate that p38α regulates the inflammatory responses in acute liver inflammation in a tissue-specific manner, and liver toxicity by p38α inhibitors may be a result of the inhibition of protective activity of p38α in the liver. Genetic ablation of p38α in T and NKT cells protected mice from liver injury in Con A-induced liver inflammation, whereas liver-specific deletion of p38α aggravated liver pathology. We found that p38α deficiency in the liver increased the expression of chemokines to recruit more inflammatory cells, indicating that p38α in the liver plays a protective anti-inflammatory role during acute liver inflammation. Therefore, our results suggest that p38α regulates the inflammatory responses in a tissue-specific manner, and that the tissue-specific p38α targeting strategies can be used for the development of an effective anti-inflammation treatment with an improved side-effect profile.

  5. An essential role for TH2-type response in limiting acute tissue damage during experimental helminth infection.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Helminths induce potent Th2-type immune responses that can lead to worm expulsion, but it remains undetermined whether components of this response can enhance the wound healing responses elicited as these large multi-cellular parasites traffic thru vital tissues. We used a model of helminth infecti...

  6. Nrf3-deficient mice are not protected against acute lung and adipose tissue damages induced by butylated hydroxytoluene.

    PubMed

    Chevillard, Grégory; Nouhi, Zaynab; Anna, Derjuga; Paquet, Marilène; Blank, Volker

    2010-03-01

    We found that both wild type and Nrf3 (NF-E2-related factor 3) deficient mice are sensitive to BHT single administration exhibiting respiratory distress and considerably lose body weight following treatment. At time of sacrifice, the BHT-treated Nrf3-/- mice had lost significantly more body weight than their WT counterparts. In the lung, transcript levels of the transcription factors Nrf1, Nrf2 and Nrf3 were differentially regulated by BHT treatment. In addition, genes implicated in adipogenesis were repressed following BHT exposure in the white adipose tissue. Together, our data provide the first evidence that BHT exposure not only affects lung function but also leads to impaired adipogenesis in adipocytes.

  7. Global sensitivity analysis of a mathematical model of acute inflammation identifies nonlinear dependence of cumulative tissue damage on host interleukin-6 responses.

    PubMed

    Mathew, Shibin; Bartels, John; Banerjee, Ipsita; Vodovotz, Yoram

    2014-10-01

    The precise inflammatory role of the cytokine interleukin (IL)-6 and its utility as a biomarker or therapeutic target have been the source of much debate, presumably due to the complex pro- and anti-inflammatory effects of this cytokine. We previously developed a nonlinear ordinary differential equation (ODE) model to explain the dynamics of endotoxin (lipopolysaccharide; LPS)-induced acute inflammation and associated whole-animal damage/dysfunction (a proxy for the health of the organism), along with the inflammatory mediators tumor necrosis factor (TNF)-α, IL-6, IL-10, and nitric oxide (NO). The model was partially calibrated using data from endotoxemic C57Bl/6 mice. Herein, we investigated the sensitivity of the area under the damage curve (AUCD) to the 51 rate parameters of the ODE model for different levels of simulated LPS challenges using a global sensitivity approach called Random Sampling High Dimensional Model Representation (RS-HDMR). We explored sufficient parametric Monte Carlo samples to generate the variance-based Sobol' global sensitivity indices, and found that inflammatory damage was highly sensitive to the parameters affecting the activity of IL-6 during the different stages of acute inflammation. The AUCIL6 showed a bimodal distribution, with the lower peak representing healthy response and the higher peak representing sustained inflammation. Damage was minimal at low AUCIL6, giving rise to a healthy response. In contrast, intermediate levels of AUCIL6 resulted in high damage, and this was due to the insufficiency of damage recovery driven by anti-inflammatory responses from IL-10 and the activation of positive feedback sustained by IL-6. At high AUCIL6, damage recovery was interestingly restored in some population of simulated animals due to the NO-mediated anti-inflammatory responses. These observations suggest that the host's health status during acute inflammation depends in a nonlinear fashion on the magnitude of the inflammatory stimulus

  8. Tissue damage detection by osmotic surveillance.

    PubMed

    Enyedi, Balázs; Kala, Snigdha; Nikolich-Zugich, Tijana; Niethammer, Philipp

    2013-09-01

    How tissue damage is detected to induce inflammatory responses is unclear. Most studies have focused on damage signals released by cell breakage and necrosis. Whether tissues use other cues in addition to cell lysis to detect that they are damaged is unknown. We find that osmolarity differences between interstitial fluid and the external environment mediate rapid leukocyte recruitment to sites of tissue damage in zebrafish by activating cytosolic phospholipase a2 (cPLA2) at injury sites. cPLA2 initiates the production of non-canonical arachidonate metabolites that mediate leukocyte chemotaxis through a 5-oxo-ETE receptor (OXE-R). Thus, tissues can detect damage through direct surveillance of barrier integrity, with cell swelling probably functioning as a pro-inflammatory intermediate in the process. PMID:23934216

  9. Tissue damage thresholds during therapeutic electrical stimulation

    NASA Astrophysics Data System (ADS)

    Cogan, Stuart F.; Ludwig, Kip A.; Welle, Cristin G.; Takmakov, Pavel

    2016-04-01

    Objective. Recent initiatives in bioelectronic modulation of the nervous system by the NIH (SPARC), DARPA (ElectRx, SUBNETS) and the GlaxoSmithKline Bioelectronic Medicines effort are ushering in a new era of therapeutic electrical stimulation. These novel therapies are prompting a re-evaluation of established electrical thresholds for stimulation-induced tissue damage. Approach. In this review, we explore what is known and unknown in published literature regarding tissue damage from electrical stimulation. Main results. For macroelectrodes, the potential for tissue damage is often assessed by comparing the intensity of stimulation, characterized by the charge density and charge per phase of a stimulus pulse, with a damage threshold identified through histological evidence from in vivo experiments as described by the Shannon equation. While the Shannon equation has proved useful in assessing the likely occurrence of tissue damage, the analysis is limited by the experimental parameters of the original studies. Tissue damage is influenced by factors not explicitly incorporated into the Shannon equation, including pulse frequency, duty cycle, current density, and electrode size. Microelectrodes in particular do not follow the charge per phase and charge density co-dependence reflected in the Shannon equation. The relevance of these factors to tissue damage is framed in the context of available reports from modeling and in vivo studies. Significance. It is apparent that emerging applications, especially with microelectrodes, will require clinical charge densities that exceed traditional damage thresholds. Experimental data show that stimulation at higher charge densities can be achieved without causing tissue damage, suggesting that safety parameters for microelectrodes might be distinct from those defined for macroelectrodes. However, these increased charge densities may need to be justified by bench, non-clinical or clinical testing to provide evidence of device

  10. Tissue Damage and Oxidant/Antioxidant Balance

    PubMed Central

    Kisaoglu, Abdullah; Borekci, Bunyamin; Yapca, O. Erkan; Bilen, Habib; Suleyman, Halis

    2013-01-01

    The oxidant/antioxidant balance in healthy tissues is maintained with a predominance of antioxidants. Various factors that can lead to tissue damage disrupt the oxidant/antioxidant balance in favor of oxidants. In this study, disruptions of the oxidant/antioxidant balance in favor of oxidants were found to be a consequence of the over-consumption of antioxidants. For this reason, antioxidants are considered to be of importance in the prevention and treatment of various types of tissue damage that are aggravated by stress. PMID:25610248

  11. Soft tissue damage after minimally invasive THA

    PubMed Central

    2010-01-01

    Background and purpose Minimally invasive surgery (MIS) for hip replacement is thought to minimize soft tissue damage. We determined the damage caused by 4 different MIS approaches as compared to a conventional lateral transgluteal approach. Methods 5 surgeons each performed a total hip arthroplasty on 5 fresh frozen cadaver hips, using either a MIS anterior, MIS anterolateral, MIS 2-incision, MIS posterior, or lateral transgluteal approach. Postoperatively, the hips were dissected and muscle damage color-stained. We measured proportional muscle damage relative to the midsubstance cross-sectional surface area (MCSA) using computerized color detection. The integrity of external rotator muscles, nerves, and ligaments was assessed by direct observation. Results None of the other MIS approaches resulted in less gluteus medius muscle damage than the lateral transgluteal approach. However, the MIS anterior approach completely preserved the gluteus medius muscle in 4 cases while partial damage occurred in 1 case. Furthermore, the superior gluteal nerve was transected in 4 cases after a MIS anterolateral approach and in 1 after the lateral transgluteal approach. The lateral femoral cutaneous nerve was transected once after both the MIS anterior approach and the MIS 2-incision approach. Interpretation The MIS anterior approach may preserve the gluteus medius muscle during total hip arthroplasty, but with a risk of damaging the lateral femoral cutaneous nerve. PMID:21110702

  12. Autophagy, Innate Immunity and Tissue Repair in Acute Kidney Injury

    PubMed Central

    Duann, Pu; Lianos, Elias A.; Ma, Jianjie; Lin, Pei-Hui

    2016-01-01

    Kidney is a vital organ with high energy demands to actively maintain plasma hemodynamics, electrolytes and water homeostasis. Among the nephron segments, the renal tubular epithelium is endowed with high mitochondria density for their function in active transport. Acute kidney injury (AKI) is an important clinical syndrome and a global public health issue with high mortality rate and socioeconomic burden due to lack of effective therapy. AKI results in acute cell death and necrosis of renal tubule epithelial cells accompanied with leakage of tubular fluid and inflammation. The inflammatory immune response triggered by the tubular cell death, mitochondrial damage, associative oxidative stress, and the release of many tissue damage factors have been identified as key elements driving the pathophysiology of AKI. Autophagy, the cellular mechanism that removes damaged organelles via lysosome-mediated degradation, had been proposed to be renoprotective. An in-depth understanding of the intricate interplay between autophagy and innate immune response, and their roles in AKI pathology could lead to novel therapies in AKI. This review addresses the current pathophysiology of AKI in aspects of mitochondrial dysfunction, innate immunity, and molecular mechanisms of autophagy. Recent advances in renal tissue regeneration and potential therapeutic interventions are also discussed. PMID:27153058

  13. Autophagy, Innate Immunity and Tissue Repair in Acute Kidney Injury.

    PubMed

    Duann, Pu; Lianos, Elias A; Ma, Jianjie; Lin, Pei-Hui

    2016-01-01

    Kidney is a vital organ with high energy demands to actively maintain plasma hemodynamics, electrolytes and water homeostasis. Among the nephron segments, the renal tubular epithelium is endowed with high mitochondria density for their function in active transport. Acute kidney injury (AKI) is an important clinical syndrome and a global public health issue with high mortality rate and socioeconomic burden due to lack of effective therapy. AKI results in acute cell death and necrosis of renal tubule epithelial cells accompanied with leakage of tubular fluid and inflammation. The inflammatory immune response triggered by the tubular cell death, mitochondrial damage, associative oxidative stress, and the release of many tissue damage factors have been identified as key elements driving the pathophysiology of AKI. Autophagy, the cellular mechanism that removes damaged organelles via lysosome-mediated degradation, had been proposed to be renoprotective. An in-depth understanding of the intricate interplay between autophagy and innate immune response, and their roles in AKI pathology could lead to novel therapies in AKI. This review addresses the current pathophysiology of AKI in aspects of mitochondrial dysfunction, innate immunity, and molecular mechanisms of autophagy. Recent advances in renal tissue regeneration and potential therapeutic interventions are also discussed. PMID:27153058

  14. A radiation damage repair model for normal tissues

    NASA Astrophysics Data System (ADS)

    Partridge, Mike

    2008-07-01

    A cellular Monte Carlo model describing radiation damage and repair in normal epithelial tissues is presented. The deliberately simplified model includes cell cycling, cell motility and radiation damage response (cell cycle arrest and cell death) only. Results demonstrate that the model produces a stable equilibrium system for mean cell cycle times in the range 24-96 h. Simulated irradiation of these stable equilibrium systems produced a range of responses that are shown to be consistent with experimental and clinical observation, including (i) re-epithelialization of radiation-induced lesions by a mixture of cell migration into the wound and repopulation at the periphery; (ii) observed radiosensitivity that is quantitatively consistent with both rate of induction of irreparable DNA lesions and, independently, with the observed acute oral and pharyngeal mucosal reactions to radiotherapy; (iii) an observed time between irradiation and maximum toxicity that is consistent with experimental data for skin; (iv) quantitatively accurate predictions of low-dose hyper-radiosensitivity; (v) Gomperzian repopulation for very small lesions (~2000 cells) and (vi) a linear rate of re-epithelialization of 5-10 µm h-1 for large lesions (>15 000 cells).

  15. Tissue factor in predicted severe acute pancreatitis

    PubMed Central

    Andersson, Ellen; Axelsson, Jakob; Eckerwall, Gunilla; Ansari, Daniel; Andersson, Roland

    2010-01-01

    AIM: To study tissue factor (TF) in acute pancreatitis and evaluate the role of TF as a predictive marker of severity. METHODS: Forty-nine consecutive patients admitted to Lund University Hospital, fulfilling the criteria of predicted severe acute pancreatitis (AP), were recruited prospectively between 2002 and 2004. Blood samples for TF analyses were drawn at inclusion in the study and 12 h, 1 d and 3 d later. RESULTS: Twenty-seven patients developed mild AP, and 22 patients severe AP. At inclusion in the study, the groups were comparable with respect to gender, aetiology, Acute Physiology and Chronic Health Evaluation II score, and duration of pain. At inclusion in the study and at 12 h, TF was higher in the severe AP group (P = 0.035 and P = 0.049, respectively). After 1 and 3 d, no differences in TF levels were noted. Interleukin (IL)-6 was significantly higher in the severe AP group at all of the studied time points. C-reactive protein (CRP) was significantly higher in the AP group at 1 and 3 d. In receiver operating characteristic-curves, the area under the curve (AUC) for TF was 0.679 (P = 0.035) at inclusion in the study, and a cut off level for TF of 40 pg/mL showed a sensitivity of 71% and a specificity of 67%, whereas corresponding AUC for IL-6 was 0.775, P = 0.001, and for CRP was 0.653. IL-6 showed better AUC-values than TF at all time points studied. CONCLUSION: TF-levels are raised early in severe AP. TF as an early predictive marker of severe AP is superior to CRP, but inferior to IL-6. PMID:21182229

  16. Re-assessment of chronic radio-induced tissue damage in a rat hindlimb model

    PubMed Central

    PHULPIN, BÉRENGÈRE; DOLIVET, GILLES; MARIE, PIERRE-YVES; POUSSIER, SYLVAIN; GALLET, PATRICE; LEROUX, AGNÈS; GRAFF, PIERRE; GROUBACH, FREDERIQUE; BRAVETTI, PIERRE; MERLIN, JEAN-LOUIS; TRAN, NGUYEN

    2010-01-01

    Radiotherapy is successfully used to treat neoplastic lesions, but may adversely affect normal tissues within the irradiated volume. However, additional clinical and para-clinical data are required for a comprehensive understanding of the pathogenesis of this damage. We assessed a rat model using clinical records and medical imaging to gain a better understanding of irradiation-induced tissue damage. The hindlimbs of the rats in this model were irradiated with a single dose of 30 or 50 Gy. Sequential analysis was based on observation records of stage and planar scintigraphy. Additional radiography, radiohistology and histology studies were performed to detect histological alterations. All animals developed acute and late effects, with an increased severity after a dose of 50 Gy. The bone uptake of 99mTc-HDP was significantly decreased in a dose- and time-dependent manner. Histologically, significant tissue damage was observed. After the 50 Gy irradiation, the animals developed lesions characteristic of osteoradionecrosis (ORN). Radiographic and histological studies provided evidence of lytic bone lesions. Our rat model developed tissue damage characteristic of radiation injury after a single 30 Gy irradiation and tissue degeneration similar to that which occurs during human ORN after a 50 Gy irradiation. The development of this animal model is an essential step in exploring the pathogenesis of irradiation-induced tissue damage, and may be used to test the efficacy of new treatments. PMID:22993575

  17. Continuum theory of fibrous tissue damage mechanics using bond kinetics: application to cartilage tissue engineering.

    PubMed

    Nims, Robert J; Durney, Krista M; Cigan, Alexander D; Dusséaux, Antoine; Hung, Clark T; Ateshian, Gerard A

    2016-02-01

    This study presents a damage mechanics framework that employs observable state variables to describe damage in isotropic or anisotropic fibrous tissues. In this mixture theory framework, damage is tracked by the mass fraction of bonds that have broken. Anisotropic damage is subsumed in the assumption that multiple bond species may coexist in a material, each having its own damage behaviour. This approach recovers the classical damage mechanics formulation for isotropic materials, but does not appeal to a tensorial damage measure for anisotropic materials. In contrast with the classical approach, the use of observable state variables for damage allows direct comparison of model predictions to experimental damage measures, such as biochemical assays or Raman spectroscopy. Investigations of damage in discrete fibre distributions demonstrate that the resilience to damage increases with the number of fibre bundles; idealizing fibrous tissues using continuous fibre distribution models precludes the modelling of damage. This damage framework was used to test and validate the hypothesis that growth of cartilage constructs can lead to damage of the synthesized collagen matrix due to excessive swelling caused by synthesized glycosaminoglycans. Therefore, alternative strategies must be implemented in tissue engineering studies to prevent collagen damage during the growth process. PMID:26855751

  18. Continuum theory of fibrous tissue damage mechanics using bond kinetics: application to cartilage tissue engineering.

    PubMed

    Nims, Robert J; Durney, Krista M; Cigan, Alexander D; Dusséaux, Antoine; Hung, Clark T; Ateshian, Gerard A

    2016-02-01

    This study presents a damage mechanics framework that employs observable state variables to describe damage in isotropic or anisotropic fibrous tissues. In this mixture theory framework, damage is tracked by the mass fraction of bonds that have broken. Anisotropic damage is subsumed in the assumption that multiple bond species may coexist in a material, each having its own damage behaviour. This approach recovers the classical damage mechanics formulation for isotropic materials, but does not appeal to a tensorial damage measure for anisotropic materials. In contrast with the classical approach, the use of observable state variables for damage allows direct comparison of model predictions to experimental damage measures, such as biochemical assays or Raman spectroscopy. Investigations of damage in discrete fibre distributions demonstrate that the resilience to damage increases with the number of fibre bundles; idealizing fibrous tissues using continuous fibre distribution models precludes the modelling of damage. This damage framework was used to test and validate the hypothesis that growth of cartilage constructs can lead to damage of the synthesized collagen matrix due to excessive swelling caused by synthesized glycosaminoglycans. Therefore, alternative strategies must be implemented in tissue engineering studies to prevent collagen damage during the growth process.

  19. Tissue kallikrein-kinin therapy in hypertension and organ damage.

    PubMed

    Chao, Julie; Bledsoe, Grant; Chao, Lee

    2014-01-01

    Tissue kallikrein is a serine proteinase that cleaves low molecular weight kininogen to produce kinin peptides, which in turn activate kinin receptors to trigger multiple biological functions. In addition to its kinin-releasing activity, tissue kallikrein directly interacts with the kinin B2 receptor, protease-activated receptor-1, and gamma-epithelial Na channel. The tissue kallikrein-kinin system (KKS) elicits a wide spectrum of biological activities, including reducing hypertension, cardiac and renal damage, restenosis, ischemic stroke, and skin wound injury. Both loss-of-function and gain-of-function studies have shown that the KKS plays an important endogenous role in the protection against health pathologies. Tissue kallikrein/kinin treatment attenuates cardiovascular, renal, and brain injury by inhibiting oxidative stress, apoptosis, inflammation, hypertrophy, and fibrosis and promoting angiogenesis and neurogenesis. Approaches that augment tissue kallikrein-kinin activity might provide an effective strategy for the treatment of hypertension and associated organ damage. PMID:25130039

  20. Acute liver damage and anorexia nervosa: a case report.

    PubMed

    Bridet, Lionel; Martin, Juan Jose Beitia; Nuno, Jose Luis Cabriada

    2014-04-01

    Anorexia nervosa is an eating disorder predominantly affecting young women and characterized by an intense fear of gaining weight and becoming fat. Liver injury with mild elevation of hepatic enzymes is a frequent complication, and steatosis of the liver is thought to be the major underlying pathology. However, acute hepatic failure with transaminase levels over 1000 u/L is a very rare complication, and the precise mechanism of the liver injury is still unclear. We report a case of a 35-year-old woman with a history of anorexia nervosa who developed acute liver damage with deep coma in relation to profound hypoglycemia. The treatment was hydration, correction of electrolyte and fluid imbalance, and gradual nutritional support to prevent refeeding syndrome. Our patient's consciousness was significantly improved with the recovery of liver function and normalization of transaminase levels. Although the mechanism of pathogenesis is largely unknown, we discuss the two principal hypotheses: starvation-induced autophagy and acute hypoperfusion.

  1. Free radical tissue damage: Protective role of antioxidant nutrients

    SciTech Connect

    Machling, L.J.; Bendich, A. )

    1987-12-01

    Highly reactive molecules called free radicals can cause tissue damage by reacting with polyunsaturated fatty acids in cellular membranes, nucleotides in DNA, and critical sulfhydryl bonds in proteins. Free radicals can originate endogenously from normal metabolic reactions or exogenously as components of tobacco smoke and air pollutants and indirectly through the metabolism of certain solvents, drugs, and pesticides as well as through exposure to radiation. There is some evidence that free radical damage contributes to the etiology of many chronic health problems such as emphysema, cardiovascular and inflammatory diseases, cataracts, and cancer. The extent of tissue damage is the result of the balance between the free radicals generated and the antioxidant protective defense system. Several dietary micronutrients contribute greatly to the protective system. Based on the growing interest in free radical biology and the lack of effective therapies for many of the chronic diseases, the usefulness of essential, safe nutrients in protecting against the adverse effects of oxidative injury warrants further study.

  2. Effects of tissue mechanical properties on susceptibility to histotripsy-induced tissue damage

    NASA Astrophysics Data System (ADS)

    Vlaisavljevich, Eli; Kim, Yohan; Owens, Gabe; Roberts, William; Cain, Charles; Xu, Zhen

    2014-01-01

    Histotripsy is a non-invasive tissue ablation method capable of fractionating tissue by controlling acoustic cavitation. To determine the fractionation susceptibility of various tissues, we investigated histotripsy-induced damage on tissue phantoms and ex vivo tissues with different mechanical strengths. A histotripsy bubble cloud was formed at tissue phantom surfaces using 5-cycle long ultrasound pulses with peak negative pressure of 18 MPa and PRFs of 10, 100, and 1000 Hz. Results showed significantly smaller lesions were generated in tissue phantoms of higher mechanical strength. Histotripsy was also applied to 43 different ex vivo porcine tissues with a wide range of mechanical properties. Gross morphology demonstrated stronger tissues with higher ultimate stress, higher density, and lower water content were more resistant to histotripsy damage in comparison to weaker tissues. Based on these results, a self-limiting vessel-sparing treatment strategy was developed in an attempt to preserve major vessels while fractionating the surrounding target tissue. This strategy was tested in porcine liver in vivo. After treatment, major hepatic blood vessels and bile ducts remained intact within a completely fractionated liver volume. These results identify varying susceptibilities of tissues to histotripsy therapy and provide a rational basis to optimize histotripsy parameters for treatment of specific tissues.

  3. Zebrafish fin regeneration after cryoinjury-induced tissue damage

    PubMed Central

    Chassot, Bérénice; Pury, David

    2016-01-01

    ABSTRACT Although fin regeneration following an amputation procedure has been well characterized, little is known about the impact of prolonged tissue damage on the execution of the regenerative programme in the zebrafish appendages. To induce histolytic processes in the caudal fin, we developed a new cryolesion model that combines the detrimental effects of freezing/thawing and ischemia. In contrast to the common transection model, the damaged part of the fin was spontaneously shed within two days after cryoinjury. The remaining stump contained a distorted margin with a mixture of dead material and healthy cells that concomitantly induced two opposing processes of tissue debris degradation and cellular proliferation, respectively. Between two and seven days after cryoinjury, this reparative/proliferative phase was morphologically featured by displaced fragments of broken bones. A blastemal marker msxB was induced in the intact mesenchyme below the damaged stump margin. Live imaging of epithelial and osteoblastic transgenic reporter lines revealed that the tissue-specific regenerative programmes were initiated after the clearance of damaged material. Despite histolytic perturbation during the first week after cryoinjury, the fin regeneration resumed and was completed without further alteration in comparison to the simple amputation model. This model reveals the powerful ability of the zebrafish to restore the original appendage architecture after the extended histolysis of the stump. PMID:27215324

  4. Rac1 signaling regulates neutrophil-dependent tissue damage in experimental colitis.

    PubMed

    Yu, Changhui; Zhang, Su; Song, Lei; Wang, Yusheng; Hwaiz, Rundk; Luo, Lingtao; Thorlacius, Henrik

    2014-10-15

    Excessive neutrophil recruitment in the colon is a major feature in acute colitis although the signaling mechanisms behind colonic recruitment of neutrophils remain elusive. Herein, we hypothesized that Rac1 activity might play an important role in neutrophil infiltration in the inflamed colon. Female Balb/c mice were treated with the Rac1 inhibitor NSC23766 (0.5 and 5mg/kg) before and daily after administration of 5% dextran sodium sulfate (DSS). Colonic tissue was collected for quantification of neutrophil recruitment, interleukin-6 (IL-6) and CXC chemokine formation as well as histological damage score five days after challenge with DSS. Rac1 activity was determined by western blot and Mac-1 expression by flow cytometry in neutrophils. Administration of NSC23766 decreased DSS-induced neutrophil recruitment and tissue damage in the colon. Rac1 inhibition decreased colonic formation of IL-6 and CXC chemokines in experimental colitis. Chemokine challenge increased Rac1 activity in neutrophils and NSC23766 markedly reduced this neutrophil activity of Rac1. Inhibition of Rac1 abolished CXC chemokine-induced neutrophil chemotaxis and up-regulation of Mac-1 in vitro. Taken together, Rac1 signaling plays a significant role in controlling accumulation of neutrophils and tissue injury in experimental colitis. Thus, our novel results suggest that targeting Rac1 signaling might be a useful way to protect against neutrophil-mediated tissue injury in acute colitis.

  5. Near-Infrared Optical Imaging Noninvasively Detects Acutely Damaged Muscle.

    PubMed

    Chrzanowski, Stephen M; Batra, Abhinandan; Lee-McMullen, Brittany; Vohra, Ravneet S; Forbes, Sean C; Jiang, Huabei; Vandenborne, Krista; Walter, Glenn A

    2016-10-01

    Muscle damage is currently assessed through methods such as muscle biopsy, serum biomarkers, functional testing, and imaging procedures, each with its own inherent limitations, and a pressing need for a safe, repeatable, inexpensive, and noninvasive modality to assess the state of muscle health remains. Our aim was to develop and assess near-infrared (NIR) optical imaging as a novel noninvasive method of detecting and quantifying muscle damage. An immobilization-reambulation model was used for inducing muscle damage and recovery in the lower hindlimbs in mice. Confirmation of muscle damage was obtained using in vivo indocyanine green-enhanced NIR optical imaging, magnetic resonance imaging, and ex vivo tissue analysis. The soleus of the immobilized-reambulated hindlimb was found to have a greater amount of muscle damage compared to that in the contralateral nonimmobilized limb, confirmed by in vivo indocyanine green-enhanced NIR optical imaging (3.86-fold increase in radiant efficiency), magnetic resonance imaging (1.41-fold increase in T2), and an ex vivo spectrophotometric assay of indocyanine green uptake (1.87-fold increase in normalized absorbance). Contrast-enhanced NIR optical imaging provides a sensitive, rapid, and noninvasive screening method that can be used for imaging and quantifying muscle damage and recovery in vivo. PMID:27565039

  6. Pancreatic tissue damage by transcatheter arterial embolization for hepatoma.

    PubMed

    Khan, K N; Nakata, K; Shima, M; Kusumoto, Y; Ishii, N; Koji, T; Nagataki, S

    1993-01-01

    We analyzed the serial changes in serum pancreatic enzyme activities by transcatheter arterial embolization (TAE) in 20 hepatoma patients with liver cirrhosis in an attempt to evaluate the incidence of the pancreatic tissue damage by TAE. Serum amylase activities increased in two (10%) cases, elastase 1 levels in six (30%) cases, and trypsin and pancreatic secretory trypsin inhibitor (PSTI) levels in each of five (25%) cases. Consequently, TAE resulted in the elevation of at least more than one serum pancreatic enzyme in eight (40%) of 20 cases, although none had clinical symptoms related to pancreatitis. When the adverse effect on the pancreatic tissue was compared among 6 cases of the superselective TAE and 14 cases of the nonsuperselective TAE, which were performed from the segmental and the nonsegmental hepatic arteries, respectively, the elevation of serum pancreatic enzymes was caused only by nonsuperselective TAE, not by superselective TAE. The volumes of Spongel and Lipiodol used or the injected doses of the anticancer agent mitomycin C were not different between the two groups. These results indicate that TAE for the treatment of hepatoma frequently causes pancreatic tissue damage, and the position of the inserted catheter tip is very important to avoid the pancreatic tissue damage by TAE.

  7. [Organ damage and cardiorenal syndrome in acute heart failure].

    PubMed

    Casado Cerrada, Jesús; Pérez Calvo, Juan Ignacio

    2014-03-01

    Heart failure is a complex syndrome that affects almost all organs and systems of the body. Signs and symptoms of organ dysfunction, in particular kidney dysfunction, may be accentuated or become evident for the first time during acute decompensation of heart failure. Cardiorenal syndrome has been defined as the simultaneous dysfunction of both the heart and the kidney, regardless of which of the two organs may have suffered the initial damage and regardless also of their previous functional status. Research into the mechanisms regulating the complex relationship between the two organs is prompting the search for new biomarkers to help physicians detect renal damage in subclinical stages. Hence, a preventive approach to renal dysfunction may be adopted in the clinical setting in the near future. This article provides a general overview of cardiorenal syndrome and an update of the physiopathological mechanisms involved. Special emphasis is placed on the role of visceral congestion as an emergent mechanism in this syndrome.

  8. Systemic inflammation regulates microglial responses to tissue damage in vivo

    PubMed Central

    Gyoneva, Stefka; Davalos, Dimitrios; Biswas, Dipankar; Swanger, Sharon A.; Garnier-Amblard, Ethel; Loth, Francis; Akassoglou, Katerina; Traynelis, Stephen F.

    2015-01-01

    Microglia, the resident immune cells of the central nervous system, exist in either a “resting” state associated with physiological tissue surveillance or an “activated” state in neuroinflammation. We recently showed that ATP is the primary chemoattractor to tissue damage in vivo and elicits opposite effects on the motility of activated microglia in vitro through activation of adenosine A2A receptors. However, whether systemic inflammation affects microglial responses to tissue damage in vivo remains largely unknown. Using in vivo two-photon imaging of mice, we show that injection of lipopolysaccharide (LPS) at levels that can produce both clear neuroinflammation and some features of sepsis significantly reduced the rate of microglial response to laser-induced ablation injury in vivo. Under pro-inflammatory conditions, microglial processes initially retracted from the ablation site, but subsequently moved toward and engulfed the damaged area. Analyzing the process dynamics in 3D cultures of primary microglia indicated that only A2A, but not A1 or A3 receptors, mediate process retraction in LPS-activated microglia. The A2A receptor antagonists caffeine and preladenant reduced adenosine-mediated process retraction in activated microglia in vitro. Finally, administration of preladenant before induction of laser ablation in vivo accelerated the microglial response to injury following systemic inflammation. The regulation of rapid microglial responses to sites of injury by A2A receptors could have implications for their ability to respond to the neuronal death occurring under conditions of neuroinflammation in neurodegenerative disorders. PMID:24807189

  9. Tissue Damage Characterization Using Non-invasive Optical Modalities

    NASA Astrophysics Data System (ADS)

    Diaz, David

    The ability to determine the degree of cutaneous and subcutaneous tissue damage is essential for proper wound assessment and a significant factor for determining patient treatment and morbidity. Accurate characterization of tissue damage is critical for a number of medical applications including surgical removal of nonviable tissue, severity assessment of subcutaneous ulcers, and depth assessment of visually open wounds. The main objective of this research was to develop a non-invasive method for identifying the extent of tissue damage underneath intact skin that is not apparent upon visual examination. This work investigated the relationship between tissue optical properties, blood flow, and tissue viability by testing the hypotheses that (a) changes in tissue oxygenation and/or microcirculatory blood flow measurable by Diffuse Near Infrared Spectroscopy (DNIRS) and Diffuse Correlation Spectroscopy (DCS) differ between healthy and damaged tissue and (b) the magnitude of those changes differs for different degrees of tissue damage. This was accomplished by developing and validating a procedure for measuring microcirculatory blood flow and tissue oxygenation dynamics at multiple depths (up to 1 centimeter) using non-invasive DCS and DNIRS technologies. Due to the lack of pressure ulcer animal models that are compatible with our optical systems, a proof of concept was conducted in a porcine burn model prior to conducting clinical trials in order to assess the efficacy of the system in-vivo. A reduction in total hemoglobin was observed for superficial (5%) and deep burns (35%) along with a statistically significant difference between the optical properties of superficial and deep burns (p < 0.05). Burn depth and viable vessel density were estimated via histological samples. 42% of vessels in the dermal layer were viable for superficial burns, compared to 25% for deep burns. The differences detected in optical properties and hemoglobin content by optical measurements

  10. Ultrastructure damage of oviduct telocytes in rat model of acute salpingitis

    PubMed Central

    Yang, Jian; Chi, Chi; Liu, Zhen; Yang, Gang; Shen, Zong-Ji; Yang, Xiao-Jun

    2015-01-01

    Acute salpingitis (AS) is an inflammatory disease which causes severe damage to a subset of classically described cells lining in oviduct wall and contributes to interstitial fibrosis and fertility problems. Telocytes (TCs), a newly discovered peculiar type of stromal cells, have been identified in many organs, including oviduct, with proposed multiple potential bio-functions. However, with recent increasing reports regarding TCs alterations in disease-affected tissues, there is still lack of evidence about TCs involvement in AS-affected oviduct tissues and potential pathophysiological roles. We presently identified normal TCs by their characteristic ultrastructural features and immunophenotype. However, in AS-affected oviduct tissues, TCs displayed multiple ultrastructural damage both in cellular body and prolongations, with obvious loss of TCs and development of tissue fibrosis. Furthermore, TCs lose their interstitial 3-D network connected by homocellular or heterocellular junctions between TCs and adjacent cells. And especially, TCs connected to the activated immunocytes (mononuclear cells, eosinophils) and affected local immune state (repression or activation). Meanwhile, massive neutrophils infiltration and overproduced Inducible Nitric Oxide Synthase (iNOS), COX-2, suggested mechanism of inflammatory-induced TCs damage. Consequently, TCs damage might contribute to AS-induced structural and reproductive functional abnormalities of oviduct, probably via: (i) substances, energy and functional insufficiency, presumably, e.g. TC-specific genetic material profiles, ion channels, cytoskeletal elements, Tps dynamics, etc., (ii) impaired TCs-mediated multicellular signalling, such as homeostasis/angiogenesis, tissue repair/regeneration, neurotransmission, (iii) derangement of 3-D network and impaired mechanical support for TCs-mediated multicellular signals within the stromal compartment, consequently induced interstitial fibrosis, (iv) involvement in local

  11. Macrophage Migration Inhibitory Factor in Acute Adipose Tissue Inflammation.

    PubMed

    Kim, Bong-Sung; Rongisch, Robert; Hager, Stephan; Grieb, Gerrit; Nourbakhsh, Mahtab; Rennekampff, Hans-Oliver; Bucala, Richard; Bernhagen, Juergen; Pallua, Norbert

    2015-01-01

    Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and has been implicated in inflammatory diseases. However, little is known about the regulation of MIF in adipose tissue and its impact on wound healing. The aim of this study was to investigate MIF expression in inflamed adipose and determine its role in inflammatory cell recruitment and wound healing. Adipose tissue was harvested from subcutaneous adipose tissue layers of 24 healthy subjects and from adipose tissue adjacent to acutely inflamed wounds of 21 patients undergoing wound debridement. MIF protein and mRNA expression were measured by ELISA and RT-PCR. Cell-specific MIF expression was visualized by immunohistochemistry. The functional role of MIF in cell recruitment was investigated by a chemotaxis assay and by flow cytometry of labeled macrophages that were injected into Mif-/-and wildtype mice. Wound healing was evaluated by an in vitro scratch assay on human fibroblast monolayers. MIF protein levels of native adipose tissue and supernatants from acutely inflamed wounds were significantly elevated when compared to healthy controls. MIF mRNA expression was increased in acutely inflamed adipose tissue indicating the activation of MIF gene transcription in response to adipose tissue inflammation. MIF is expressed in mature adipocytes and in infiltrated macrophages. Peripheral blood mononuclear cell migration was significantly increased towards supernatants derived from inflamed adipose tissue. This effect was partially abrogated by MIF-neutralizing antibodies. Moreover, when compared to wildtype mice, Mif-/-mice showed reduced infiltration of labeled macrophages into LPS-stimulated epididymal fat pads in vivo. Finally, MIF antibodies partially neutralized the detrimental effect of MIF on fibroblast wound healing. Our results indicate that increased MIF expression and rapid activation of the MIF gene in fat tissue adjacent to acute wound healing disorders may play a role in cell

  12. Fatigue-induced damage in glutaraldehyde-preserved heart valve tissue.

    PubMed

    Broom, N D

    1978-08-01

    Glutaraldehyde-preserved porcine mitral leaflet tissue has been subjected to extended accelerated fatigue loading in Ringer's solution containing 0.15% glutaraldehyde. Five tissue test pieces were subjected to cyclic tensile stresses of 50 and 200 Gm. per square millimeter and to 300 million to 800 million accumulated fatigue cycles. Tissue disruption occurred in each of the fatigued test pieces. Tensile loading, apart from reducing the acuteness of the collagen waveform and thereby decreasing tissue compliance, does not contribute significantly to the disruption process nor its rate of occurrence. Compressive flexure occurring during the unloading half of the fatigue cycle, however, does induce damage in the tissue. Mechanisms involved in the disruptive processes have been identified by conducting simultaneous morphologic and stress/strain observations on both the fatigued and unfatigued tissues in their wet functional condition. This vulnerability of the preserved tissue to compressive flexure could well affect the long-term durability of the glutaraldehyde-preserved heterograft valve, and this possibility is discussed in relation to the clinical use of these valves.

  13. Tissue Damage Disrupts Developmental Progression and Ecdysteroid Biosynthesis in Drosophila

    PubMed Central

    Hackney, Jennifer F.; Zolali-Meybodi, Omid; Cherbas, Peter

    2012-01-01

    In humans, chronic inflammation, severe injury, infection and disease can result in changes in steroid hormone titers and delayed onset of puberty; however the pathway by which this occurs remains largely unknown. Similarly, in insects injury to specific tissues can result in a global developmental delay (e.g. prolonged larval/pupal stages) often associated with decreased levels of ecdysone – a steroid hormone that regulates developmental transitions in insects. We use Drosophila melanogaster as a model to examine the pathway by which tissue injury disrupts developmental progression. Imaginal disc damage inflicted early in larval development triggers developmental delays while the effects are minimized in older larvae. We find that the switch in injury response (e.g. delay/no delay) is coincident with the mid-3rd instar transition – a developmental time-point that is characterized by widespread changes in gene expression and marks the initial steps of metamorphosis. Finally, we show that developmental delays induced by tissue damage are associated with decreased expression of genes involved in ecdysteroid synthesis and signaling. PMID:23166607

  14. Assessing laser-tissue damage with bioluminescent imaging

    NASA Astrophysics Data System (ADS)

    Wilmink, Gerald J.; Opalenik, Susan R.; Beckham, Josh T.; Davidson, Jeffrey M.; Jansen, Eric D.

    2006-07-01

    Effective medical laser procedures are achieved by selecting laser parameters that minimize undesirable tissue damage. Traditionally, human subjects, animal models, and monolayer cell cultures have been used to study wound healing, tissue damage, and cellular effects of laser radiation. Each of these models has significant limitations, and consequently, a novel skin model is needed. To this end, a highly reproducible human skin model that enables noninvasive and longitudinal studies of gene expression was sought. In this study, we present an organotypic raft model (engineered skin) used in combination with bioluminescent imaging (BLI) techniques. The efficacy of the raft model was validated and characterized by investigating the role of heat shock protein 70 (hsp70) as a sensitive marker of thermal damage. The raft model consists of human cells incorporated into an extracellular matrix. The raft cultures were transfected with an adenovirus containing a murine hsp70 promoter driving transcription of luciferase. The model enables quantitative analysis of spatiotemporal expression of proteins using BLI. Thermal stress was induced on the raft cultures by means of a constant temperature water bath or with a carbon dioxide (CO2) laser (λ=10.6 µm, 0.679 to 2.262 W/cm2, cw, unfocused Gaussian beam, ωL=4.5 mm, 1 min exposure). The bioluminescence was monitored noninvasively with an IVIS 100 Bioluminescent Imaging System. BLI indicated that peak hsp70 expression occurs 4 to 12 h after exposure to thermal stress. A minimum irradiance of 0.679 W/cm2 activated the hsp70 response, and a higher irradiance of 2.262 W/cm2 was associated with a severe reduction in hsp70 response due to tissue ablation. Reverse transcription polymerase chain reaction demonstrated that hsp70 mRNA levels increased with prolonged heating exposures. Enzyme-linked immunosorbent protein assays confirmed that luciferase was an accurate surrogate for hsp70 intracellular protein levels. Hematoxylin and

  15. Acute sun damage and photoprotective responses in whales.

    PubMed

    Martinez-Levasseur, Laura M; Gendron, Diane; Knell, Rob J; O'Toole, Edel A; Singh, Manuraj; Acevedo-Whitehouse, Karina

    2011-05-22

    Rising levels of ultraviolet radiation (UVR) secondary to ozone depletion are an issue of concern for public health. Skin cancers and intraepidermal dysplasia are increasingly observed in individuals that undergo chronic or excessive sun exposure. Such alterations of skin integrity and function are well established for humans and laboratory animals, but remain unexplored for mammalian wildlife. However, effects are unlikely to be negligible, particularly for species such as whales, whose anatomical or life-history traits force them to experience continuous sun exposure. We conducted photographic and histological surveys of three seasonally sympatric whale species to investigate sunburn and photoprotection. We find that lesions commonly associated with acute severe sun damage in humans are widespread and that individuals with fewer melanocytes have more lesions and less apoptotic cells. This suggests that the pathways used to limit and resolve UVR-induced damage in humans are shared by whales and that darker pigmentation is advantageous to them. Furthermore, lesions increased significantly in time, as would be expected under increasing UV irradiance. Apoptosis and melanocyte proliferation mirror this trend, suggesting that whales are capable of quick photoprotective responses. We conclude that the thinning ozone layer may pose a risk to the health of whales and other vulnerable wildlife.

  16. Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration

    PubMed Central

    Li, Na; Parrish, Marcus; Chan, Tze Khee; Yin, Lu; Rai, Prashant; Yoshiyuki, Yamada; Abolhassani, Nona; Tan, Kong Bing; Kiraly, Orsolya; Chow, Vincent TK; Engelward, Bevin P.

    2016-01-01

    Influenza viruses account for significant morbidity worldwide. Inflammatory responses, including excessive generation of reactive oxygen and nitrogen species (RONS), mediate lung injury in severe Influenza infections. However, the molecular basis of inflammation-induced lung damage is not fully understood. Here, we studied influenza H1N1 infected cells in vitro, as well as H1N1 infected mice, and we monitored molecular and cellular responses over the course of two weeks in vivo. We show that influenza induces DNA damage both when cells are directly exposed to virus in vitro (measured using the comet assay) and also when cells are exposed to virus in vivo (estimated via γH2AX foci). We show that DNA damage, as well as responses to DNA damage, persist in vivo until long after virus has been cleared, at times when there are inflammation associated RONS (measured by xanthine oxidase activity and oxidative products). The frequency of lung epithelial and immune cells with increased γH2AX foci is elevated in vivo, especially for dividing cells (Ki-67 positive) exposed to oxidative stress during tissue regeneration. Additionally, we observed a significant increase in apoptotic cells as well as increased levels of DSB repair proteins Ku70, Ku86 and Rad51 during the regenerative phase. In conclusion, results show that influenza induces DNA both in vitro and in vivo, and that DNA damage responses are activated, raising the possibility that DNA repair capacity may be a determining factor for tissue recovery and disease outcome. PMID:25809161

  17. Protective Effect of Pyruvate Against Radiation-Induced Damage in Collagenized Tissues

    NASA Technical Reports Server (NTRS)

    Griko, Y. V.; Yan, Xiaoli

    2016-01-01

    Exposure to high doses of ionizing radiation produces both acute and late effects on the collagenized tissues and have profound effects on wound healing. Because of the crucial practical importance for new radioprotective agents, our study has been focused on evaluation of the efficacy of non-toxic naturally occurring compounds to protect tissue integrity against high-dose gamma radiation. Here, we demonstrate that molecular integrity of collagen may serve as a sensitive biological marker for quantitative evaluation of molecular damage to collagenized tissue and efficacy of radioprotective agents. Increasing doses of gamma radiation (0-50kGy) result in progressive destruction of the native collagen fibrils, which provide a structural framework, strength, and proper milieu for the regenerating tissue. The strategy used in this study involved the thermodynamic specification of all structural changes in collagenized matrix of skin, aortic heart valve, and bone tissue induced by different doses and conditions of g-irradiation. This study describes a simple biophysical approach utilizing the Differential Scanning Calorimetry (DSC) to characterize the structural resistance of the aortic valve matrix exposed to different doses of g-irradiation. It allows us to identify the specific response of each constituent as well as to determine the influence of the different treatments on the characteristic parameters of protein structure. We found that pyruvate, a substance that naturally occurs in the body, provide significant protection (up to 80%) from biochemical and biomechanical damage to the collagenized tissue through the effective targeting of reactive oxygen species. The recently discovered role of pyruvate in the cell antioxidant defense to O2 oxidation, and its essential constituency in the daily human diet, indicate that the administration of pyruvate-based radioprotective formulations may provide safe and effective protection from deleterious effects of ionizing

  18. Tissue-specific splicing mutation in acute intermittent porphyria

    SciTech Connect

    Grandchamp, B.; Picat, C. ); Mignotte, V.; Romeo, P.H.; Goossens, M. ); Wilson, J.H.P.; Sandkuyl, L. ); Te Velde, K. ); Nordmann, Y. )

    1989-01-01

    An inherited deficiency of porphobilinogen deaminase in humans is responsible for the autosomal dominant disease acute intermittent porphyria. Different classes of mutations have been described at the protein level suggesting that this is a heterogeneous disease. It was previously demonstrated that porphobilinogen deaminase is encoded by two distinct mRNA species expressed in a tissue-specific manner. Analysis of the genomic sequences indicated that these two mRNAs are transcribed from two promoters and only differ in their first exon. The first mutation identified in the human porphobilinogen deaminase gene is a single-base substitution (G {yields} A) in the canonical 5{prime} splice donor site of intron 1. This mutation leads to a particular subtype of acute intermittent porphyria characterized by the restriction of the enzymatic defect to nonerythropoietic tissues. Hybridization analysis using olignonucleotide probes after in vitro amplification of genomic DNA offers another possibility of detecting asymptomatic carriers of the mutation in affected families.

  19. Chemical modification of normal tissue damage induced by photodynamic therapy.

    PubMed Central

    Sigdestad, C. P.; Fingar, V. H.; Wieman, T. J.; Lindberg, R. D.

    1996-01-01

    One of the limitations of successful use of photodynamic therapy (PDT) employing porphyrins is the acute and long-term cutaneous photosensitivity. This paper describes results of experiments designed to test the effects of two radiation protective agents (WR-2721, 500 mg kg-1 or WR-3689, 700 mg kg-1) on murine skin damage induced by PDT. C3H mice were shaved and depilated three days prior to injection with the photosensitiser, Photofrin (5 or 10 mg kg-1). Twenty-four hours later, the mice were injected intraperitoneally with a protector 30 min prior to Argon dye laser (630 nm) exposure. The skin response was followed for two weeks post irradiation using an arbitrary response scale. A light dose response as well as a drug dose response was obtained. The results indicate that both protectors reduced the skin response to PDT, however WR-2721 was demonstrated to be the most effective. The effect of the protectors on vascular stasis after PDT was determined using a fluorescein dye exclusion assay. In mice treated with Photofrin (5 mg kg-1), and 630 nm light (180 J cm-2) pretreatment with either WR-2721 or WR-3689 resulted in significant protection of the vascular effects of PDT. These studies document the ability of the phosphorothioate class of radiation protective agents to reduce the effects of light on photosensitized skin. They do so in a drug dose-dependent fashion with maximum protection at the highest drug doses. PMID:8763855

  20. Single-cell resolution mapping of neuronal damage in acute focal cerebral ischemia using thallium autometallography.

    PubMed

    Stöber, Franziska; Baldauf, Kathrin; Ziabreva, Iryna; Harhausen, Denise; Zille, Marietta; Neubert, Jenni; Reymann, Klaus G; Scheich, Henning; Dirnagl, Ulrich; Schröder, Ulrich H; Wunder, Andreas; Goldschmidt, Jürgen

    2014-01-01

    Neuronal damage shortly after onset or after brief episodes of cerebral ischemia has remained difficult to assess with clinical and preclinical imaging techniques as well as with microscopical methods. We here show, in rodent models of middle cerebral artery occlusion (MCAO), that neuronal damage in acute focal cerebral ischemia can be mapped with single-cell resolution using thallium autometallography (TlAMG), a histochemical technique for the detection of the K(+)-probe thallium (Tl(+)) in the brain. We intravenously injected rats and mice with thallium diethyldithiocarbamate (TlDDC), a lipophilic chelate complex that releases Tl(+) after crossing the blood-brain barrier. We found, within the territories of the affected arteries, areas of markedly reduced neuronal Tl(+) uptake in all animals at all time points studied ranging from 15 minutes to 24 hours after MCAO. In large lesions at early time points, areas with neuronal and astrocytic Tl(+) uptake below thresholds of detection were surrounded by putative penumbral zones with preserved but diminished Tl(+) uptake. At 24 hours, the areas of reduced Tl(+)uptake matched with areas delineated by established markers of neuronal damage. The results suggest the use of (201)TlDDC for preclinical and clinical single-photon emission computed tomography (SPECT) imaging of hyperacute alterations in brain K(+) metabolism and prediction of tissue viability in cerebral ischemia.

  1. Hypoxia-Induced miR-210 Modulates Tissue Response to Acute Peripheral Ischemia

    PubMed Central

    Zaccagnini, Germana; Maimone, Biagina; Di Stefano, Valeria; Fasanaro, Pasquale; Greco, Simona; Perfetti, Alessandra; Capogrossi, Maurizio C.; Gaetano, Carlo

    2014-01-01

    Abstract Aims: Peripheral artery disease is caused by the restriction or occlusion of arteries supplying the leg. Better understanding of the molecular mechanisms underpinning tissue response to ischemia is urgently needed to improve therapeutic options. The aim of this study is to investigate hypoxia-induced miR-210 regulation and its role in a mouse model of hindlimb ischemia. Results: miR-210 expression was induced by femoral artery dissection. To study the role of miR-210, its function was inhibited by the systemic administration of a miR-210 complementary locked nucleic acid (LNA)-oligonucleotide (anti-miR-210). In the ischemic skeletal muscle, anti-miR-210 caused a marked decrease of miR-210 compared with LNA-scramble control, while miR-210 target expression increased accordingly. Histological evaluation of acute tissue damage showed that miR-210 inhibition increased both apoptosis at 1 day and necrosis at 3 days. Capillary density decrease caused by ischemia was significantly more pronounced in anti-miR-210-treated mice; residual limb perfusion decreased accordingly. To investigate the molecular mechanisms underpinning the increased damage triggered by miR-210 blockade, we tested the impact of anti-miR-210 treatment on the transcriptome. Gene expression analysis highlighted the deregulation of mitochondrial function and redox balance. Accordingly, oxidative damage was more severe in the ischemic limb of anti-miR-210-treated mice and miR-210 inhibition increased oxidative metabolism. Further, oxidative-stress resistant p66Shc-null mice displayed decreased tissue damage following ischemia. Innovation: This study identifies miR-210 as a crucial element in the adaptive mechanisms to acute peripheral ischemia. Conclusions: The physiopathological significance of miR-210 is context dependent. In the ischemic skeletal muscle it seems to be cytoprotective, regulating oxidative metabolism and oxidative stress. Antioxid. Redox Signal. 21, 1177–1188. PMID:23931770

  2. Tissue plasminogen activator prevents white matter damage following stroke

    PubMed Central

    Correa, Fernando; Gauberti, Maxime; Parcq, Jérôme; Macrez, Richard; Hommet, Yannick; Obiang, Pauline; Hernangómez, Miriam; Montagne, Axel; Liot, Géraldine; Guaza, Carmen; Maubert, Eric; Ali, Carine; Vivien, Denis

    2011-01-01

    Tissue plasminogen activator (tPA) is the only available treatment for acute stroke. In addition to its vascular fibrinolytic action, tPA exerts various effects within the brain, ranging from synaptic plasticity to control of cell fate. To date, the influence of tPA in the ischemic brain has only been investigated on neuronal, microglial, and endothelial fate. We addressed the mechanism of action of tPA on oligodendrocyte (OL) survival and on the extent of white matter lesions in stroke. We also investigated the impact of aging on these processes. We observed that, in parallel to reduced levels of tPA in OLs, white matter gets more susceptible to ischemia in old mice. Interestingly, tPA protects murine and human OLs from apoptosis through an unexpected cytokine-like effect by the virtue of its epidermal growth factor–like domain. When injected into aged animals, tPA, although toxic to the gray matter, rescues white matter from ischemia independently of its proteolytic activity. These studies reveal a novel mechanism of action of tPA and unveil OL as a target cell for cytokine effects of tPA in brain diseases. They show overall that tPA protects white matter from stroke-induced lesions, an effect which may contribute to the global benefit of tPA-based stroke treatment. PMID:21576385

  3. Spaceflight environment induces mitochondrial oxidative damage in ocular tissue.

    PubMed

    Mao, Xiao W; Pecaut, Michael J; Stodieck, Louis S; Ferguson, Virginia L; Bateman, Ted A; Bouxsein, Mary; Jones, Tamako A; Moldovan, Maria; Cunningham, Christopher E; Chieu, Jenny; Gridley, Daila S

    2013-10-01

    A recent report shows that more than 30% of the astronauts returning from Space Shuttle missions or the International Space Station (ISS) were diagnosed with eye problems that can cause reduced visual acuity. We investigate here whether spaceflight environment-associated retinal damage might be related to oxidative stress-induced mitochondrial apoptosis. Female C57BL/6 mice were flown in the space shuttle Atlantis (STS-135), and within 3-5 h of landing, the spaceflight and ground-control mice, similarly housed in animal enclosure modules (AEMs) were euthanized and their eyes were removed for analysis. Changes in expression of genes involved in oxidative stress, mitochondrial and endothelial cell biology were examined. Apoptosis in the retina was analyzed by caspase-3 immunocytochemical analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Levels of 4-hydroxynonenal (4-HNE) protein, an oxidative specific marker for lipid peroxidation were also measured. Evaluation of spaceflight mice and AEM ground-control mice showed that expression of several genes playing central roles in regulating the mitochondria-associated apoptotic pathway were significantly altered in mouse ocular tissue after spaceflight compared to AEM ground-control mice. In addition, the mRNA levels of several genes, which are responsible for regulating the production of reactive oxygen species were also significantly up-regulated in spaceflight samples compared to AEM ground-control mice. Further more, the level of HNE protein was significantly elevated in the retina after spaceflight compared to controls. Our results also revealed that spaceflight conditions induced significant apoptosis in the retina especially inner nuclear layer (INL) and ganglion cell layer (GCL) compared to AEM ground controls. The data provided the first evidence that spaceflight conditions induce oxidative damage that results in mitochondrial apoptosis in the retina. This data suggest

  4. DNA Damage Focus Analysis in Blood Samples of Minipigs Reveals Acute Partial Body Irradiation

    PubMed Central

    Lamkowski, Andreas; Forcheron, Fabien; Agay, Diane; Ahmed, Emad A.; Drouet, Michel; Meineke, Viktor; Scherthan, Harry

    2014-01-01

    Radiation accidents frequently involve acute high dose partial body irradiation leading to victims with radiation sickness and cutaneous radiation syndrome that implements radiation-induced cell death. Cells that are not lethally hit seek to repair ionizing radiation (IR) induced damage, albeit at the expense of an increased risk of mutation and tumor formation due to misrepair of IR-induced DNA double strand breaks (DSBs). The response to DNA damage includes phosphorylation of histone H2AX in the vicinity of DSBs, creating foci in the nucleus whose enumeration can serve as a radiation biodosimeter. Here, we investigated γH2AX and DNA repair foci in peripheral blood lymphocytes of Göttingen minipigs that experienced acute partial body irradiation (PBI) with 49 Gy (±6%) Co-60 γ-rays of the upper lumbar region. Blood samples taken 4, 24 and 168 hours post PBI were subjected to γ-H2AX, 53BP1 and MRE11 focus enumeration. Peripheral blood lymphocytes (PBL) of 49 Gy partial body irradiated minipigs were found to display 1–8 DNA damage foci/cell. These PBL values significantly deceed the high foci numbers observed in keratinocyte nuclei of the directly γ-irradiated minipig skin regions, indicating a limited resident time of PBL in the exposed tissue volume. Nonetheless, PBL samples obtained 4 h post IR in average contained 2.2% of cells displaying a pan-γH2AX signal, suggesting that these received a higher IR dose. Moreover, dispersion analysis indicated partial body irradiation for all 13 minipigs at 4 h post IR. While dose reconstruction using γH2AX DNA repair foci in lymphocytes after in vivo PBI represents a challenge, the DNA damage focus assay may serve as a rapid, first line indicator of radiation exposure. The occurrence of PBLs with pan-γH2AX staining and of cells with relatively high foci numbers that skew a Poisson distribution may be taken as indicator of acute high dose partial body irradiation, particularly when samples are available early after

  5. Acute interstitial pneumonia (AIP): relationship to Hamman-Rich syndrome, diffuse alveolar damage (DAD), and acute respiratory distress syndrome (ARDS).

    PubMed

    Mukhopadhyay, Sanjay; Parambil, Joseph G

    2012-10-01

    Acute interstitial pneumonia (AIP) is a term used for an idiopathic form of acute lung injury characterized clinically by acute respiratory failure with bilateral lung infiltrates and histologically by diffuse alveolar damage (DAD), a combination of findings previously known as the Hamman-Rich syndrome. This review aims to clarify the diagnostic criteria of AIP, its relationship with DAD and acute respiratory distress syndrome (ARDS), key etiologies that need to be excluded before making the diagnosis, and the salient clinical features. Cases that meet clinical and pathologic criteria for AIP overlap substantially with those that fulfill clinical criteria for ARDS. The main differences between AIP and ARDS are that AIP requires a histologic diagnosis of DAD and exclusion of known etiologies. AIP should also be distinguished from "acute exacerbation of IPF," a condition in which acute lung injury (usually DAD) supervenes on underlying usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF).

  6. How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues

    NASA Technical Reports Server (NTRS)

    Barcellos-Hoff, M. H.; Chatterjee, A. (Principal Investigator)

    1998-01-01

    The capacity of ionizing radiation to affect tissue function, control tumor growth and elicit pathological sequelae has been attributed in great part to its effects on cellular DNA, which, as the transmitter of genetic information, can both register damage and perpetuate it. Nonetheless, multicellular organisms function as the result of the cooperation of many cell types. What then occurs when individual cells are damaged by ionizing radiation? Is tissue response a sum of cellular effects such as cell death and DNA damage? Or does the tissue respond as a coherent unit to the damage of its parts? In this paper, data in support of the latter model that indicate a role for cytokines, in particular transforming growth factor beta1, as critical components of extracellular signaling pathways that mediate tissue response to radiation will be reviewed. The key to manipulating the consequences of radiation exposure lies in understanding the complex interplay of events initiated at the cellular level, but acting on the tissue.

  7. Methamphetamine causes acute hyperthermia-dependent liver damage.

    PubMed

    Halpin, Laura E; Gunning, William T; Yamamoto, Bryan K

    2013-10-01

    Methamphetamine-induced neurotoxicity has been correlated with damage to the liver but this damage has not been extensively characterized. Moreover, the mechanism by which the drug contributes to liver damage is unknown. This study characterizes the hepatocellular toxicity of methamphetamine and examines if hyperthermia contributes to this liver damage. Livers from methamphetamine-treated rats were examined using electron microscopy and hematoxylin and eosin staining. Methamphetamine increased glycogen stores, mitochondrial aggregation, microvesicular lipid, and hydropic change. These changes were diffuse throughout the hepatic lobule, as evidenced by a lack of hematoxylin and eosin staining. To confirm if these changes were indicative of damage, serum aspartate and alanine aminotransferase were measured. The functional significance of methamphetamine-induced liver damage was also examined by measuring plasma ammonia. To examine the contribution of hyperthermia to this damage, methamphetamine-treated rats were cooled during and after drug treatment by cooling their external environment. Serum aspartate and alanine aminotransferase, as well as plasma ammonia were increased concurrently with these morphologic changes and were prevented when methamphetamine-induced hyperthermia was blocked. These findings support that methamphetamine produces changes in hepatocellular morphology and damage persisting for at least 24 h after drug exposure. At this same time point, methamphetamine treatment significantly increases plasma ammonia concentrations, consistent with impaired ammonia metabolism and functional liver damage. Methamphetamine-induced hyperthermia contributes significantly to the persistent liver damage and increases in peripheral ammonia produced by the drug. PMID:25505562

  8. Temporal Effects of Mechanical Loading on Deformation-Induced Damage in Skeletal Muscle Tissue

    PubMed Central

    Stekelenburg, A.; Strijkers, G. J.; Rijpkema, J. J. M.; Baaijens, F. P. T.; Bader, D. L.; Nicolay, K.; Oomens, C. W. J.

    2010-01-01

    Mechanical loading of soft tissues covering bony prominences can cause skeletal muscle damage, ultimately resulting in a severe pressure ulcer termed deep tissue injury. Recently, by means of an experimental-numerical approach, it was shown that local tissue deformations cause tissue damage once a deformation threshold is exceeded. In the present study, the effects of load exposure time and intermittent load relief on the development of deformation-induced muscle damage were investigated. The data showed that a 2 h loading period caused more damage than 10 min loading. Intermittent load reliefs of 2 min during a 2 h loading period had minimal effect on the evolution of skeletal muscle damage. In addition, a local deformation threshold for damage was found, which was similar for each of the loading regimes applied in this study. For short loading periods, these results imply that local tissue deformations determine whether muscle damage will develop and the exposure time influences the amount of tissue damage. Temporary load reliefs were inefficient in reducing deformation-induced damage, but may still influence the development of ischemia-induced damage during longer loading periods. PMID:20232152

  9. Maltol, a Food Flavoring Agent, Attenuates Acute Alcohol-Induced Oxidative Damage in Mice

    PubMed Central

    Han, Ye; Xu, Qi; Hu, Jiang-ning; Han, Xin-yue; Li, Wei; Zhao, Li-chun

    2015-01-01

    The purpose of this study was to evaluate the hepatoprotective effect of maltol, a food-flavoring agent, on alcohol-induced acute oxidative damage in mice. Maltol used in this study was isolated from red ginseng (Panax ginseng C.A Meyer) and analyzed by high performance liquid chromatography (HPLC) and mass spectrometry. For hepatoprotective activity in vivo, pretreatment with maltol (12.5, 25 and 50 mg/kg; 15 days) drastically prevented the elevated activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and triglyceride (TG) in serum and the levels of malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) in liver tissue (p < 0.05). Meanwhile, the levels of hepatic antioxidant, such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) were elevated by maltol pretreatment, compared to the alcohol group (p < 0.05). Histopathological examination revealed that maltol pretreatment significantly inhibited alcohol-induced hepatocyte apoptosis and fatty degeneration. Interestingly, pretreatment of maltol effectively relieved alcohol-induced oxidative damage in a dose-dependent manner. Maltol appeared to possess promising anti-oxidative and anti-inflammatory capacities. It was suggested that the hepatoprotective effect exhibited by maltol on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties. PMID:25608939

  10. Automated prediction of tissue outcome after acute ischemic stroke in computed tomography perfusion images

    NASA Astrophysics Data System (ADS)

    Vos, Pieter C.; Bennink, Edwin; de Jong, Hugo; Velthuis, Birgitta K.; Viergever, Max A.; Dankbaar, Jan Willem

    2015-03-01

    Assessment of the extent of cerebral damage on admission in patients with acute ischemic stroke could play an important role in treatment decision making. Computed tomography perfusion (CTP) imaging can be used to determine the extent of damage. However, clinical application is hindered by differences among vendors and used methodology. As a result, threshold based methods and visual assessment of CTP images has not yet shown to be useful in treatment decision making and predicting clinical outcome. Preliminary results in MR studies have shown the benefit of using supervised classifiers for predicting tissue outcome, but this has not been demonstrated for CTP. We present a novel method for the automatic prediction of tissue outcome by combining multi-parametric CTP images into a tissue outcome probability map. A supervised classification scheme was developed to extract absolute and relative perfusion values from processed CTP images that are summarized by a trained classifier into a likelihood of infarction. Training was performed using follow-up CT scans of 20 acute stroke patients with complete recanalization of the vessel that was occluded on admission. Infarcted regions were annotated by expert neuroradiologists. Multiple classifiers were evaluated in a leave-one-patient-out strategy for their discriminating performance using receiver operating characteristic (ROC) statistics. Results showed that a RandomForest classifier performed optimally with an area under the ROC of 0.90 for discriminating infarct tissue. The obtained results are an improvement over existing thresholding methods and are in line with results found in literature where MR perfusion was used.

  11. Time course of inflammation, oxidative stress and tissue damage induced by hyperoxia in mouse lungs.

    PubMed

    Nagato, Akinori C; Bezerra, Frank S; Lanzetti, Manuella; Lopes, Alan A; Silva, Marco Aurélio S; Porto, Luís Cristóvão; Valença, Samuel S

    2012-08-01

    In this study our aim was to investigate the time courses of inflammation, oxidative stress and tissue damage after hyperoxia in the mouse lung. Groups of BALB/c mice were exposed to 100% oxygen in a chamber for 12, 24 or 48 h. The controls were subjected to normoxia. The results showed that IL-6 increased progressively after 12 (P < 0.001) and 24 h (P < 0.001) of hyperoxia with a reduction at 48 h (P < 0.01), whereas TNF-α increased after 24 (P < 0.001) and 48 h (P < 0.001). The number of macrophages increased after 24 h (P < 0.001), whereas the number of neutrophils increased after 24 h (P < 0.01) and 48 h (P < 0.001). Superoxide dismutase activity decreased in all groups exposed to hyperoxia (P < 0.01). Catalase activity increased only at 48 h (P < 0.001). The reduced glutathione/oxidized glutathione ratio decreased after 12 h (P < 0.01) and 24 h (P < 0.05). Histological evidence of lung injury was observed at 24 and 48 h. This study shows that hyperoxia initially causes an inflammatory response at 12 h, resulting in inflammation associated with the oxidative response at 24 h and culminating in histological damage at 48 h. Knowledge of the time course of inflammation and oxidative stress prior to histological evidence of acute lung injury can improve the safety of oxygen therapy in patients.

  12. Time course of inflammation, oxidative stress and tissue damage induced by hyperoxia in mouse lungs

    PubMed Central

    Nagato, Akinori C; Bezerra, Frank S; Lanzetti, Manuella; Lopes, Alan A; Silva, Marco Aurélio S; Porto, Luís Cristóvão; Valença, Samuel S

    2012-01-01

    In this study our aim was to investigate the time courses of inflammation, oxidative stress and tissue damage after hyperoxia in the mouse lung. Groups of BALB/c mice were exposed to 100% oxygen in a chamber for 12, 24 or 48 h. The controls were subjected to normoxia. The results showed that IL-6 increased progressively after 12 (P < 0.001) and 24 h (P < 0.001) of hyperoxia with a reduction at 48 h (P < 0.01), whereas TNF-α increased after 24 (P < 0.001) and 48 h (P < 0.001). The number of macrophages increased after 24 h (P < 0.001), whereas the number of neutrophils increased after 24 h (P < 0.01) and 48 h (P < 0.001). Superoxide dismutase activity decreased in all groups exposed to hyperoxia (P < 0.01). Catalase activity increased only at 48 h (P < 0.001). The reduced glutathione/oxidized glutathione ratio decreased after 12 h (P < 0.01) and 24 h (P < 0.05). Histological evidence of lung injury was observed at 24 and 48 h. This study shows that hyperoxia initially causes an inflammatory response at 12 h, resulting in inflammation associated with the oxidative response at 24 h and culminating in histological damage at 48 h. Knowledge of the time course of inflammation and oxidative stress prior to histological evidence of acute lung injury can improve the safety of oxygen therapy in patients. PMID:22804763

  13. Nrf2 as a master regulator of tissue damage control and disease tolerance to infection.

    PubMed

    Soares, Miguel P; Ribeiro, Ana M

    2015-08-01

    Damage control refers to those actions made towards minimizing damage or loss. Depending on the context, these can range from emergency procedures dealing with the sinking of a ship or to a surgery dealing with severe trauma or even to an imaginary company in Marvel comics, which repairs damaged property arising from conflicts between super heroes and villains. In the context of host microbe interactions, tissue damage control refers to an adaptive response that limits the extent of tissue damage associated with infection. Tissue damage control can limit the severity of infectious diseases without interfering with pathogen burden, conferring disease tolerance to infection. This contrasts with immune-driven resistance mechanisms, which although essential to protect the host from infection, can impose tissue damage to host parenchyma tissues. This damaging effect is countered by stress responses that confer tissue damage control and disease tolerance to infection. Here we discuss how the stress response regulated by the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) acts in such a manner.

  14. Nrf2 as a master regulator of tissue damage control and disease tolerance to infection

    PubMed Central

    Soares, Miguel P.; Ribeiro, Ana M.

    2015-01-01

    Damage control refers to those actions made towards minimizing damage or loss. Depending on the context, these can range from emergency procedures dealing with the sinking of a ship or to a surgery dealing with severe trauma or even to an imaginary company in Marvel comics, which repairs damaged property arising from conflicts between super heroes and villains. In the context of host microbe interactions, tissue damage control refers to an adaptive response that limits the extent of tissue damage associated with infection. Tissue damage control can limit the severity of infectious diseases without interfering with pathogen burden, conferring disease tolerance to infection. This contrasts with immune-driven resistance mechanisms, which although essential to protect the host from infection, can impose tissue damage to host parenchyma tissues. This damaging effect is countered by stress responses that confer tissue damage control and disease tolerance to infection. Here we discuss how the stress response regulated by the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) acts in such a manner. PMID:26551709

  15. Deferoxamine reduces tissue damage during endotoxin-induced mastitis in dairy cows.

    PubMed

    Lauzon, K; Zhao, X; Lacasse, P

    2006-10-01

    The protective effects of 3 antioxidants on polymorphonuclear neutrophil-induced damage to mammary cells were evaluated in vivo using an endotoxin-induced mastitis model. Fifteen healthy, midlactation cows with no history of clinical Escherichia coli mastitis were randomly assigned to 1 of the 3 treatment groups corresponding to each modulator to be evaluated, that is, deferoxamine, catechin, and glutathione ethyl ester. Each cow had 1 quarter infused with saline and 1 quarter infused with the selected modulator; a third quarter was infused with lipopolysaccharides (LPS), whereas the fourth quarter received a combination of LPS and the modulator. Infusion of LPS caused acute mastitis as determined by visual observations and by large increases in milk somatic cell count, BSA, and proteolytic activity. These parameters were not affected by antioxidant administration. The extent of cell damage was evaluated by measuring milk levels of lactate dehydrogenase and N-acetyl-beta-D-glucosaminidase activity. Levels of these parameters were several times higher after LPS administration. Intramammary infusions of catechin or glutathione ethyl ester did not exert any protective effect, whereas infusion of deferoxamine, a chelator of iron, decreased milk lactate dehydrogenase and NA-Gase activity, suggesting a protective effect against neutrophil-induced damage. The protective effect of deferoxamine was also evidenced by a lower milk level of haptoglobin. The proteolytic activity of mastitic milk was not influenced by the presence of deferoxamine. Overall, our results suggest that local infusion of deferoxamine may be an effective tool to protect mammary tissue against neutrophil-induced oxidative stress during bovine mastitis. PMID:16960060

  16. Promotion of Growth of Tumour Cells in Acutely Inflamed Tissues

    PubMed Central

    van den Brenk, H. A. S.; Stone, M.; Kelly, H.; Orton, C.; Sharpington, C.

    1974-01-01

    Acute inflammatory reactions were induced in rats by the intravenous injection of cellulose sulphate (CS) or an extract of normal rat lung homogenate (LH), or by intraperitoneal injections of Compound 48/80. These treatments greatly increased survival and clonogenic growth in the lungs of rats of intravenously injected allogeneic W-256 and Y-P388 tumour cells. Increase in the dose of intravenously injected CS caused a logarithmic increase in colony forming efficiency (CFE) of tumour cells in the lungs. CFE was not stimulated by the intravenous injection of rats with pharmacological mediators of inflammation (histamine, 5-hydroxytryptamine, bradykinin and prostaglandins PGE1 and PGF2α) which are released from tissues by agents which induce inflammation. Stimulation of CFE by CS occurred in adrenalectomized rats but was inhibited by treatment of rats with an anti-inflammatory steroid, dexamethasone. CFE was stimulated by CS in tumour immunized rats; the inflammatory state did not prevent the expression of immunity but “rescued” a proportion (approximately 20%) of the injected tumour cells from immunodestruction in the lungs. A higher proportion of tumours grew in the paws of rats when a small number of W-256 cells were injected interdigitally into the acute inflammatory swellings produced by the local injection of paws with LH or CS. CS is a “synthetic heparin” which causes marked prolongation of blood clotting time and also increases fibrinolytic activity of the blood. Anticoagulant treatment of rats with heparin did not affect CFE. Thus, there was no direct correlation between blood clotting time and CFE of blood borne tumour cells in the rat. The mechanisms which may be responsible for the nonspecific growth promoting effects of inflammatory reactions induced by various types of tissue injury on tumour induction and growth are discussed. ImagesFig. 2 PMID:4451630

  17. Spatial Pattern of Cell Damage in Tissue from Heavy Ions

    NASA Technical Reports Server (NTRS)

    Ponomarev, Artem L.; Huff, Janice L.; Cucinotta, Francis A.

    2007-01-01

    A new Monte Carlo algorithm was developed that can model passage of heavy ions in a tissue, and their action on the cellular matrix for 2- or 3-dimensional cases. The build-up of secondaries such as projectile fragments, target fragments, other light fragments, and delta-rays was simulated. Cells were modeled as a cell culture monolayer in one example, where the data were taken directly from microscopy (2-d cell matrix). A simple model of tissue was given as abstract spheres with close approximation to real cell geometries (3-d cell matrix), as well as a realistic model of tissue was proposed based on microscopy images. Image segmentation was used to identify cells in an irradiated cell culture monolayer, or slices of tissue. The cells were then inserted into the model box pixel by pixel. In the case of cell monolayers (2-d), the image size may exceed the modeled box size. Such image was is moved with respect to the box in order to sample as many cells as possible. In the case of the simple tissue (3-d), the tissue box is modeled with periodic boundary conditions, which extrapolate the technique to macroscopic volumes of tissue. For real tissue, specific spatial patterns for cell apoptosis and necrosis are expected. The cell patterns were modeled based on action cross sections for apoptosis and necrosis estimated based on BNL data, and other experimental data.

  18. Purple sweet potato (Ipomoea batatas L.) anthocyanins: preventive effect on acute and subacute alcoholic liver damage and dealcoholic effect.

    PubMed

    Sun, Hongnan; Mu, Taihua; Liu, Xingli; Zhang, Miao; Chen, Jingwang

    2014-03-19

    This study aimed to investigate the dealcoholic effect and preventive effect of anthocyanins from purple sweet potato (PSPAs) on acute and subacute alcoholic liver damage (ALD). Seven-week-old male inbred mice were grouped into five groups: control group (without PSPAs and ethanol treatments), model group (with ethanol treatment only), low-dose group (50 mg PSPAs/kg body weight), middle-dose group (125 mg PSPAs/kg body weight), and high-dose group (375 mg PSPAs/kg body weight), and the mice in all groups were administered intragastrically. Biochemical parameters of serum and liver were determined, and the histopathological changes of liver tissue were also analyzed. Results showed that all tested parameters were ameliorated after consumption of PSPAs. Therefore, PSPAs have preventive effect on acute and subacute ALD. It is suggested that PSPAs could be used as a supplementary reagent during prophylactic and curative managements of ALD.

  19. Free radicals and tissue damage produced by exercise

    SciTech Connect

    Davies, K.J.A.; Quintanilha, A.T.; Brooks, G.A; Packer, L.

    1982-08-31

    Reported is a two- to three-fold increase in free radical (R*) concentrations of muscle and liver following exercise to exhaustion. Exhaustive exercise also resulted in decreased mitochondrial respiratory control, loss of sarcoplasmic reticulum (SR) and endoplasmic reticulum (ER) integrity, and increased levels of lipid peroxidation products. Free radical concentrations, lipid peroxidation, and SR, ER, and mitochondrial damage were similar in exercise exhausted control animals and non-exercised vitamin E deficient animals, suggesting the possibility of a common R* dependent damage process. In agreement with previous work showing that exercise endurance capacity is largely determined by the functional mitochondrial content of muscle, vitamin E deficient animals endurance was 40% lower than that of controls. The results suggest that R* induced damage may provide a stimulus to the mitochondrial biogenesis which results from endurance training.

  20. Mechanisms of cell damage in agitated microcarrier tissue culture reactors

    NASA Technical Reports Server (NTRS)

    Cherry, Robert S.; Papoutsakis, E. Terry

    1986-01-01

    Cells growing on microcarriers may be damaged by collisions of the microcarrier against another microcarrier or the reactor agitator. Bead-bead collisions are caused by small-scale turbulence, which can also cause high local shear stress on the cells. The cells are also exposed to 10-20 Hz cyclic shear stress by bead rotation.

  1. Acute and late gastrointestinal toxicity after radiotherapy in prostate cancer patients: Consequential late damage

    SciTech Connect

    Heemsbergen, Wilma D. . E-mail: w.heemsbergen@nki.nl; Peeters, Stephanie T.H.; Koper, Peter; Hoogeman, Mischa S.; Lebesque, Joos V.

    2006-09-01

    Purpose: Late gastrointestinal (GI) toxicity after radiotherapy can be partly explained by late effects of acute toxicity (consequential late damage). We studied whether there is a direct relationship between acute and late GI toxicity. Patients and Methods: A total of 553 evaluable patients from the Dutch dose escalation trial (68 Gy vs. 78 Gy) were included. We defined three outcomes for acute reactions: 1) maximum Radiation Therapy Oncology Group acute toxicity, 2) maximum acute mucous discharge (AMD), and 3) maximum acute proctitis. Within a multivariable model, late endpoints (overall toxicity and five toxicity indicators) were studied as a function of acute toxicity, pretreatment symptoms, and relevant dose parameters. Results: At multivariable analysis, AMD and acute proctitis were strong predictors for overall toxicity, 'intermittent bleeding,' and 'incontinence pads' (p {<=} 0.01). For 'stools {>=}6/day' all three were strong predictors. No significant associations were found for 'severe bleeding' and 'use of steroids.' The predictive power of the dose parameters remained at the same level or became weaker for most late endpoints. Conclusions: Acute GI toxicity is an independent significant predictor of late GI toxicity. This suggests a significant consequential component in the development of late GI toxicity.

  2. Damage induced by pulsed IR laser radiation at transitions between different tissues

    NASA Astrophysics Data System (ADS)

    Frenz, Martin; Greber, Charlotte M.; Romano, Valerio; Forrer, Martin; Weber, Heinz P.

    1991-06-01

    Due to their strong absorption in water IR-lasers are excellent sources for precision cutting with minimal thermal damage in various fields of medicine. To understand the laser tissue interaction process one has to take into account the liquefaction of target material at the region of radiation impact. The dynamics of the created liquid may cause unexpected and undesirable effects for surgical laser applications. We studied the thermal damage along the walls of incision craters in terms of the elastic material properties and the dynamics of the drilling process. We show that the extension of thermally altered tissue is strongly influenced by the amount of hot liquefied tissue material remaining in the crater. When drilling into mechanically homogeneous materials this amount is essentially determined by the laser intensity used. However, when drilling through a composite structure consisting of various tissue types with different material properties, this is no longer the case. Even at low intensities, the damage zone varies substantially between the different layers. In our investigations we compared histologically and ultrastructurally the instantaneously created damage in the connective tissue and the subjacent skeletal muscle of skin after laser cutting, with long-time heating injuries. This comparison allows a differentiation between thermal and mechanical damage and an estimation of the minimum temperature created in the crater during the laser impact. The light microscopical examinations shows that the thermal damage in the connective tissue is about three times smaller than in the subjacent muscle layer. Comparative studies made with a composite structure consisting of the tissue substitutes gelatin and agar reveal that the unexpectedly large damage in the skeletal muscle layer is a result of the abrupt change of the elastic properties at the material transition. This discontinuity changes the ejection dynamics leading to a confinement of hot liquefied

  3. Kidney Injury Molecule-1 Protects against Gα12 Activation and Tissue Damage in Renal Ischemia-Reperfusion Injury

    PubMed Central

    Ismail, Ola Z.; Zhang, Xizhong; Wei, Junjun; Haig, Aaron; Denker, Bradley M.; Suri, Rita S.; Sener, Alp; Gunaratnam, Lakshman

    2016-01-01

    Ischemic acute kidney injury is a serious untreatable condition. Activation of the G protein α12 (Gα12) subunit by reactive oxygen species is a major cause of tissue damage during renal ischemia-reperfusion injury. Kidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein that is highly up-regulated during acute kidney injury, but the physiologic significance of this up-regulation is unclear. Here, we report for the first time that Kim-1 inhibits Gα12 activation and protects mice against renal ischemia-reperfusion injury. We reveal that Kim-1 physically interacts with and inhibits cellular Gα12 activation after inflammatory stimuli, including reactive oxygen species, by blocking GTP binding to Gα12. Compared with Kim-1+/+ mice, Kim-1−/− mice exhibited greater Gα12 and downstream Src activation both in primary tubular epithelial cells after in vitro stimulation with H2O2 and in whole kidneys after unilateral renal artery clamping. Finally, we show that Kim-1–deficient mice had more severe kidney dysfunction and tissue damage after bilateral renal artery clamping, compared with wild-type mice. Our results suggest that KIM-1 is an endogenous protective mechanism against renal ischemia-reperfusion injury through inhibition of Gα12. PMID:25759266

  4. Tissue specific response to DNA damage: C. elegans as role model.

    PubMed

    Lans, Hannes; Vermeulen, Wim

    2015-08-01

    The various symptoms associated with hereditary defects in the DNA damage response (DDR), which range from developmental and neurological abnormalities and immunodeficiency to tissue-specific cancers and accelerated aging, suggest that DNA damage affects tissues differently. Mechanistic DDR studies are, however, mostly performed in vitro, in unicellular model systems or cultured cells, precluding a clear and comprehensive view of the DNA damage response of multicellular organisms. Studies performed in intact, multicellular animals models suggest that DDR can vary according to the type, proliferation and differentiation status of a cell. The nematode Caenorhabditis elegans has become an important DDR model and appears to be especially well suited to understand in vivo tissue-specific responses to DNA damage as well as the impact of DNA damage on development, reproduction and health of an entire multicellular organism. C. elegans germ cells are highly sensitive to DNA damage induction and respond via classical, evolutionary conserved DDR pathways aimed at efficient and error-free maintenance of the entire genome. Somatic tissues, however, respond differently to DNA damage and prioritize DDR mechanisms that promote growth and function. In this mini-review, we describe tissue-specific differences in DDR mechanisms that have been uncovered utilizing C. elegans as role model. PMID:25957488

  5. Role of tissue thickness on depth of morphologic skin damage

    NASA Astrophysics Data System (ADS)

    RajaMahmood, T. L. I.; Mat Jafri, M. Z.; Omar, Khalid M.

    2013-05-01

    Different zonal areas of the skins have different thickness and different adnexal composition. For this reason, the power density and exposure duration have to be adjusted to the area that being treated. The effects of laser expose to the different area of the skin has been studied by using the power density of 20.31 W/cm2 and the times when the cracking sound heard is the explosive duration recorded for each area of the skins. As a result, the histologic sections revealed that the explosive duration varied significantly with the difference in thickness of the skin tissue. Also, the expanding spaces between hair follicles and its surrounding tissue as well as denaturation of collagen fiberswere shownin each skin section and were mainly affected by the photothermal effect produced from the CO2 laser-skin tissue interaction.

  6. Ethanol-induced oxidative DNA damage and CYP2E1 expression in liver tissue of Aldh2 knockout mice.

    PubMed

    Kim, Yong-Dae; Eom, Sang-Yong; Ogawa, Masanori; Oyama, Tsunehiro; Isse, Toyohi; Kang, Jong-Won; Zhang, Yan Wei; Kawamoto, Toshihiro; Kim, Heon

    2007-09-01

    Excessive alcohol consumption is associated with increased risks of many diseases including cancer. We evaluated oxidative DNA damage in Aldh2 +/+ and Aldh2 -/- mice after they had been subjected to acute ethanol exposure. Olive tail moment, which was measured using a comet assay, was not increased by ethanol treatment in both Aldh2 +/+ and Aldh2 -/- mice. However, after controlling for the effect of ethanol exposure, the Aldh2 genotype was a significant determinant for Olive tail moments. Although the ethanol treatment significantly increased the hepatic 8-OHdG generation in only Aldh2 +/+ mice, the level of 8-OHdG was the highest in Aldh2 -/- ethanol treated mice. The increase in the level of 8-OHdG was associated with hepatic expression of cytochrome P450 2E1 (CYP2E1). The levels of Olive tail moment and the hepatic 8-OHdG in the Aldh2 -/- control group were significantly higher than those of the Aldh2 +/+ control group. The level of CYP2E1 in liver tissue showed a similar pattern to those of the oxidative DNA damage markers. This study shows that acute ethanol consumption increases oxidative DNA damage and that expression of CYP2E1 protein may play a pivotal role in the induction of oxidative DNA damage. The finding that oxidative DNA damage was more intense in Aldh2 -/- mice than in Aldh2 +/+ mice suggests that ALDH2-deficient individuals may be more susceptible than wild-type ALDH2 individuals to ethanol-mediated liver disease, including cancer. PMID:17951967

  7. Changes of color coordinates of biological tissue with superficial skin damage due to mechanical trauma

    NASA Astrophysics Data System (ADS)

    Pteruk, Vail; Mokanyuk, Olexander; Kvaternuk, Olena; Yakenina, Lesya; Kotyra, Andrzej; Romaniuk, Ryszard S.; Dussembayeva, Shynar

    2015-12-01

    Change of color coordinates of normal and pathological biological tissues is based on calculated spectral diffuse reflection. The proposed color coordinates of normal and pathological biological tissues of skin provided using standard light sources, allowing accurately diagnose skin damage due to mechanical trauma with a blunt object for forensic problems.

  8. Nanog expression in heart tissues induced by acute myocardial infarction.

    PubMed

    Luo, Huanhuan; Li, Qiong; Pramanik, Jogen; Luo, Jiankai; Guo, Zhikun

    2014-10-01

    Nanog is a potential stem cell marker and is considered a regeneration factor during tissue repair. In the present study, we investigated expression patterns of nanog in the rat heart after acute myocardial infarction by semi-quantitative RT-PCR, immunohistochemistry and Western blot analyses. Our results show that nanog at both mRNA and protein levels is positively expressed in myocardial cells, fibroblasts and small round cells in different myocardial zones at different stages after myocardial infarction, showing a spatio-temporal and dynamic change. After myocardial infarction, the nanog expression in fibroblasts and small round cells in the infarcted zone (IZ) is much stronger than that in the margin zone (MZ) and remote infarcted zone (RIZ). From day 7 after myocardial infarction, the fibroblasts and small cells strongly expressed nanog protein in the IZ, and a few myocardial cells in the MZ and the RIZ and the numbers of nanog-positive fibroblasts and small cells reached the highest peak at 21 days after myocardial infarction, but in this period the number of nanog-positive myocardial cells decreased gradually. At 28 days after myocardial infarction, the numbers of all nanog-positive cells decreased into a low level. Therefore, our data suggest that all myocardial cells, fibroblasts and small round cells are involved in myocardial reconstruction after cardiac infarction. The nanog-positive myocardial cells may respond to early myocardial repair, and the nanog-positive fibroblasts and small round cells are the main source for myocardial reconstruction after cardiac infarction.

  9. Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1

    PubMed Central

    Calvo, Jennifer A.; Moroski-Erkul, Catherine A.; Lake, Annabelle; Eichinger, Lindsey W.; Shah, Dharini; Jhun, Iny; Limsirichai, Prajit; Bronson, Roderick T.; Christiani, David C.; Meira, Lisiane B.; Samson, Leona D.

    2013-01-01

    Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag−/− mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage. PMID:23593019

  10. Effect of mechanical tissue properties on thermal damage in skin after IR-laser ablation

    NASA Astrophysics Data System (ADS)

    Frenz, M.; Mischler, Ch.; Romano, V.; Forrer, M.; Müller, O. M.; Weber, H. P.

    1991-04-01

    The damage created instantaneously in dorsal skin and in the subjacent skeletal muscle layer after CO2 and Er3+ laser incisions is histologically and ultrastructurally investigated. Light microscopical examinations show an up to three times larger damage zone in the subcutaneous layer of skeletal muscle than in the connective tissue above. The extent of thermally altered muscle tissue is classified by different zones and characterized by comparison to long time heating injuries. The unexpectedly large damage is a result of the change of elastic properties occurring abruptly at the transition between different materials. This leads to a discontinuity of the cutting dynamics that reduces the ejection of tissue material. We show that the degree of thermal damage originates from the amount of hot material that is not ejected out of the crater acting as a secondary heat source.

  11. Anti-Human Tissue Factor Antibody Ameliorated Intestinal Ischemia Reperfusion-Induced Acute Lung Injury in Human Tissue Factor Knock-In Mice

    PubMed Central

    Mura, Marco; Li, Li; Cypel, Marcelo; Soderman, Avery; Picha, Kristen; Yang, Jing; Liu, Mingyao

    2008-01-01

    Background Interaction between the coagulation and inflammation systems plays an important role in the development of acute respiratory distress syndrome (ARDS). Anti-coagulation is an attractive option for ARDS treatment, and this has promoted development of new antibodies. However, preclinical trials for these antibodies are often limited by the high cost and availability of non-human primates. In the present study, we developed a novel alternative method to test the role of a humanized anti-tissue factor mAb in acute lung injury with transgenic mice. Methodology/Principal Findings Human tissue factor knock-in (hTF-KI) transgenic mice and a novel humanized anti-human tissue factor mAb (anti-hTF mAb, CNTO859) were developed. The hTF-KI mice showed a normal and functional expression of hTF. The anti-hTF mAb specifically blocked the pro-coagulation activity of brain extracts from the hTF-KI mice and human, but not from wild type mice. An extrapulmonary ARDS model was used by intestinal ischemia-reperfusion. Significant lung tissue damage in hTF-KI mice was observed after 2 h reperfusion. Administration of CNTO859 (5 mg/kg, i.v.) attenuated the severity of lung tissue injury, decreased the total cell counts and protein concentration in bronchoalveolar lavage fluid, and reduced Evans blue leakage. In addition, the treatment significantly reduced alveolar fibrin deposition, and decreased tissue factor and plasminogen activator inhibitor-1 activity in the serum. This treatment also down-regulated cytokine expression and reduced cell death in the lung. Conclusions This novel anti-hTF antibody showed beneficial effects on intestinal ischemia-reperfusion induced acute lung injury, which merits further investigation for clinical usage. In addition, the use of knock-in transgenic mice to test the efficacy of antibodies against human-specific proteins is a novel strategy for preclinical studies. PMID:18231608

  12. Of flies, mice, and men: evolutionarily conserved tissue damage responses and aging.

    PubMed

    Neves, Joana; Demaria, Marco; Campisi, Judith; Jasper, Heinrich

    2015-01-12

    Studies in flies, mice, and human models have provided a conceptual framework for how paracrine interactions between damaged cells and the surrounding tissue control tissue repair. These studies have amassed evidence for an evolutionarily conserved secretory program that regulates tissue homeostasis. This program coordinates cell survival and proliferation during tissue regeneration and repair in young animals. By virtue of chronic engagement, however, it also contributes to the age-related decline of tissue homeostasis leading to degeneration, metabolic dysfunction, and cancer. Here, we review recent studies that shed light on the nature and regulation of this evolutionarily conserved secretory program. PMID:25584795

  13. Of flies, mice, and men: evolutionarily conserved tissue damage responses and aging.

    PubMed

    Neves, Joana; Demaria, Marco; Campisi, Judith; Jasper, Heinrich

    2015-01-12

    Studies in flies, mice, and human models have provided a conceptual framework for how paracrine interactions between damaged cells and the surrounding tissue control tissue repair. These studies have amassed evidence for an evolutionarily conserved secretory program that regulates tissue homeostasis. This program coordinates cell survival and proliferation during tissue regeneration and repair in young animals. By virtue of chronic engagement, however, it also contributes to the age-related decline of tissue homeostasis leading to degeneration, metabolic dysfunction, and cancer. Here, we review recent studies that shed light on the nature and regulation of this evolutionarily conserved secretory program.

  14. Bone marrow mesenchymal stem cell implantation for the treatment of radioactivity‑induced acute skin damage in rats.

    PubMed

    Zheng, Kai; Wu, Weizhen; Yang, Shunliang; Huang, Lianghu; Chen, Jin; Gong, Chungui; Fu, Zhichao; Zhang, Linlin; Tan, Jianming

    2015-11-01

    The present study aimed to observe the role of mesenchymal stem cells (MSCs) in the repair of acute skin damage caused by radiation. Rat bone marrow MSCs (BMSCs) were isolated and cultured in vitro. A rat model of radiation‑induced acute skin damage was established by irradiation of the hind legs of Sprague-Dawley rats using a linear accelerator (45 Gy). After irradiation, rats were randomly divided into two groups: BMSC group and control group. Rats in the BMSC group were treated with a tail vein injection of 2x106 BMSCs (1 ml) immediately after irradiation and a local multipoint injection of 2x106 BMSCs at the injured area two weeks later. Then the wound healing of each rat was observed. The expression of transforming growth factor (TGF)‑β1, stromal cell‑derived factor-1 (SDF‑1) and prostaglandin E2 (PGE2) in the wounded tissues was determined by immunohistochemistry. The results demonstrated that skin damage was milder in the BMSC group than in the control group. Moreover, the speed of healing in the BMSC group was better than that in the control group. In addition, the wound score, it was significantly lower in the BMSC group than in the control group (P<0.05). The expression of PGE2 and TGF‑β1 in the BMSC group was also significantly lower than that in the control group (P<0.05), whereas the SDF‑1 expression was significantly higher in the BMSC group than that in the control group (P<0.05). BMSCs can effectively reduce inflammation and fibrosis in the wounded skin and promote the repair of acute radioactive skin injury. Thus, may be developed as a novel treatment for wound healing. PMID:26323987

  15. Tissue responses to low protracted doses of high let radiations or photons - Early and late damage relevant to radio-protective countermeasures

    NASA Technical Reports Server (NTRS)

    Ainsworth, E. J.; Afzal, S. M. J.; Crouse, D. A.; Hanson, W. R.; Fry, R. J. M.

    1989-01-01

    Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Recent studies on protection against early and late effects by aminothiols, prostaglandins, and other compounds are discussed.

  16. Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration

    PubMed Central

    Smith, Joshua A.; Park, Sookyoung; Krause, James S.; Banik, Naren L.

    2013-01-01

    Oxidative stress has been identified as an important contributor to neurodegeneration associated with acute CNS injuries and diseases such as spinal cord injury (SCI), traumatic brain injury (TBI), and ischemic stroke. In this review, we briefly detail the damaging effects of oxidative stress (lipid peroxidation, protein oxidation, etc.) with a particular emphasis on DNA damage. Evidence for DNA damage in acute CNS injuries is presented along with its downstream effects on neuronal viability. In particular, unchecked oxidative DNA damage initiates a series of signaling events (e.g. activation of p53 and PARP-1, cell cycle re-activation) which have been shown to promote neuronal loss following CNS injury. These findings suggest that preventing DNA damage might be an effective way to promote neuronal survival and enhance neurological recovery in these conditions. Finally, we identify the telomere and telomere-associated proteins (e.g. telomerase) as novel therapeutic targets in the treatment of neurodegeneration due to their ability to modulate the neuronal response to both oxidative stress and DNA damage. PMID:23422879

  17. Systematic analysis of axonal damage and inflammatory response in different white matter tracts of acutely injured rat spinal cord.

    PubMed

    Gomes-Leal, W; Corkill, D J; Picanço-Diniz, C W

    2005-12-20

    The mechanisms of white matter (WM) damage during secondary degeneration are a fundamental issue in the pathophysiology of central nervous system (CNS) diseases. Our main goal was to describe the pattern of an acute inflammatory response and secondary damage to axons in different WM tracts of acutely injured rat spinal cord. Adult rats were deeply anesthetized and injected with 20 nmol of NMDA into the spinal cord ventral horn on T7. Animals were perfused after survival times of 1 day, 3 days and 7 days. Ten micrometer sections were submitted to immunocytochemical analysis for activated macrophages/microglia, neutrophils and damaged axons. There were inflammatory response and progressive tissue destruction of ventral WM (VWM) with formation of microcysts in both VWM and lateral WM (LWM). In the VWM, the number of beta-amyloid precursor protein (beta-APP) end-bulbs increased from 1 day with a peak at 3 days, decreasing by 7 days following the injection. APP end-bulbs were present in the dorsal WM (DWM) at 3 days survival time but were not in the LWM. Electron microscopic analysis revealed different degrees of myelin disruption and axonal pathology in the vacuolated WM up to 14 mm along the rostrocaudal axis. Quantitative analysis revealed a significant loss of medium and large axons (P < 0.05), but not of small axons (P > 0.05). Our results suggest that bystander axonal damage and myelin vacuolation are important secondary component of the pathology of WM tracts following rat SCI. Further studies are needed to understand the mechanisms of these pathological events.

  18. Acute exposure of uranyl nitrate causes lipid peroxidation and histopathological damage in brain and bone of Wistar rat.

    PubMed

    Ghosh, Somnath; Kumar, Amit; Pandey, Badri Narain; Mishra, Kaushala Prasad

    2007-01-01

    Although the kidneys are the main target organs for uranium (U) toxicity, recent studies have shown that U can cross the blood-brain barrier to accumulate in the brain. Uranyl nitrate (U-238)induced oxidative damage was investigated in brain and bone of Wistar rats after intraperitoneal injection of uranyl nitrate at acute doses either nephrotoxic (576 microg of U/kg body weight) or subnephrotoxic (144 microg U/kg body weight). The health effects of U administration at 576 microg of U/kg body weight were seen in terms of decrease in food intake and no gain in body weight compared to respective controls. These alterations were correlated with increased lipid peroxidation as measured by thiobarbituric acid reactive substances in rat brain and bone. However, at lower dosage of U (144 microg U/kg body weight), no significant lipid peroxidation was observed in brain and bone. Histological examination of U-treated (576 microg of U/kg body weight) rat brain tissues showed marked and diffuse cystic degeneration and a similar pattern in histological alterations was observed in kidneys in treated animals; whereas no significant histological change was observed in rat brains and kidney treated with a lower dose of U (144 microg U/kg body weight). It is concluded that administration of U at an acute nephrotoxic dose caused oxidative stress in brain and bone manifested as lipid peroxidation and histopathological damage.

  19. Synthesis of a novel photopolymerized nanocomposite hydrogel for the treatment of acute mechanical damage to cartilage

    NASA Astrophysics Data System (ADS)

    Schlichting, Kathryn; Copeland-Johnson, Trishelle; Goodman, Matthew; Lipert, Robert; McKinley, Todd; Martin, James; Mallapragada, Surya; Lin, Zhiqun

    2011-03-01

    Posttraumatic osteoarthritis is caused by a cascade of pathobiologic and pathomechanical events starting with intraarticular fractures in the cartilage. Currently, treatment of fractures is completely focused on restoration of the macroanatomy of the joint. The premise is that restoring the macroanatomy will prevent ongoing stresses and in turn prevent cartilage degeneration. However, current treatment ignores acute mechanical damage sustained by cartilage at the time of injury. This study describes the initial development of a novel nanocomposite photopolymerizing copolymer that has potential to restore local structural integrity to acutely injured cartilage, and subsequently act as a carrier for chondrocyte-enhancing bioactive agents.

  20. Vitamin D deficiency contributes to vascular damage in sustained ischemic acute kidney injury.

    PubMed

    de Bragança, Ana C; Volpini, Rildo A; Mehrotra, Purvi; Andrade, Lúcia; Basile, David P

    2016-07-01

    Reductions in renal microvasculature density and increased lymphocyte activity may play critical roles in the progression of chronic kidney disease (CKD) following acute kidney injury (AKI) induced by ischemia/reperfusion injury (IRI). Vitamin D deficiency is associated with tubulointerstitial damage and fibrosis progression following IRI-AKI We evaluated the effect of vitamin D deficiency in sustained IRI-AKI, hypothesizing that such deficiency contributes to the early reduction in renal capillary density or alters the lymphocyte response to IRI Wistar rats were fed vitamin D-free or standard diets for 35 days. On day 28, rats were randomized into four groups: control, vitamin D deficient (VDD), bilateral IRI, and VDD+IRI Indices of renal injury and recovery were evaluated for up to 7 days following the surgical procedures. VDD rats showed reduced capillary density (by cablin staining), even in the absence of renal I/R. In comparison with VDD and IRI rats, VDD+IRI rats manifested a significant exacerbation of capillary rarefaction as well as higher urinary volume, kidney weight/body weight ratio, tissue injury scores, fibroblast-specific protein-1, and alpha-smooth muscle actin. VDD+IRI rats also had higher numbers of infiltrating activated CD4(+) and CD8(+) cells staining for interferon gamma and interleukin-17, with a significant elevation in the Th17/T-regulatory cell ratio. These data suggest that vitamin D deficiency impairs renal repair responses to I/R injury, exacerbates changes in renal capillary density, as well as promoting fibrosis and inflammation, which may contribute to the transition from AKI to CKD.

  1. Evaluation of an attenuated Trypanosoma cruzi strain in rats. Analysis of survival, parasitemia and tissue damage.

    PubMed

    Revelli, S; Basombrío, M A; Valenti, J L; Moreno, H; Poli, H; Morini, J C

    1993-01-01

    Infection and tissue damage induced by parasites of an attenuated Trypanosoma cruzi culture strain (TCC) were studied in "I" line of inbred rats. Suckling rats (S), 3-5 day old were inoculated i.p. with 10(6) TCC (S1), 10(7) TCC (S2) and 10(8) TCC (S3). Weaned rats (W), 21-25 day old were inoculated s.c. with 10(6) TCC (W1), 10(7) TCC (W2) and 10(8) TCC (W3). The cultures yielded up to 2% of trypomastigotes. Controls inoculated either i.p. or s.c. with 10(6) blood form trypomastigotes (SC and WC) as well as normal controls (NC) were included. Survival was 100% in S1, S2 and S3, and 0% in SC on day 13 post-infection (p.i.). The latter animals died with acute Chagas disease signs. Survival was 100% in the W groups. In the first 30 days p.i. parasites were detected in S1, S2 and S3 and W1, W2, W3 groups after exhaustive examination. Parasites were easily found in WC and SC until day 13. Xeno-diagnoses were positive (5/5) at 2 months p.i. and negative at 6 months p.i. (W1, W2, W3, 0/23; WC, 0/5). Only cardiac lesions were slightly increased. The frequency of focal chronic myocarditis seemed to be increased in a dose-independent manner (S1, S2, S3, 26%; W1, W2, W3, 46%) but was not significant in comparison with NC, and even was lower than usually found in WC (61.3%). The reduced virulence and pathogenicity suggest that the TCC strain suffered a remarkable attenuation after long term in vitro culture. PMID:8246729

  2. Dissecting the molecular mechanism of ionizing radiation-induced tissue damage in the feather follicle.

    PubMed

    Chen, Xi; Liao, Chunyan; Chu, Qiqi; Zhou, Guixuan; Lin, Xiang; Li, Xiaobo; Lu, Haijie; Xu, Benhua; Yue, Zhicao

    2014-01-01

    Ionizing radiation (IR) is a common therapeutic agent in cancer therapy. It damages normal tissue and causes side effects including dermatitis and mucositis. Here we use the feather follicle as a model to investigate the mechanism of IR-induced tissue damage, because any perturbation of feather growth will be clearly recorded in its regular yet complex morphology. We find that IR induces defects in feather formation in a dose-dependent manner. No abnormality was observed at 5 Gy. A transient, reversible perturbation of feather growth was induced at 10 Gy, leading to defects in the feather structure. This perturbation became irreversible at 20 Gy. Molecular and cellular analysis revealed P53 activation, DNA damage and repair, cell cycle arrest and apoptosis in the pathobiology. IR also induces patterning defects in feather formation, with disrupted branching morphogenesis. This perturbation is mediated by cytokine production and Stat1 activation, as manipulation of cytokine levels or ectopic Stat1 over-expression also led to irregular feather branching. Furthermore, AG-490, a chemical inhibitor of Stat1 signaling, can partially rescue IR-induced tissue damage. Our results suggest that the feather follicle could serve as a useful model to address the in vivo impact of the many mechanisms of IR-induced tissue damage.

  3. Fourier transform infrared spectroscopic imaging identifies early biochemical markers of tissue damage

    NASA Astrophysics Data System (ADS)

    Varma, Vishal K.; Ohlander, Samuel; Nguyen, Peter; Vendryes, Christopher; Parthiban, Sujeeth; Hamilton, Blake; Wallis, M. Chad; Kajdacsy-Balla, Andre; Hannaford, Blake; Lendvay, Thomas; Hotaling, James M.; Walsh, Michael J.

    2014-03-01

    Fourier Transform Infrared (FT-IR) spectroscopic imaging can allow for the rapid imaging of tissue biochemistry in a label-free and non-perturbing fashion. With the rapid adoption of new minimally invasive surgery (MIS) technologies over the last 20 years, adequate skill to safely and effectively use these technologies may not be achieved and risk of undue physical pressure being placed on tissues is a concern. Previous work has demonstrated that a number of histological stains can detect tissue damage, however, this process requires the initiation and progression of a signaling cascade that results in the epitope of interest being expressed. We proposed to identify the early biochemical markers associated with physical tissue damage from applied forces, thus not requiring transcriptional and translational protein synthesis as traditional immunohistochemistry does. To demonstrate that FT-IR can measure biochemical changes in tissues that have undergone physical force, we took ex-vivo lamb's liver that had been freshly excised and applied varying levels of physical pressure (0kPa to 30kPa). Tissues were then formalin-fixed, paraffin-embedded, and sectioned on to glass for H and E staining to identify damage and on to an IR slide for FT-IR imaging. Regions of interest containing hepatocytes were identified and average FT-IR spectra were extracted from the damaged and undamaged livers. FT-IR spectra showed clear biochemical changes associated with tissue damage. In addition, chemical changes could be observed proceeding histological changes observed when using conventional staining approaches.

  4. Evaluation of plasma von Willebrand factor as a biomarker for acute arterial damage in rats.

    PubMed

    Newsholme, S J; Thudium, D T; Gossett, K A; Watson, E S; Schwartz, L W

    2000-01-01

    Plasma von Willebrand factor (vWF) was evaluated as a potential biomarker of acute arterial damage in rats after a vasotoxic dose of the dopaminergic vasodilator, fenoldopam (FP). Male Sprague-Dawley rats were given FP or isotonic saline by subcutaneous injection, and plasma vWF was measured at 2, 6, and 24 hours after challenge. Mean plasma vWF values increased in FP-treated rats compared to controls at 2 hours (167 vs 122%; p < 0.05) and 6 hours postdose (172 vs 130%; p < 0.01) but were comparable to control values after 24 hours. Mesenteric arterial lesions were observed microscopically in all FP-treated rats 24 hours postdose but were not present in rats at 1, 2, 4, 6, or 8 hours after FP challenge. Further, plasma vWF concentrations increased in saline-treated rats after only the minimal perturbation of repeated venipuncture. These results indicate an early, minimal, and transient release of vWF that precedes the onset of morphologically evident vascular damage. The minimal increases in plasma vWF concentrations were of limited predictive value, may be more reflective of an acute-phase reactant response, and were not considered a reliable biomarker of acute FP-induced arterial damage in the rat.

  5. Investigations of the Cavitation and Damage Thresholds of Histotripsy and Applications in Targeted Tissue Ablation

    NASA Astrophysics Data System (ADS)

    Vlaisavljevich, Eli

    Histotripsy is a noninvasive ultrasound therapy that controls acoustic cavitation to mechanically fractionate soft tissue. This dissertation investigates the physical thresholds to initiate cavitation and produce tissue damage in histotripsy and factors affecting these thresholds in order to develop novel strategies for targeted tissue ablation. In the first part of this dissertation, the effects of tissue properties on histotripsy cavitation thresholds and damage thresholds were investigated. Results demonstrated that the histotripsy shock scattering threshold using multi-cycle pulses increases in stiffer tissues, while the histotripsy intrinsic threshold using single-cycle pulses is independent of tissue stiffness. Further, the intrinsic threshold slightly decreases with lower frequencies and significantly decreases with increasing temperature. The effects of tissue properties on the susceptibility to histotripsy-induced tissue damage were also investigated, demonstrating that stiffer tissues are more resistant to histotripsy. Two strategies were investigated for increasing the effectiveness of histotripsy for the treatment of stiffer tissues, with results showing that thermal preconditioning may be used to alter tissue susceptibility to histotripsy and that lower frequency treatments may increase the efficiency of histotripsy tissue ablation due to enhanced bubble expansion. In the second part of this dissertation, the feasibility of using histotripsy for targeted liver ablation was investigated in an intact in vivo porcine model, with results demonstrating that histotripsy was capable of non-invasively creating precise lesions throughout the entire liver. Additionally, a tissue selective ablation approach was developed, where histotripsy completely fractionated the liver tissue surrounding the major hepatic vessels and gallbladder while being self-limited at the boundaries of these critical structures. Finally, the long-term effects of histotripsy liver

  6. Prediction of acute renal failure following soft-tissue injury using the venous bicarbonate concentration.

    PubMed

    Muckart, D J; Moodley, M; Naidu, A G; Reddy, A D; Meineke, K R

    1992-12-01

    Sixty-four patients with soft-tissue injuries were studied prospectively to determine whether an initial venous bicarbonate concentration (VBC) of less than 17 mmol/L would predict the development of myoglobin-induced acute renal failure. The VBC was > 17 mmol/L in 59 patients, seven of whom had myoglobinuria. All recovered without renal complications. The remaining five patients all had VBC < 17 mmol/L and four had myoglobinuria. Acute renal failure developed in four patients (p < 0.001). The VBC on hospital arrival was the most accurate predictor of these patients' risk for the development of acute renal failure following soft-tissue injury. PMID:1474620

  7. Aberrant Synaptic Integration in Adult Lamina I Projection Neurons Following Neonatal Tissue Damage

    PubMed Central

    Li, Jie; Kritzer, Elizabeth; Craig, Paige E.

    2015-01-01

    Mounting evidence suggests that neonatal tissue damage evokes alterations in spinal pain reflexes which persist into adulthood. However, less is known about potential concomitant effects on the transmission of nociceptive information to the brain, as the degree to which early injury modulates synaptic integration and membrane excitability in mature spinal projection neurons remains unclear. Here we demonstrate that neonatal surgical injury leads to a significant shift in the balance between synaptic excitation and inhibition onto identified lamina I projection neurons of the adult mouse spinal cord. The strength of direct primary afferent input to mature spino-parabrachial neurons was enhanced following neonatal tissue damage, whereas the efficacy of both GABAergic and glycinergic inhibition onto the same population was compromised. This was accompanied by reorganization in the pattern of sensory input to adult projection neurons, which included a greater prevalence of monosynaptic input from low-threshold A-fibers when preceded by early tissue damage. In addition, neonatal incision resulted in greater primary afferent-evoked action potential discharge in mature projection neurons. Overall, these results demonstrate that tissue damage during early life causes a long-term increase in the gain of spinal nociceptive circuits, and suggest that the prolonged consequences of neonatal trauma may not be restricted to the spinal cord but rather include excessive ascending signaling to supraspinal pain centers. PMID:25673839

  8. TGF-{beta} antagonists as mitigators of radiation-induced tissue damage

    DOEpatents

    Barcellos-Hoff, M.H.

    1997-04-01

    A method for treating tissue damage caused by radiation is described by use of a TGF-{beta} antagonist, such as an anti-TGF-{beta} antibody or a TGF-{beta} latency associated protein. It is administered not more than a week after exposure, and is particularly useful in mitigating the side effects of breast cancer therapy.

  9. TGF-.beta. antagonists as mitigators of radiation-induced tissue damage

    DOEpatents

    Barcellos-Hoff, Mary H.

    1997-01-01

    A method for treating tissue damage caused by radiation is described by use of a TGF-.beta. antagonist, such as an anti-TGF-.beta. antibody or a TGF-.beta. latency associated protein. It is administered not more than a week after exposure, and is particularly useful in mitigating the side effects of breast cancer therapy.

  10. Flaxseed Mitigates Acute Oxidative Lung Damage in a Mouse Model of Repeated Radiation and Hyperoxia Exposure Associated with Space Exploration

    PubMed Central

    Pietrofesa, Ralph A.; Solomides, Charalambos C.; Christofidou-Solomidou, Melpo

    2015-01-01

    Background Spaceflight missions may require crewmembers to conduct extravehicular activities (EVA). Pre-breathe protocols in preparation for an EVA entail 100% hyperoxia exposure that may last for a few hours and be repeated 2-3 times weekly. Each EVA is associated with additional challenges such as low levels of total body cosmic/galactic radiation exposure that may present a threat to crewmember health. We have developed a mouse model of total body radiation and hyperoxia exposure and identified acute damage of lung tissues. In the current study we evaluated the usefulness of dietary flaxseed (FS) as a countermeasure agent for such double-hit exposures. Methods We evaluated lung tissue changes 2 weeks post-initiation of exposure challenges. Mouse cohorts (n=5/group) were pre-fed diets containing either 0% FS or 10% FS for 3 weeks and exposed to: a) normoxia (Untreated); b) >95% O2 (O2); c) 0.25Gy single fraction gamma radiation (IR); or d) a combination of O2 and IR (O2+IR) 3 times per week for 2 consecutive weeks, where 8-hour hyperoxia treatments were spanned by normoxic intervals. Results At 2 weeks post challenge, while control-diet fed mice developed significant lung injury and inflammation across all challenges, FS protected lung tissues by decreasing bronchoalveolar lavage fluid (BALF) neutrophils (p<0.003) and protein levels, oxidative tissue damage, as determined by levels of malondialdehyde (MDA) (p<0.008) and nitrosative stress as determined by nitrite levels. Lung hydroxyproline levels, a measure of lung fibrosis, were significantly elevated in mice fed 0% FS (p<0.01) and exposed to hyperoxia/radiation or the combination treatment, but not in FS-fed mice. FS also decreased levels of a pro-inflammatory, pro-fibrogenic cytokine (TGF-β1) gene expression levels in lung. Conclusion Flaxseed mitigated adverse effects in lung of repeat exposures to radiation/hyperoxia. This data will provide useful information in the design of countermeasures to early

  11. Chinese green tea consumption reduces oxidative stress, inflammation and tissues damage in smoke exposed rats

    PubMed Central

    Al-Awaida, Wajdy; Akash, Muhanad; Aburubaiha, Zaid; Talib, Wamidh H.; Shehadeh, Hayel

    2014-01-01

    Objective(s): One cause of cigarette smoking is oxidative stress that may alter the cellular antioxidant defense system, induce apoptosis in lung tissue, inflammation and damage in liver, lung, and kidney. It has been shown that Chinese green tea (CGT) (Lung Chen Tea) has higher antioxidant property than black tea. In this paper, we will explore the preventive effect of CGT on cigarette smoke-induced oxidative damage, apoptosis and tissues inflammation in albino rat model. Materials and Methods: Albino rats were randomly divided into four groups, i.e. sham air (SA), cigarette smoke (CS), CGT 2% plus SA or plus CS. The exposure to smoking was carried out as a single daily dose (1 cigarette/rat) for a period of 90 days using an electronically controlled smoking machine. Sham control albino rats were exposed to air instead of cigarette smoke. Tissues were collected 24 hr after last CS exposure for histology and all enzyme assays. Apoptosis was evidenced by the fragmentation of DNA using TUNEL assay. Results: Long-term administration of cigarette smoke altered the cellular antioxidant defense system, induced apoptosis in lung tissue, inflammation and damage in liver, lung, and kidney. All these pathophysiological and biochemical events were significantly improved when the cigarette smoke-exposed albino rats were given CGT infusion as a drink instead of water. Conclusion: Exposure of albino rat model to cigarette smoke caused oxidative stress, altered the cellular antioxidant defense system, induced apoptosis in lung tissue, inflammation and tissues damage, which could be prevented by supplementation of CGT. PMID:25729541

  12. Magnetic Resonance Imaging Allows the Evaluation of Tissue Damage and Regeneration in a Mouse Model of Critical Limb Ischemia

    PubMed Central

    Zaccagnini, Germana; Palmisano, Anna; Canu, Tamara; Maimone, Biagina; Lo Russo, Francesco M.; Ambrogi, Federico; Gaetano, Carlo; De Cobelli, Francesco; Del Maschio, Alessandro; Esposito, Antonio; Martelli, Fabio

    2015-01-01

    Magnetic resonance imaging (MRI) provides non-invasive, repetitive measures in the same individual, allowing the study of a physio-pathological event over time. In this study, we tested the performance of 7 Tesla multi-parametric MRI to monitor the dynamic changes of mouse skeletal muscle injury and regeneration upon acute ischemia induced by femoral artery dissection. T2-mapping (T2 relaxation time), diffusion-tensor imaging (Fractional Anisotropy) and perfusion by Dynamic Contrast-Enhanced MRI (K-trans) were measured and imaging results were correlated with histological morphometric analysis in both Gastrocnemius and Tibialis anterior muscles. We found that tissue damage positively correlated with T2-relaxation time, while myofiber regeneration and capillary density positively correlated with Fractional Anisotropy. Interestingly, K-trans positively correlated with capillary density. Accordingly, repeated MRI measurements between day 1 and day 28 after surgery in ischemic muscles showed that: 1) T2-relaxation time rapidly increased upon ischemia and then gradually declined, returning almost to basal level in the last phases of the regeneration process; 2) Fractional Anisotropy dropped upon ischemic damage induction and then recovered along with muscle regeneration and neoangiogenesis; 3) K-trans reached a minimum upon ischemia, then progressively recovered. Overall, Gastrocnemius and Tibialis anterior muscles displayed similar patterns of MRI parameters dynamic, with more marked responses and less variability in Tibialis anterior. We conclude that MRI provides quantitative information about both tissue damage after ischemia and the subsequent vascular and muscle regeneration, accounting for the differences between subjects and, within the same individual, between different muscles. PMID:26554362

  13. Association between Peripheral Oxidative Stress and White Matter Damage in Acute Traumatic Brain Injury

    PubMed Central

    Lin, Wei-Ming; Chen, Meng-Hsiang; Wang, Hung-Chen; Lu, Cheng-Hsien; Chen, Pei-Chin; Chen, Hsiu-Ling; Tsai, Nai-Wen; Su, Yu-Jih; Li, Shau-Hsuan; Kung, Chia-Te; Chiu, Tsui-Min; Weng, Hsu-Huei; Lin, Wei-Che

    2014-01-01

    The oxidative stress is believed to be one of the mechanisms involved in the neuronal damage after acute traumatic brain injury (TBI). However, the disease severity correlation between oxidative stress biomarker level and deep brain microstructural changes in acute TBI remains unknown. In present study, twenty-four patients with acute TBI and 24 healthy volunteers underwent DTI. The peripheral blood oxidative biomarkers, like serum thiol and thiobarbituric acid-reactive substances (TBARS) concentrations, were also obtained. The DTI metrics of the deep brain regions, as well as the fractional anisotropy (FA) and apparent diffusion coefficient, were measured and correlated with disease severity, serum thiol, and TBARS levels. We found that patients with TBI displayed lower FAs in deep brain regions with abundant WMs and further correlated with increased serum TBARS level. Our study has shown a level of anatomic detail to the relationship between white matter (WM) damage and increased systemic oxidative stress in TBI which suggests common inflammatory processes that covary in both the peripheral and central reactions after TBI. PMID:24804213

  14. Erythrocyte membrane fluidity and indices of plasmatic oxidative damage after acute physical exercise in humans.

    PubMed

    Berzosa, C; Gómez-Trullén, E M; Piedrafita, E; Cebrián, I; Martínez-Ballarín, E; Miana-Mena, F J; Fuentes-Broto, L; García, J J

    2011-06-01

    Optimal levels of membrane fluidity are essential for numerous cell functions including cell growth, solute transport and signal transduction. Since exercise enhances free radical production, our aim was to evaluate in healthy male subjects the effects of an acute bout of maximal and submaximal exercise on the erythrocyte membrane fluidity and its possible relation to the oxidative damage overproduction due to exercise. Subjects (n = 34) performed three cycloergometric tests: a continuous progressive exercise, a strenuous exercise until exhaustion and an acute bout of exercise at an intensity corresponding to 70% of maximal work capacity for 30 min. Venous blood samples were collected before and immediately after these exercises. Erythrocyte membrane fluidity was assessed by fluorescence spectroscopy. Plasma malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA) concentrations and carbonyl content of plasmatic proteins were used as an index of lipid and protein oxidation, respectively. Exercise produced a dramatic drop in the erythrocyte membrane fluidity as compared to resting time, but this was not accompanied by significant changes in the plasmatic MDA and 4-HDA concentrations. The highest erythrocyte membrane rigidity was detected immediately after strenuous exercise until exhaustion was performed. Protein carbonyl levels were higher after exhaustive exercises than at rest. Continuous progressive and strenuous exercises until exhaustion, but not submaximal workload, resulted in a significant enhanced accumulation of carbonylated proteins in the plasma. These findings are consistent with the idea that exercise exaggerates oxidative damage, which may contribute, at least partially, to explain the rigidity in the membrane of the erythrocytes due to acute exercise.

  15. Acute toxicity and superficial damage to goldfish from the ionic liquid 1-methyl-3-octylimidazolium bromide.

    PubMed

    Li, Xiao-Yu; Zeng, Shi-Hu; Zhang, Wei-Hong; Liu, Li; Ma, Shuai; Wang, Jian-Ji

    2013-04-01

    In the present study, goldfish toxicity and superficial damage from 1-methyl-3-octylimidazolium bromide ([C8 mim]Br) exposure were evaluated by an acute toxicity test. These results show that the 24-h 50% lethal concentration for [C8 mim]Br in goldfish is 244 mg L(-1) , and this indicates that [C8 mim]Br is a chemical with moderate or low toxicity to organisms. Scanning electronic microscope and histological observations revealed that acute exposure to [C8 mim]Br induced obvious superficial damage to the skin, gill filaments, and intestinal villi of the goldfish, and this suggests that the skin, gills, and intestines may be the first direct targets of the ionic liquid in this fish. Histological examination also indicated that [C8 mim]Br-exposure caused damage to the goldfish's hepatopancreas and kidney, consisting mainly of hepatic cords in a loose connection, hepatic cytoplasmic vacuolation, renal parenchyma vacuolization, and intumescence of the renal tubule. In addition, we found that [C8 mim]Br caused a significant increase in malondialdehyde (MDA) level in the hepatopancreases from these goldfish, and thus we suggest that the MDA level may be a biomarker of [C8 mim]Br-toxicity in goldfish.

  16. High elastic modulus nanoparticles: a novel tool for subfailure connective tissue matrix damage.

    PubMed

    Empson, Yvonne M; Ekwueme, Emmanuel C; Hong, Jung K; Paynter, Danielle M; Kwansa, Albert L; Brown, Chalmers; Pekkanen, Allison M; Roman, Maren; Rylander, Nichole M; Brolinson, Gunnar P; Freeman, Joseph W

    2014-09-01

    Subfailure matrix injuries such as sprains and strains account for a considerable portion of ligament and tendon pathologies. In addition to the lack of a robust biological healing response, these types of injuries are often characterized by seriously diminished matrix biomechanics. Recent work has shown nanosized particles, such as nanocarbons and nanocellulose, to be effective in modulating cell and biological matrix responses for biomedical applications. In this article, we investigate the feasibility and effect of using high stiffness nanostructures of varying size and shape as nanofillers to mechanically reinforce damaged soft tissue matrices. To this end, nanoparticles (NPs) were characterized using atomic force microscopy and dynamic light scattering techniques. Next, we used a uniaxial tensile injury model to test connective tissue (porcine skin and tendon) biomechanical response to NP injections. After injection into damaged skin and tendon specimens, the NPs, more notably nanocarbons in skin, led to an increase in elastic moduli and yield strength. Furthermore, rat primary patella tendon fibroblast cell activity evaluated using the metabolic water soluble tetrazolium salt assay showed no cytotoxicity of the NPs studied, instead after 21 days nanocellulose-treated tenocytes exhibited significantly higher cell activity when compared with nontreated control tenocytes. Dispersion of nanocarbons injected by solution into tendon tissue was investigated through histologic studies, revealing effective dispersion and infiltration in the treated region. Such results suggest that these high modulus NPs could be used as a tool for damaged connective tissue repair.

  17. Metabolic fingerprinting to understand therapeutic effects and mechanisms of silybin on acute liver damage in rat

    PubMed Central

    Liang, Qun; Wang, Cong; Li, Binbing; Zhang, Ai-hua

    2015-01-01

    Background: Metabolic fingerprinting is a rapid and noninvasive analysis, representing a powerful approach for the characterization of phenotypes and the distinction of specific metabolic states due to environmental alterations. It has become a valuable analytical approach for the characterization of phenotypes and is the rapidly evolving field of the comprehensive measurement of ideally all endogenous metabolites in bio-samples. Silybin has displayed bright prospects in the prevention and therapy of liver injury, and we had conducted a preliminary exploration on the molecular mechanism of the hepatoprotective effects of silybin. Because the knowledge on the metabolic responses of an acute liver damage rat to the silybin is still scarce, metabolic fingerprinting can provide relevant information on the intrinsic metabolic adjustments. Materials and Methods: Here, the physiological and metabolic changes in the acute liver damage rat were investigated by performing a metabolic analysis. The phenotypic response was assessed by liquid chromatography/mass spectrometry (LC/MS) combined with pattern recognition approaches such as principal components analysis and partial least squares projection to supervised latent structures and discriminant analysis. Multivariate analysis of the data showed trends in scores plots that were related to the concentration of the silybin. Results: Results indicate 10 ions (7 upregulated and 3 downregulated) as differentiating metabolites. Key observations include perturbations of metabolic pathways linked to glutathione metabolism, tryptophan metabolism, cysteine and methionine metabolism, etc., Overall, this investigation illustrates the power of the LC/MS combined with the pattern recognition methods that can engender new insights into silybin affecting on metabolism pathways of an acute liver damage rat. Conclusion: The present study demonstrates that the combination of metabolic fingerprinting with appropriate chemometric analysis is a

  18. Non-damaging laser therapy of the macula: Titration algorithm and tissue response

    NASA Astrophysics Data System (ADS)

    Palanker, Daniel; Lavinsky, Daniel; Dalal, Roopa; Huie, Philip

    2014-02-01

    Retinal photocoagulation typically results in permanent scarring and scotomata, which limit its applicability to the macula, preclude treatments in the fovea, and restrict the retreatments. Non-damaging approaches to laser therapy have been tested in the past, but the lack of reliable titration and slow treatment paradigms limited their clinical use. We developed and tested a titration algorithm for sub-visible and non-damaging treatments of the retina with pulses sufficiently short to be used with pattern laser scanning. The algorithm based on Arrhenius model of tissue damage optimizes the power and duration for every energy level, relative to the threshold of lesion visibility established during titration (and defined as 100%). Experiments with pigmented rabbits established that lesions in the 50-75% energy range were invisible ophthalmoscopically, but detectable with Fluorescein Angiography and OCT, while at 30% energy there was only very minor damage to the RPE, which recovered within a few days. Patients with Diabetic Macular Edema (DME) and Central Serous Retinopathy (CSR) have been treated over the edematous areas at 30% energy, using 200μm spots with 0.25 diameter spacing. No signs of laser damage have been detected with any imaging modality. In CSR patients, subretinal fluid resolved within 45 days. In DME patients the edema decreased by approximately 150μm over 60 days. After 3-4 months some patients presented with recurrence of edema, and they responded well to retreatment with the same parameters, without any clinically visible damage. This pilot data indicates a possibility of effective and repeatable macular laser therapy below the tissue damage threshold.

  19. Hydrogen peroxide as a damage signal in tissue injury and inflammation: murderer, mediator, or messenger?

    PubMed

    van der Vliet, Albert; Janssen-Heininger, Yvonne M W

    2014-03-01

    Tissue injury and inflammation are associated with increased production of reactive oxygen species (ROS), which have the ability to induce oxidative injury to various biomolecules resulting in protein dysfunction, genetic instability, or cell death. However, recent observations indicate that formation of hydrogen peroxide (H2 O2 ) during tissue injury is also an essential feature of the ensuing wound healing response, and functions as an early damage signal to control several critical aspects of the wound healing process. Because innate oxidative wound responses must be tightly coordinated to avoid chronic inflammation or tissue injury, a more complete understanding is needed regarding the origins and dynamics of ROS production, and their critical biological targets. This prospect highlights the current experimental evidence implicating H2 O2 in early epithelial wound responses, and summarizes technical advances and approaches that may help distinguish its beneficial actions from its more deleterious actions in conditions of chronic tissue injury or inflammation. PMID:24122865

  20. In vivo Photoacoustic Spectroscopic Imaging of Hemoglobin Derivatives in Thermally Damaged Tissue

    NASA Astrophysics Data System (ADS)

    Aizawa, Kazuya; Sato, Shunichi; Saitoh, Daizoh; Ashida, Hiroshi; Obara, Minoru

    2009-06-01

    Photoacoustic (PA) spectroscopic measurement was performed for thermally damaged skin in a rat in vivo to analyze hemoglobin derivatives in the tissue. We observed PA signals at around 500 and 633 nm, which are center wavelengths of methemoglobin (MetHb) absorption peaks, at depths corresponding the uppermost dermis (˜0.16 mm) and hair follicles (˜0.62 mm), indicating formation of MetHb in these tissue regions. By scanning a PA detector on the tissue, two-dimensional PA images (tomograms) were produced. Subtraction imaging technique was used for multispectral PA tomograms to analyze specific components of hemoglobin derivatives in the tissue, by which the contrast of oxyhemogobin (HbO2)-associated PA signal has been improved and the distribution of PA signal that seems to reflect the concentration of MetHb has been visualized.

  1. Quantitative Estimations of Thermal Damage in Skin Tissue Using Monte Carlo Simulation of Polarized Light

    NASA Astrophysics Data System (ADS)

    Lee, G. W.; Kim, T. H.; Youn, J. I.

    2016-03-01

    Thermal treatment has been used for collagen tightening and tissue contour enhancement. It is important to monitor the condition of collagenous tissue during and immediately after thermal treatment. Collagen denaturation changes the optical properties such as scattering coefficient and anisotropy. In this study, Monte Carlo simulation of polarized light was used to calculate the degree of linear polarization (DOLP) of backscattered light from thermally damaged porcine skin, and the Mueller matrix was calculated to verify the result of DOLP. We observed a decrease in the DOLP and a significant change in the radial distribution of the Mueller matrix elements at temperatures ranging from 55 to 65°C. This could be attributed to the increase in scattering coefficient and decrease in anisotropy caused by thermal denaturation in the tissue. The DOLP method has a potential implementation as a real-time closed-loop feedback system for use in various thermal treatment methods through measuring changes in optical properties of target tissues.

  2. Laser treatment of female stress urinary incontinence: optical, thermal, and tissue damage simulations

    NASA Astrophysics Data System (ADS)

    Hardy, Luke A.; Chang, Chun-Hung; Myers, Erinn M.; Kennelly, Michael J.; Fried, Nathaniel M.

    2016-02-01

    Treatment of female stress urinary incontinence (SUI) by laser thermal remodeling of subsurface tissues is studied. Light transport, heat transfer, and thermal damage simulations were performed for transvaginal and transurethral methods. Monte Carlo (MC) provided absorbed photon distributions in tissue layers (vaginal wall, endopelvic fascia, urethral wall). Optical properties (n,μa,μs,g) were assigned to each tissue at λ=1064 nm. A 5-mm-diameter laser beam and power of 5 W for 15 s was used, based on previous experiments. MC output was converted into absorbed energy, serving as input for ANSYS finite element heat transfer simulations of tissue temperatures over time. Convective heat transfer was simulated with contact cooling probe set at 0 °C. Thermal properties (κ,c,ρ) were assigned to each tissue layer. MATLAB code was used for Arrhenius integral thermal damage calculations. A temperature matrix was constructed from ANSYS output, and finite sum was incorporated to approximate Arrhenius integral calculations. Tissue damage properties (Ea,A) were used to compute Arrhenius sums. For the transvaginal approach, 37% of energy was absorbed in endopelvic fascia layer with 0.8% deposited beyond it. Peak temperature was 71°C, treatment zone was 0.8-mm-diameter, and almost all of 2.7-mm-thick vaginal wall was preserved. For transurethral approach, 18% energy was absorbed in endopelvic fascia with 0.3% deposited beyond it. Peak temperature was 80°C, treatment zone was 2.0-mm-diameter, and only 0.6 mm of 2.4-mm-thick urethral wall was preserved. A transvaginal approach is more feasible than transurethral approach for laser treatment of SUI.

  3. Gastroprotective effect of 2-mercaptoethane sulfonate against acute gastric mucosal damage induced by ethanol.

    PubMed

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2016-05-01

    Gastric mucosal damage induced by ethanol is a serious medical problem. Recent evidences suggest that reactive oxygen species and inflammatory mediators play a key role in the destruction of gastric mucosa. The present study was aimed to evaluate the potential beneficial effect of MESNA (2-mercaptoethane sulfonate) against ethanol-induced gastric mucosal damage in mice. The animals were orally pretreated with vehicle or MESNA and then treated with acidified ethanol to induce gastric mucosal damage. One hour after ethanol ingestion mice were euthanized and stomach samples were collected for biochemical analysis. Macroscopic and histopathological evaluation of gastric mucosa showed that pretreatment with MESNA attenuated gastric lesions induced by ethanol. Administration of MESNA significantly increased glutathione content and superoxide dismutase and catalase activity in the gastric tissues. In addition, MESNA markedly reduced ethanol-induced lipid peroxidation, myeloperoxidase activity, tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, and monocyte chemotactic protein-1 levels. These findings suggest that the thiol-containing compound MESNA is able to decrease alcohol-induced oxidative stress and inflammation in the gastric tissue. It seems that MESNA may have a protective effect against ethanol-induced gastric mucosal damage. PMID:26967742

  4. Direct acute tubular damage contributes to Shigatoxin-mediated kidney failure.

    PubMed

    Porubsky, Stefan; Federico, Giuseppina; Müthing, Johannes; Jennemann, Richard; Gretz, Norbert; Büttner, Stefan; Obermüller, Nicholas; Jung, Oliver; Hauser, Ingeborg A; Gröne, Elisabeth; Geiger, Helmut; Gröne, Hermann-Josef; Betz, Christoph

    2014-09-01

    The pathogenesis and therapy of Shigatoxin 2 (Stx2)-mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2-producing E. coli (STEC), Stx2 exerts direct effects on renal tubular epithelium and thereby possibly contributes to acute renal failure. Mice represent a suitable model because they, like humans, express the Stx2-receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular thrombotic microangiopathy (TMA). In wild-type mice, Stx2 caused acute tubular dysfunction with consequent electrolyte disturbance, which was most likely the cause of death. Tubule-specific depletion of Gb3 protected the mice from acute renal failure. In vitro, Stx2 induced secretion of proinflammatory cytokines and apoptosis in human tubular epithelial cells, thus implicating a direct effect of Stx2 on the tubular epithelium. To correlate these results to human disease, kidney biopsies and outcome were analysed in patients with Stx2-associated kidney failure (n = 11, aged 22-44 years). The majority of kidney biopsies showed different stages of an ongoing TMA; however, no glomerular complement activation could be demonstrated. All biopsies, including those without TMA, showed severe acute tubular damage. Due to these findings, patients were treated with supportive therapy without complement-inhibiting antibodies (eculizumab) or immunoadsorption. Despite the severity of the initial disease [creatinine 6.34 (1.31-17.60) mg/dl, lactate dehydrogenase 1944 (753-2792) U/l, platelets 33 (19-124)/nl and haemoglobin 6.2 (5.2-7.8) g/dl; median (range)], all patients were discharged after 33 (range 19-43) days with no neurological symptoms and no dialysis requirement [creatinine 1.39 (range 0.84-2.86) mg/dl]. The creatinine decreased further to 0.90 (range 0.66-1.27) mg/dl after 24 months. Based on these data, one may surmise that acute tubular damage represents a separate

  5. Regenerative repair of damaged meniscus with autologous adipose tissue-derived stem cells.

    PubMed

    Pak, Jaewoo; Lee, Jung Hun; Lee, Sang Hee

    2014-01-01

    Mesenchymal stem cells (MSCs) are defined as pluripotent cells found in numerous human tissues, including bone marrow and adipose tissue. Such MSCs, isolated from bone marrow and adipose tissue, have been shown to differentiate into bone and cartilage, along with other types of tissues. Therefore, MSCs represent a promising new therapy in regenerative medicine. The initial treatment of meniscus tear of the knee is managed conservatively with nonsteroidal anti-inflammatory drugs and physical therapy. When such conservative treatment fails, an arthroscopic resection of the meniscus is necessary. However, the major drawback of the meniscectomy is an early onset of osteoarthritis. Therefore, an effective and noninvasive treatment for patients with continuous knee pain due to damaged meniscus has been sought. Here, we present a review, highlighting the possible regenerative mechanisms of damaged meniscus with MSCs (especially adipose tissue-derived stem cells (ASCs)), along with a case of successful repair of torn meniscus with significant reduction of knee pain by percutaneous injection of autologous ASCs into an adult human knee.

  6. Inhibitory effect of tea polyphenols on local tissue damage induced by snake venoms.

    PubMed

    Pithayanukul, P; Leanpolchareanchai, J; Bavovada, R

    2010-01-01

    The methanolic extract of fresh tea leaves of Camellia sinensis L. (Theaceae) (CS) was assayed for its potential to inhibit enzymes with hydrolytic activity in Naja naja kaouthia Lesson (Elapidae) and Calloselasma rhodostoma Kuhl (Viperidae) venoms. These snake venom enzymes are responsible for the early effects of envenomation, such as local tissue damage and inflammation. The CS extract inhibited phospholipase A(2), proteases, hyaluronidase and L-amino acid oxidase in both venoms by in vitro neutralization and inhibited the hemorrhagic and the dermonecrotic activities of the venoms in vivo. It is suggested that the inhibitory potential of the CS extract against local tissue damage induced by snake venoms may be attributed to complexation and chelation between the venom proteins and the phenolic contents of the extract.

  7. Matrix metalloproteinase and tissue inhibitor of metalloproteinase responses to muscle damage after eccentric exercise

    PubMed Central

    Kim, Jooyoung; Lee, Joohyung

    2016-01-01

    High-intensity eccentric exercise is known to induce muscle damage leading to inflammatory responses and extracellular matrix (ECM) degradation. These degradation processes involve enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). MMPs are calcium and zinc-dependent proteolytic enzymes that play a role in ECM degradation and recruitment of inflammatory and myogenic cells into the damaged site. In contrast, TIMPs inhibit MMP-induced ECM degradation to maintain normal homeostasis in ECM. Recently, several studies have examined the process of muscle remodeling and the roles of ECM, MMPs, and TIMPs in exercise-induced muscle damage. However, the results of these studies are not inconsistent. In the present mini-review, we will discuss the responses of MMP and TIMP to eccentric exercise based on the literature review. PMID:27656621

  8. Matrix metalloproteinase and tissue inhibitor of metalloproteinase responses to muscle damage after eccentric exercise

    PubMed Central

    Kim, Jooyoung; Lee, Joohyung

    2016-01-01

    High-intensity eccentric exercise is known to induce muscle damage leading to inflammatory responses and extracellular matrix (ECM) degradation. These degradation processes involve enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). MMPs are calcium and zinc-dependent proteolytic enzymes that play a role in ECM degradation and recruitment of inflammatory and myogenic cells into the damaged site. In contrast, TIMPs inhibit MMP-induced ECM degradation to maintain normal homeostasis in ECM. Recently, several studies have examined the process of muscle remodeling and the roles of ECM, MMPs, and TIMPs in exercise-induced muscle damage. However, the results of these studies are not inconsistent. In the present mini-review, we will discuss the responses of MMP and TIMP to eccentric exercise based on the literature review.

  9. Matrix metalloproteinase and tissue inhibitor of metalloproteinase responses to muscle damage after eccentric exercise.

    PubMed

    Kim, Jooyoung; Lee, Joohyung

    2016-08-01

    High-intensity eccentric exercise is known to induce muscle damage leading to inflammatory responses and extracellular matrix (ECM) degradation. These degradation processes involve enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). MMPs are calcium and zinc-dependent proteolytic enzymes that play a role in ECM degradation and recruitment of inflammatory and myogenic cells into the damaged site. In contrast, TIMPs inhibit MMP-induced ECM degradation to maintain normal homeostasis in ECM. Recently, several studies have examined the process of muscle remodeling and the roles of ECM, MMPs, and TIMPs in exercise-induced muscle damage. However, the results of these studies are not inconsistent. In the present mini-review, we will discuss the responses of MMP and TIMP to eccentric exercise based on the literature review. PMID:27656621

  10. Damage to pancreatic acinar cells and preservation of islets of Langerhans in a rat model of acute pancreatitis induced by Karwinskia humboldtiana (buckthorn).

    PubMed

    Carcano-Diaz, Katya; Garcia-Garcia, Aracely; Segoviano-Ramirez, Juan Carlos; Rodriguez-Rocha, Humberto; Loera-Arias, Maria de Jesus; Garcia-Juarez, Jaime

    2016-09-01

    Karwinskia humboldtiana (Kh) is a poisonous plant that grows in some regions of the American continent. Consuming large amounts of Kh fruit results in acute intoxication leading to respiratory failure, culminating in death within days. There is evidence of histological damage to the lungs, liver, and kidneys following accidental and experimental Kh intoxication. To date, the microscopic effect of Kh consumption on the pancreas has not been described. We examined the early effects of Kh fruit on pancreatic tissue at different stages of acute intoxication in the Wistar rat. We found progressive damage confined to the exocrine pancreas, starting with a reduction in the number of zymogen granules, loss of acinar architecture, the presence of autophagy-like vesicles, apoptosis and inflammatory infiltrate. The pancreatic pathology culminated in damaged acini characterized by necrosis and edema, with a complete loss of lobular architecture. Interestingly, the morphology of the islets of Langerhans was conserved throughout our evaluations. Taken together, our results indicate the damage induced by a high dose of Kh fruit in the Wistar rat is consistent with an early acute necrotizing pancreatitis that exclusively affects the exocrine pancreas. Therefore, this system might be useful as an animal model to study the treatment of pancreatic diseases. More importantly, as the islets of Langerhans were preserved, the active compounds of Kh fruit could be utilized for the treatment of acinar pancreatic cancer. Further studies might provide insight into the severity of acute Kh intoxication in humans and influence the design of treatments for pancreatic diseases and acinar pancreatic cancer. PMID:26877198

  11. Innovation in tissue viability documentation for acute services.

    PubMed

    Parnham, A

    2011-09-01

    This paper discusses the developmental process, outcome and delivery of an innovative approach to standardising tissue viability documentation across two sites within Nottingham University Hospitals NHS Trust, following the results of benchmarking pressure ulcer preventive care strategies and recommendations from pressure ulcer root cause analysis. It reflects upon the process, highlighting the lessons learnt.

  12. Limited damage of tissue mimic caused by a collapsing bubble under low-frequency ultrasound exposure.

    PubMed

    Yoshida, Kenji; Obata, Kazuya; Tsukamoto, Akira; Ushida, Takashi; Watanabe, Yoshiaki

    2014-08-01

    In this study, we investigated the bubble induced serious damage to tissue mimic exposed to 27-kHz ultrasound. The initial bubble radius ranged from 80 to 100 μm, which corresponded approximately to the experimentally-evaluated resonant radius of the given ultrasound frequency. The tissue mimic consisted of 10 wt% gelatine gel covered with cultured canine kidney epithelial cells. The collapsing bubble behaviour during the ultrasound exposure with negative peak pressures of several hundred kPa was captured by a high-speed camera system. After ultrasound exposure, a cell viability test was conducted based on microscopic bright-field images and fluorescence images for living and dead cells. In the viability test, cells played a role in indicating the damaged area. The bubble oscillations killed the cells, and on occasion detached layers of cultured cells from the gel. The damaged area was comparable or slightly larger than the initial bubble size, and smaller than the maximum bubble size. We concluded that only a small area in close proximity to the bubble could be damaged even above transient cavitation threshold.

  13. Dystrophic amyloidosis: a local complication of tissue damage with heterogeneous distribution.

    PubMed

    Looi, L M

    1991-08-01

    Seventeen consecutive patients with dystrophic amyloidosis are reported here (eight Chinese, three Indian, three Iban, two Malay and one Caucasian). Ten were females and seven males, with ages ranging from 12 to 80 years (mean of 48 years). Five instances of dystrophic amyloidosis occurred in areas of tissue damage in the cardiovascular system, including fibrotic cardiac valves and an atheromatous plaque. Three occurred in osteoarthritic joint tissue. Of note were three occurrences in endometriotic cyst walls, four in the fibrotic walls of epidermal cysts, one in a hernial sac and one at the edge of a skin ulcer. All deposits were congophilic and exhibited green-birefringence and permanganate-resistance. Immunohistochemistry did not reveal reactivity for AA protein or immunoglobulin lambda or kappa light-chains. AP protein was detected in 35% of cases. Our results show that, besides the usual sites of osteoarthritic joints and damaged heart valves, dystrophic amyloidosis can complicate other areas of chronic tissue damage and fibrosis such as walls of cysts and ulcers. While the pathogenesis and biochemical nature remain unresolved, immunohistochemistry indicates that neither AA nor AL proteins are present in the deposits, and suggests that a different amyloid protein is involved. PMID:1757071

  14. The Cell Nucleus Serves as a Mechanotransducer of Tissue Damage-Induced Inflammation.

    PubMed

    Enyedi, Balázs; Jelcic, Mark; Niethammer, Philipp

    2016-05-19

    Tissue damage activates cytosolic phospholipase A2 (cPLA2), releasing arachidonic acid (AA), which is oxidized to proinflammatory eicosanoids by 5-lipoxygenase (5-LOX) on the nuclear envelope. How tissue damage is sensed to activate cPLA2 is unknown. We investigated this by live imaging in wounded zebrafish larvae, where damage of the fin tissue causes osmotic cell swelling at the wound margin and the generation of a chemotactic eicosanoid signal. Osmotic swelling of cells and their nuclei activates cPla2 by translocating it from the nucleoplasm to the nuclear envelope. Elevated cytosolic Ca(2+) was necessary but not sufficient for cPla2 translocation, and nuclear swelling was required in parallel. cPla2 translocation upon nuclear swelling was reconstituted in isolated nuclei and appears to be a simple physical process mediated by tension in the nuclear envelope. Our data suggest that the nucleus plays a mechanosensory role in inflammation by transducing cell swelling and lysis into proinflammatory eicosanoid signaling.

  15. The Cell Nucleus Serves as a Mechanotransducer of Tissue Damage-Induced Inflammation.

    PubMed

    Enyedi, Balázs; Jelcic, Mark; Niethammer, Philipp

    2016-05-19

    Tissue damage activates cytosolic phospholipase A2 (cPLA2), releasing arachidonic acid (AA), which is oxidized to proinflammatory eicosanoids by 5-lipoxygenase (5-LOX) on the nuclear envelope. How tissue damage is sensed to activate cPLA2 is unknown. We investigated this by live imaging in wounded zebrafish larvae, where damage of the fin tissue causes osmotic cell swelling at the wound margin and the generation of a chemotactic eicosanoid signal. Osmotic swelling of cells and their nuclei activates cPla2 by translocating it from the nucleoplasm to the nuclear envelope. Elevated cytosolic Ca(2+) was necessary but not sufficient for cPla2 translocation, and nuclear swelling was required in parallel. cPla2 translocation upon nuclear swelling was reconstituted in isolated nuclei and appears to be a simple physical process mediated by tension in the nuclear envelope. Our data suggest that the nucleus plays a mechanosensory role in inflammation by transducing cell swelling and lysis into proinflammatory eicosanoid signaling. PMID:27203112

  16. Tissue concentrations of cefepime in acute cholecystitis patients.

    PubMed

    Okamoto, M P; Gill, M A; Nakahiro, R K; Chin, A; Yellin, A E; Berne, T V; Sclar, D A; Knupp, C A; Heseltine, P N; Appleman, M D

    1992-06-01

    Cefepime is a new broad-spectrum cephalosporin with activity against Staphylococcus, Streptococcus, Pseudomonas, and the Enterobacteriaceae. The purpose of this study was to measure cefepime concentrations in plasma, peritoneal fluid, bile fluid and appendix tissue in patients undergoing elective cholecystectomy. Patients were randomly assigned to receive either cefepime, 2 g intravenously in phosphate buffer (IVPB) q 12 h or gentamicin 1.5 mg/kg IVPB q 8 h plus mezlocillin 4 g IVPB q 6 h. During surgery, gall bladder tissue, plasma, peritoneal fluid, and bile fluid samples were obtained at approximately the same time. Thirty-three patients had data acceptable for analysis. Values are given as mean +/- standard deviation. The mean delta time (defined as the time between the administration of cefepime and the time the samples were obtained) was 8.58 +/- 3.53 h. The values for plasma, peritoneal fluid, bile fluid, and gall bladder tissue concentrations were 7.63 +/- 14.17 micrograms/ml, 5.66 +/- 6.80 micrograms/ml, 15.51 +/- 16.94 micrograms/ml, and 5.36 +/- 6.57 micrograms/gm, respectively. The peritoneal fluid/plasma ratio was 2.10 +/- 2.33, the bile fluid/plasma ratio was 14.44 +/- 31.99, and the gall bladder tissue/plasma ratio was 1.44 +/- 1.82. There was a significant correlation between peritoneal fluid and plasma concentration (r = 0.91, p less than 0.0005), and gall bladder tissue and plasma concentration (r = 0.90, p less than 0.0005). There was no correlation between bile fluid and plasma cefepime concentrations. The minimum inhibitory concentration (MIC) data from previous in vitro studies indicate that cefepime concentrations achieved in this patient population would be adequate against typical biliary tract pathogens.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Oxidative damage induced by cigarette smoke exposure in mice: impact on lung tissue and diaphragm muscle*,**

    PubMed Central

    de Carlos, Samanta Portão; Dias, Alexandre Simões; Forgiarini, Luiz Alberto; Patricio, Patrícia Damiani; Graciano, Thaise; Nesi, Renata Tiscoski; Valença, Samuel; Chiappa, Adriana Meira Guntzel; Cipriano, Gerson; de Souza, Claudio Teodoro; Chiappa, Gaspar Rogério da Silva

    2014-01-01

    OBJECTIVE: To evaluate oxidative damage (lipid oxidation, protein oxidation, thiobarbituric acid-reactive substances [TBARS], and carbonylation) and inflammation (expression of phosphorylated AMP-activated protein kinase and mammalian target of rapamycin [p-AMPK and p-mTOR, respectively]) in the lung parenchyma and diaphragm muscles of male C57BL-6 mice exposed to cigarette smoke (CS) for 7, 15, 30, 45, or 60 days. METHODS: Thirty-six male C57BL-6 mice were divided into six groups (n = 6/group): a control group; and five groups exposed to CS for 7, 15, 30, 45, and 60 days, respectively. RESULTS: Compared with control mice, CS-exposed mice presented lower body weights at 30 days. In CS-exposed mice (compared with control mice), the greatest differences (increases) in TBARS levels were observed on day 7 in diaphragm-muscle, compared with day 45 in lung tissue; the greatest differences (increases) in carbonyl levels were observed on day 7 in both tissue types; and sulfhydryl levels were lower, in both tissue types, at all time points. In lung tissue and diaphragm muscle, p-AMPK expression exhibited behavior similar to that of TBARS. Expression of p-mTOR was higher than the control value on days 7 and 15 in lung tissue, as it was on day 45 in diaphragm muscle. CONCLUSION: Our data demonstrate that CS exposure produces oxidative damage, not only in lung tissue but also (primarily) in muscle tissue, having an additional effect on respiratory muscle, as is frequently observed in smokers with COPD. PMID:25210964

  18. Neuroprotection by gonadal steroid hormones in acute brain damage requires cooperation with astroglia and microglia.

    PubMed

    Johann, Sonja; Beyer, Cordian

    2013-09-01

    The neuroactive steroids 17β-estradiol and progesterone control a broad spectrum of neural functions. Besides their roles in the regulation of classical neuroendocrine loops, they strongly influence motor and cognitive systems, behavior, and modulate brain performance at almost every level. Such a statement is underpinned by the widespread and lifelong expression pattern of all types of classical and non-classical estrogen and progesterone receptors in the CNS. The life-sustaining power of neurosteroids for tattered or seriously damaged neurons aroused interest in the scientific community in the past years to study their ability for therapeutic use under neuropathological challenges. Documented by excellent studies either performed in vitro or in adequate animal models mimicking acute toxic or chronic neurodegenerative brain disorders, both hormones revealed a high potency to protect neurons from damage and saved neural systems from collapse. Unfortunately, neurons, astroglia, microglia, and oligodendrocytes are comparably target cells for both steroid hormones. This hampers the precise assignment and understanding of neuroprotective cellular mechanisms activated by both steroids. In this article, we strive for a better comprehension of the mutual reaction between these steroid hormones and the two major glial cell types involved in the maintenance of brain homeostasis, astroglia and microglia, during acute traumatic brain injuries such as stroke and hypoxia. In particular, we attempt to summarize steroid-activated cellular signaling pathways and molecular responses in these cells and their contribution to dampening neuroinflammation and neural destruction. This article is part of a Special Issue entitled 'CSR 2013'. PMID:23196064

  19. High and Low LET Radiation Differentially Induce Normal Tissue Damage Signals

    SciTech Connect

    Niemantsverdriet, Maarten; Goethem, Marc-Jan van; Bron, Reinier; Hogewerf, Wytse; Brandenburg, Sytze; Langendijk, Johannes A.; Luijk, Peter van; Coppes, Robert P.

    2012-07-15

    Purpose: Radiotherapy using high linear energy transfer (LET) radiation is aimed at efficiently killing tumor cells while minimizing dose (biological effective) to normal tissues to prevent toxicity. It is well established that high LET radiation results in lower cell survival per absorbed dose than low LET radiation. However, whether various mechanisms involved in the development of normal tissue damage may be regulated differentially is not known. Therefore the aim of this study was to investigate whether two actions related to normal tissue toxicity, p53-induced apoptosis and expression of the profibrotic gene PAI-1 (plasminogen activator inhibitor 1), are differentially induced by high and low LET radiation. Methods and Materials: Cells were irradiated with high LET carbon ions or low LET photons. Cell survival assays were performed, profibrotic PAI-1 expression was monitored by quantitative polymerase chain reaction, and apoptosis was assayed by annexin V staining. Activation of p53 by phosphorylation at serine 315 and serine 37 was monitored by Western blotting. Transfections of plasmids expressing p53 mutated at serines 315 and 37 were used to test the requirement of these residues for apoptosis and expression of PAI-1. Results: As expected, cell survival was lower and induction of apoptosis was higher in high -LET irradiated cells. Interestingly, induction of the profibrotic PAI-1 gene was similar with high and low LET radiation. In agreement with this finding, phosphorylation of p53 at serine 315 involved in PAI-1 expression was similar with high and low LET radiation, whereas phosphorylation of p53 at serine 37, involved in apoptosis induction, was much higher after high LET irradiation. Conclusions: Our results indicate that diverse mechanisms involved in the development of normal tissue damage may be differentially affected by high and low LET radiation. This may have consequences for the development and manifestation of normal tissue damage.

  20. C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

    PubMed Central

    Muthana, Munitta; Hawtree, Sarah; Wilshaw, Adam; Linehan, Eimear; Roberts, Hannah; Khetan, Sachin; Adeleke, Gbadebo; Wright, Fiona; Akil, Mohammed; Fearon, Ursula; Veale, Douglas; Ciani, Barbara; Wilson, Anthony G.

    2015-01-01

    The variant rs26232, in the first intron of the chromosome 5 open reading frame 30 (C5orf30) locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation, implying a central function in these organisms. Here, we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro, and gene profiling following C5orf30 inhibition confirmed up-regulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a previously unidentified negative regulator of tissue damage in RA, and this protein may act by modulating the autoaggressive phenotype that is characteristic of RASFs. PMID:26316022

  1. Thermal damage of tissue during near-infrared laser irradiation with assistance of light-absorbing dye

    NASA Astrophysics Data System (ADS)

    Gnyawali, Surya C.; Le, Kelvin; Le, Henry; Wicksted, James P.; Bartels, Kenneth E.; Liu, Hong; Chen, Yichao; Chen, Wei R.

    2008-02-01

    The selective photothermal-tissue interaction using dye enhancement has been proven to be effective in minimizing the peripheral normal tissue damage during cancer treatment. It is important that the tissue-thermal damage be analyzed and the damage rate process be estimated before the photothermal-immunotherapy for cancer treatment. In this study, we have used the EMT6 mouse tumor model for the laser-tumor treatment with a simultaneous surface temperature measurement using infrared thermography. The images acquired were processed to obtain the temperature profiles. The saturation temperature and corresponding time of irradiation from the temporal profiles were used to calculate the damage parameter using Arrhenius rate process equation. The damage parameters obtained from six mice were compared. Our results of in vivo study show that the damage analyses agree with the previous in vitro study on skins.

  2. Life-threatening acute pneumonitis in mixed connective tissue disease: a case report and literature review.

    PubMed

    Rath, Eva; Zandieh, Shahin; Löckinger, Alexander; Hirschl, Mirko; Klaushofer, Klaus; Zwerina, Jochen

    2015-10-01

    Mixed connective tissue disease (MCTD) is a rare connective tissue disease frequently involving the lungs. The main characteristic is a systemic sclerosis-like picture of slowly progressing interstitial lung disease consistent with lung fibrosis, while pulmonary arterial hypertension is rare. Herein, we present a case of a newly diagnosed MCTD patient developing life-threatening acute pneumonitis similar to lupus pneumonitis. Previous literature on this exceptionally rare complication of MCTD is reviewed and differential diagnosis and management discussed.

  3. Multiscale Model Predicts Tissue-Level Failure From Collagen Fiber-Level Damage

    PubMed Central

    Hadi, Mohammad F.; Sander, Edward A.; Barocas, Victor H.

    2013-01-01

    Excessive tissue-level forces communicated to the microstructure and extracellular matrix of soft tissues can lead to damage and failure through poorly understood physical processes that are multiscale in nature. In this work, we propose a multiscale mechanical model for the failure of collagenous soft tissues that incorporates spatial heterogeneity in the microstructure and links the failure of discrete collagen fibers to the material response of the tissue. The model, which is based on experimental failure data derived from different collagen gel geometries, was able to predict the mechanical response and failure of type I collagen gels, and it demonstrated that a fiber-based rule (at the micrometer scale) for discrete failure can strongly shape the macroscale failure response of the gel (at the millimeter scale). The model may be a useful tool in predicting the macroscale failure conditions for soft tissues and engineered tissue analogs. In addition, the multiscale model provides a framework for the study of failure in complex fiber-based mechanical systems in general. PMID:22938372

  4. Vitamin D3 Reduces Tissue Damage and Oxidative Stress Caused by Exhaustive Exercise.

    PubMed

    Ke, Chun-Yen; Yang, Fwu-Lin; Wu, Wen-Tien; Chung, Chen-Han; Lee, Ru-Ping; Yang, Wan-Ting; Subeq, Yi-Maun; Liao, Kuang-Wen

    2016-01-01

    Exhaustive exercise results in inflammation and oxidative stress, which can damage tissue. Previous studies have shown that vitamin D has both anti-inflammatory and antiperoxidative activity. Therefore, we aimed to test if vitamin D could reduce the damage caused by exhaustive exercise. Rats were randomized to one of four groups: control, vitamin D, exercise, and vitamin D+exercise. Exercised rats received an intravenous injection of vitamin D (1 ng/mL) or normal saline after exhaustive exercise. Blood pressure, heart rate, and blood samples were collected for biochemical testing. Histological examination and immunohistochemical (IHC) analyses were performed on lungs and kidneys after the animals were sacrificed. In comparison to the exercise group, blood markers of skeletal muscle damage, creatine kinase and lactate dehydrogenase, were significantly (P < 0.05) lower in the vitamin D+exercise group. The exercise group also had more severe tissue injury scores in the lungs (average of 2.4 ± 0.71) and kidneys (average of 3.3 ± 0.6) than the vitamin D-treated exercise group did (1.08 ± 0.57 and 1.16 ± 0.55). IHC staining showed that vitamin D reduced the oxidative product 4-Hydroxynonenal in exercised animals from 20.6% to 13.8% in the lungs and from 29.4% to 16.7% in the kidneys. In summary, postexercise intravenous injection of vitamin D can reduce the peroxidation induced by exhaustive exercise and ameliorate tissue damage, particularly in the kidneys and lungs. PMID:26941574

  5. Vitamin D3 Reduces Tissue Damage and Oxidative Stress Caused by Exhaustive Exercise

    PubMed Central

    Ke, Chun-Yen; Yang, Fwu-Lin; Wu, Wen-Tien; Chung, Chen-Han; Lee, Ru-Ping; Yang, Wan-Ting; Subeq, Yi-Maun; Liao, Kuang-Wen

    2016-01-01

    Exhaustive exercise results in inflammation and oxidative stress, which can damage tissue. Previous studies have shown that vitamin D has both anti-inflammatory and antiperoxidative activity. Therefore, we aimed to test if vitamin D could reduce the damage caused by exhaustive exercise. Rats were randomized to one of four groups: control, vitamin D, exercise, and vitamin D+exercise. Exercised rats received an intravenous injection of vitamin D (1 ng/mL) or normal saline after exhaustive exercise. Blood pressure, heart rate, and blood samples were collected for biochemical testing. Histological examination and immunohistochemical (IHC) analyses were performed on lungs and kidneys after the animals were sacrificed. In comparison to the exercise group, blood markers of skeletal muscle damage, creatine kinase and lactate dehydrogenase, were significantly (P < 0.05) lower in the vitamin D+exercise group. The exercise group also had more severe tissue injury scores in the lungs (average of 2.4 ± 0.71) and kidneys (average of 3.3 ± 0.6) than the vitamin D-treated exercise group did (1.08 ± 0.57 and 1.16 ± 0.55). IHC staining showed that vitamin D reduced the oxidative product 4-Hydroxynonenal in exercised animals from 20.6% to 13.8% in the lungs and from 29.4% to 16.7% in the kidneys. In summary, postexercise intravenous injection of vitamin D can reduce the peroxidation induced by exhaustive exercise and ameliorate tissue damage, particularly in the kidneys and lungs. PMID:26941574

  6. Extract of grapefruit-seed reduces acute pancreatitis induced by ischemia/reperfusion in rats: possible implication of tissue antioxidants.

    PubMed

    Dembinski, A; Warzecha, Z; Konturek, S J; Ceranowicz, P; Dembinski, M; Pawlik, W W; Kusnierz-Cabala, B; Naskalski, J W

    2004-12-01

    Grapefruit seed extract (GSE) has been shown to exert antibacterial, antifungal and antioxidant activity possibly due to the presence of naringenin, the flavonoid with cytoprotective action on the gastric mucosa. No study so far has been undertaken to determine whether this GSE is also capable of preventing acute pancreatic damage induced by ischemia/reperfusion (I/R), which is known to result from reduction of anti-oxidative capability of pancreatic tissue, and whether its possible preventive effect involves an antioxidative action of this biocomponent. In this study carried out on rats with acute hemorrhagic pancreatitis induced by 30 min partial pancreatic ischemia followed by 6 h of reperfusion, the GSE or vehicle (vegetable glycerin) was applied intragastrically in gradually increasing amounts (50-500 microl) 30 min before I/R. Pretreatment with GSE decreased the extent of pancreatitis with maximal protective effect of GSE at the dose 250 microl. GSE reduced the pancreatitis-evoked increase in serum lipase and poly-C specific ribonuclease activity, and attenuated the marked fall in pancreatic blood flow and pancreatic DNA synthesis. GSE administered alone increased significantly pancreatic tissue content of lipid peroxidation products, malondialdehyde and 4-hydroxyalkens, and when administered before I/R, GSE reduced the pancreatitis-induced lipid peroxidation. We conclude that GSE exerts protective activity against I/R-induced pancreatitis probably due to the activation of antioxidative mechanisms in the pancreas and the improvement of pancreatic blood flow.

  7. TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE AFTER ACUTE ORAL ADMINISTRATION

    EPA Science Inventory

    TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE
    AFTER ACUTE ORAL ADMINISTRATION

    Michael F. Hughes, Ph.D., Brenda C. Edwards, Carol T. Mitchell and Elaina M. Kenyon, Ph.D. United States Environmental Protection Agency, Office of Research and Development, Nation...

  8. An experimental study on photothermal damage to tissue: the role of irradiance and wavelength

    NASA Astrophysics Data System (ADS)

    Yildiz, F.; Gulsoy, M.; Cilesiz, I.

    2016-09-01

    Laser exposure time and irradiance are crucial parameters governing the process of thermal damage. The goal of our in vitro study was to study and determine optimal parameters for the onset of coagulation and carbonization at three different wavelengths (980, 1070 and 1940 nm). We also compared photothermal effects at these three wavelengths by varying laser exposure time and irradiance. Fresh bovine liver specimens were used for experimentation. The onset of thermal damage at different irradiances and for different exposure time was studied macroscopically and histologically. Photothermal damage or lesion volume generally decreased with irradiance and increasing exposure time. We observed an exponential and linear relationship between irradiance and exposure time for specific thermal endpoints. These specific endpoints were the onset of (i) coagulation, and (ii) carbonization. The time interval or difference between these specific endpoints termed as Δt (t carbonization  -  t coagulation) (s) was also determined. This relation between irradiance and exposure time will make possible the pre-estimation of thermal tissue lesion volume before operation, and photothermal therapy may thus be performed with minimum side effects on liver tissue.

  9. Ion-induced electron production in tissue-like media and DNA damage mechanisms

    NASA Astrophysics Data System (ADS)

    Surdutovich, E.; Obolensky, O. I.; Scifoni, E.; Pshenichnov, I.; Mishustin, I.; Solov'yov, A. V.; Greiner, W.

    2009-01-01

    This work is the first stage in the development of an inclusive approach to calculation of the DNA damage caused by irradiation of biological tissue by ion/proton beams. The project starts with an analysis of ionization caused by the projectiles and the characteristics of secondary electrons produced in tissue-like media. We consider interactions with the medium on a microscopic level and this allows us to obtain the energy spectrum and abundance of secondary electrons as functions of the projectile’s kinetic energy. The physical information obtained in this analysis is related to biological processes responsible for the DNA damage induced by the projectile. In particular, we consider double strand breaks of DNA caused by secondary electrons and free radicals, and local heating in the ion’s track. The heating may enhance the biological effectiveness of electron/free radical nteractions with the DNA and may even be considered as an independent mechanism of DNA damage. Numerical estimates are performed for the case of carbon-ion beams. The obtained dose-depth curves are compared with results of the MCHIT model based on the GEANT4 toolkit.

  10. Gastric Tissue Damage Analysis Generated by Ischemia: Bioimpedance, Confocal Endomicroscopy, and Light Microscopy

    PubMed Central

    Beltran, Nohra E.; Garcia, Laura E.; Garcia-Lorenzana, Mario

    2013-01-01

    The gastric mucosa ischemic tissular damage plays an important role in critical care patients' outcome, because it is the first damaged tissue by compensatory mechanism during shock. The aim of the study is to relate bioimpedance changes with tissular damage level generated by ischemia by means of confocal endomicroscopy and light microscopy. Bioimpedance of the gastric mucosa and confocal images were obtained from Wistar male rats during basal and ischemia conditions. They were anesthetized, and stain was applied (fluorescein and/or acriflavine). The impedance spectroscopy catheter was inserted and then confocal endomicroscopy probe. After basal measurements and biopsy, hepatic and gastric arteries clamping induced ischemia. Finally, pyloric antrum tissue was preserved in buffered formaldehyde (10%) for histology processing using light microscopy. Confocal images were equalized, binarized, and boundary defined, and infiltrations were quantified. Impedance and infiltrations increased with ischemia showing significant changes between basal and ischemia conditions (P < 0.01). Light microscopy analysis allows detection of general alterations in cellular and tissular integrity, confirming gastric reactance and confocal images quantification increments obtained during ischemia. PMID:23841094

  11. An experimental study on photothermal damage to tissue: the role of irradiance and wavelength

    NASA Astrophysics Data System (ADS)

    Yildiz, F.; Gulsoy, M.; Cilesiz, I.

    2016-09-01

    Laser exposure time and irradiance are crucial parameters governing the process of thermal damage. The goal of our in vitro study was to study and determine optimal parameters for the onset of coagulation and carbonization at three different wavelengths (980, 1070 and 1940 nm). We also compared photothermal effects at these three wavelengths by varying laser exposure time and irradiance. Fresh bovine liver specimens were used for experimentation. The onset of thermal damage at different irradiances and for different exposure time was studied macroscopically and histologically. Photothermal damage or lesion volume generally decreased with irradiance and increasing exposure time. We observed an exponential and linear relationship between irradiance and exposure time for specific thermal endpoints. These specific endpoints were the onset of (i) coagulation, and (ii) carbonization. The time interval or difference between these specific endpoints termed as Δt (t carbonization  ‑  t coagulation) (s) was also determined. This relation between irradiance and exposure time will make possible the pre-estimation of thermal tissue lesion volume before operation, and photothermal therapy may thus be performed with minimum side effects on liver tissue.

  12. Low Doses of Oxygen Ion Irradiation Cause Acute Damage to Hematopoietic Cells in Mice.

    PubMed

    Chang, Jianhui; Luo, Yi; Wang, Yingying; Pathak, Rupak; Sridharan, Vijayalakshmi; Jones, Tamako; Mao, Xiao Wen; Nelson, Gregory; Boerma, Marjan; Hauer-Jensen, Martin; Zhou, Daohong; Shao, Lijian

    2016-01-01

    One of the major health risks to astronauts is radiation on long-duration space missions. Space radiation from sun and galactic cosmic rays consists primarily of 85% protons, 14% helium nuclei and 1% high-energy high-charge (HZE) particles, such as oxygen (16O), carbon, silicon, and iron ions. HZE particles exhibit dense linear tracks of ionization associated with clustered DNA damage and often high relative biological effectiveness (RBE). Therefore, new knowledge of risks from HZE particle exposures must be obtained. In the present study, we investigated the acute effects of low doses of 16O irradiation on the hematopoietic system. Specifically, we exposed C57BL/6J mice to 0.1, 0.25 and 1.0 Gy whole body 16O (600 MeV/n) irradiation and examined the effects on peripheral blood (PB) cells, and bone marrow (BM) hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) at two weeks after the exposure. The results showed that the numbers of white blood cells, lymphocytes, monocytes, neutrophils and platelets were significantly decreased in PB after exposure to 1.0 Gy, but not to 0.1 or 0.25 Gy. However, both the frequency and number of HPCs and HSCs were reduced in a radiation dose-dependent manner in comparison to un-irradiated controls. Furthermore, HPCs and HSCs from irradiated mice exhibited a significant reduction in clonogenic function determined by the colony-forming and cobblestone area-forming cell assays. These acute adverse effects of 16O irradiation on HSCs coincided with an increased production of reactive oxygen species (ROS), enhanced cell cycle entry of quiescent HSCs, and increased DNA damage. However, none of the 16O exposures induced apoptosis in HSCs. These data suggest that exposure to low doses of 16O irradiation induces acute BM injury in a dose-dependent manner primarily via increasing ROS production, cell cycling, and DNA damage in HSCs. This finding may aid in developing novel strategies in the protection of the hematopoietic

  13. Low Doses of Oxygen Ion Irradiation Cause Acute Damage to Hematopoietic Cells in Mice

    PubMed Central

    Wang, Yingying; Pathak, Rupak; Sridharan, Vijayalakshmi; Jones, Tamako; Mao, Xiao Wen; Nelson, Gregory; Boerma, Marjan; Hauer-Jensen, Martin; Zhou, Daohong; Shao, Lijian

    2016-01-01

    One of the major health risks to astronauts is radiation on long-duration space missions. Space radiation from sun and galactic cosmic rays consists primarily of 85% protons, 14% helium nuclei and 1% high-energy high-charge (HZE) particles, such as oxygen (16O), carbon, silicon, and iron ions. HZE particles exhibit dense linear tracks of ionization associated with clustered DNA damage and often high relative biological effectiveness (RBE). Therefore, new knowledge of risks from HZE particle exposures must be obtained. In the present study, we investigated the acute effects of low doses of 16O irradiation on the hematopoietic system. Specifically, we exposed C57BL/6J mice to 0.1, 0.25 and 1.0 Gy whole body 16O (600 MeV/n) irradiation and examined the effects on peripheral blood (PB) cells, and bone marrow (BM) hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) at two weeks after the exposure. The results showed that the numbers of white blood cells, lymphocytes, monocytes, neutrophils and platelets were significantly decreased in PB after exposure to 1.0 Gy, but not to 0.1 or 0.25 Gy. However, both the frequency and number of HPCs and HSCs were reduced in a radiation dose-dependent manner in comparison to un-irradiated controls. Furthermore, HPCs and HSCs from irradiated mice exhibited a significant reduction in clonogenic function determined by the colony-forming and cobblestone area-forming cell assays. These acute adverse effects of 16O irradiation on HSCs coincided with an increased production of reactive oxygen species (ROS), enhanced cell cycle entry of quiescent HSCs, and increased DNA damage. However, none of the 16O exposures induced apoptosis in HSCs. These data suggest that exposure to low doses of 16O irradiation induces acute BM injury in a dose-dependent manner primarily via increasing ROS production, cell cycling, and DNA damage in HSCs. This finding may aid in developing novel strategies in the protection of the hematopoietic

  14. Low Doses of Oxygen Ion Irradiation Cause Acute Damage to Hematopoietic Cells in Mice.

    PubMed

    Chang, Jianhui; Luo, Yi; Wang, Yingying; Pathak, Rupak; Sridharan, Vijayalakshmi; Jones, Tamako; Mao, Xiao Wen; Nelson, Gregory; Boerma, Marjan; Hauer-Jensen, Martin; Zhou, Daohong; Shao, Lijian

    2016-01-01

    One of the major health risks to astronauts is radiation on long-duration space missions. Space radiation from sun and galactic cosmic rays consists primarily of 85% protons, 14% helium nuclei and 1% high-energy high-charge (HZE) particles, such as oxygen (16O), carbon, silicon, and iron ions. HZE particles exhibit dense linear tracks of ionization associated with clustered DNA damage and often high relative biological effectiveness (RBE). Therefore, new knowledge of risks from HZE particle exposures must be obtained. In the present study, we investigated the acute effects of low doses of 16O irradiation on the hematopoietic system. Specifically, we exposed C57BL/6J mice to 0.1, 0.25 and 1.0 Gy whole body 16O (600 MeV/n) irradiation and examined the effects on peripheral blood (PB) cells, and bone marrow (BM) hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) at two weeks after the exposure. The results showed that the numbers of white blood cells, lymphocytes, monocytes, neutrophils and platelets were significantly decreased in PB after exposure to 1.0 Gy, but not to 0.1 or 0.25 Gy. However, both the frequency and number of HPCs and HSCs were reduced in a radiation dose-dependent manner in comparison to un-irradiated controls. Furthermore, HPCs and HSCs from irradiated mice exhibited a significant reduction in clonogenic function determined by the colony-forming and cobblestone area-forming cell assays. These acute adverse effects of 16O irradiation on HSCs coincided with an increased production of reactive oxygen species (ROS), enhanced cell cycle entry of quiescent HSCs, and increased DNA damage. However, none of the 16O exposures induced apoptosis in HSCs. These data suggest that exposure to low doses of 16O irradiation induces acute BM injury in a dose-dependent manner primarily via increasing ROS production, cell cycling, and DNA damage in HSCs. This finding may aid in developing novel strategies in the protection of the hematopoietic

  15. Cavitation-induced damage in soft tissue phantoms by focused ultrasound bursts

    NASA Astrophysics Data System (ADS)

    Movahed, Pooya; Kreider, Wayne; Maxwell, Adam D.; Bailey, Michael R.; Hutchens, Shelby B.; Freund, Jonathan B.

    2015-11-01

    Cavitation in soft tissues, similar to that in purely hydrodynamic configurations, is thought to cause tissue injury in therapeutic ultrasound treatments. Our goal is to generalize bubble dynamics models to represent this phenomenon, which we pursue experimentally with observations in tissue-mimicking polyacrylamide and agarose phantoms and semi-analytic generalization of Rayleigh-Plesset-type bubble dynamics models. The phantoms were imaged with high-speed cameras while subjected to a series of multiple pressure wave bursts, of the kind being considered specifically for burst-wave lithotripsy (BWL). The experimental observations show bubble activation at multiple sites during the initial pulses. After multiple pulses, a further onset of cavitation is observed at some new locations suggesting material failure due to fatigue under cyclic loading. A nonlinear strain-energy with strain hardening is used to represent the elasticity of the surrounding medium. Griffith's fracture criterion is then applied in order to determine the onset of material damage. The damaged material is then represented as a Newtonian fluid. By assuming that such a decrease in the fracture toughness occurs under cyclic loading, the fatigue behavior observed in the experiments can be reproduced by our model. This work was supported by NIH grant NIDDK PO1-DK043881.

  16. DNA damage precedes apoptosis during the regression of the interdigital tissue in vertebrate embryos

    PubMed Central

    Montero, Juan A.; Sanchez-Fernandez, Cristina; Lorda-Diez, Carlos I.; Garcia-Porrero, Juan A.; Hurle, Juan M.

    2016-01-01

    DNA damage independent of caspase activation accompanies programmed cell death in different vertebrate embryonic organs. We analyzed the significance of DNA damage during the regression of the interdigital tissue, which sculpts the digits in the embryonic limb. Interdigit remodeling involves oxidative stress, massive apoptosis and cell senescence. Phosphorylation of H2AX mediated by ATM precedes caspase dependent apoptosis and cell senescence during interdigit regression. The association of γH2AX with other downstream DNA repair factors, including MDC1, Rad50 and 53BP1 suggests a defensive response of cells against DNA damage. The relative distribution of cells γH2AX-only positive, TUNEL-only positive, and cells double positive for both markers is consistent with a sequence of degenerative events starting by damage of the DNA. In support of this interpretation, the relative number of γH2AX-only cells increases after caspase inhibition while the relative number of TUNEL-only cells increases after inhibition of ATM. Furthermore, cultured interdigits survived and maintained intense chondrogenic potential, even at advanced stages of degeneration, discarding a previous commitment to die. Our findings support a new biological paradigm considering embryonic cell death secondary to genotoxic stimuli, challenging the idea that considers physiological cell death a cell suicide regulated by an internal death clock that pre-programmes degeneration. PMID:27752097

  17. Acute O 3 damage on first year coppice sprouts of aspen and maple sprouts in an open-air experiment.

    PubMed

    Darbah, Joseph N T; Jones, Wendy S; Burton, Andrew J; Nagy, John; Kubiske, Mark E

    2011-09-01

    We studied the effect of high ozone (O(3)) concentration (110-490 nmol mol(-1)) on regenerating aspen (Populus tremuloides) and maple (Acer saccharum) trees at an open-air O(3) pollution experiment near Rhinelander WI USA. This study is the first of its kind to examine the effects of acute O(3) exposure on aspen and maple sprouts after the parent trees, which were grown under elevated O(3) and/or CO(2) for 12 years, were harvested. Acute O(3) damage was not uniform within the crowns of aspen suckers; it was most severe in the mature, fully expanded photosynthesizing leaves. Young expanding leaves showed no visible signs of acute O(3) damage contrary to expectations. Stomatal conductance played a primary role in the severity of acute O(3) damage as it directly controlled O(3) uptake. Maple sprouts, which had lower stomatal conductance, smaller stomatal aperture, higher stomatal density and larger leaf surface area, were tolerant of acute O(3) exposure. Moreover, elevated CO(2) did not ameliorate the adverse effects of acute O(3) dose on aspen and maple sprouts, in contrast to its ability to counteract the effects of long-term chronic exposure to lower O(3) levels.

  18. Acute O3 damage on first year coppice sprouts of aspen and maple sprouts in an open-air experiment

    SciTech Connect

    Darbah, J.N.; Nagy, J.; Jones, W. S.; Burton, A. J.; Kubiske, M. E.

    2011-10-01

    We studied the effect of high ozone (O{sub 3}) concentration (110-490 nmol mol{sup -1}) on regenerating aspen (Populus tremuloides) and maple (Acer saccharum) trees at an open-air O{sub 3} pollution experiment near Rhinelander WI USA. This study is the first of its kind to examine the effects of acute O{sub 3} exposure on aspen and maple sprouts after the parent trees, which were grown under elevated O{sub 3} and/or CO{sub 2} for 12 years, were harvested. Acute O{sub 3} damage was not uniform within the crowns of aspen suckers; it was most severe in the mature, fully expanded photosynthesizing leaves. Young expanding leaves showed no visible signs of acute O{sub 3} damage contrary to expectations. Stomatal conductance played a primary role in the severity of acute O{sub 3} damage as it directly controlled O{sub 3} uptake. Maple sprouts, which had lower stomatal conductance, smaller stomatal aperture, higher stomatal density and larger leaf surface area, were tolerant of acute O{sub 3} exposure. Moreover, elevated CO{sub 2} did not ameliorate the adverse effects of acute O{sub 3} dose on aspen and maple sprouts, in contrast to its ability to counteract the effects of long-term chronic exposure to lower O{sub 3} levels.

  19. [Connective tissue growth factor (CTGF): a key factor in the onset and progression of kidney damage].

    PubMed

    Sánchez-López, E; Rodrigues Díez, R; Rodríguez Vita, J; Rayego Mateos, S; Rodrigues Díez, R R; Rodríguez García, E; Lavoz Barria, C; Mezzano, S; Egido, J; Ortiz, A; Ruiz-Ortega, M; Selgas, R

    2009-01-01

    Connective tissue growth factor (CTGF) is increased in several pathologies associated with fibrosis, including multiple renal diseases. CTGF is involved in biological processes such as cell cycle regulation, migration, adhesion and angiogenesis. Its expression is regulated by various factors involved in renal damage, such as transforming growth factor- , Angiotensin II, high concentrations of glucose and cellular stress. CTGF is involved in the initiation and progression of renal damage to be able to induce an inflammatory response and promote fibrosis, identified as a potential therapeutic target in the treatment of kidney diseases. In this paper we review the main actions of CTGF in renal disease, the intracellular action mechanisms and therapeutic strategies for its blocking.

  20. The involvement of immune reactions in cardiac damage during acute myocardial infarction: role of cell-mediated immune response.

    PubMed

    Dimitrijevic, M; Vasiljevic, Z; Vuckovic-Dekic, L; Spasic, S

    1997-06-01

    This study was undertaken with the aim of investigating humoral and cell-mediated immune response in acute myocardial infarction (AMI) as possible mechanisms involved in the infarction enlargement. Twenty three patients with first AMI and 15 healthy volunteers were examined. Of the AMI patients, 14 had extensive infarction (group A), while 9 patients had small infarction (group B). Immunologic analyses were performed at admission, and repeated after 3, 7, 14 and 21 days of the acute event. Following parameters were tested: number of CD3+, CD4+, CD8+ and CD20+ cells; serum IgG, IgA, IgM, C3, C4, immune complex and anticardiac antibody levels; polymorphonuclear cell (PMN) function (chemotaxis, phagocytosis, metabolic activity); leukocyte migration in vitro in the presence of water-soluble homologous heart extract. It was demonstrated that the number of B cells, serum IgG, C3, immune complex and anticardiac antibody levels were elevated from 7th-14th days after AMI. Concerning these parameters, however, no significant differences were obtained between group A and group B of AMI patients. Chemotaxis and metabolic activity of peripheral blood PMN, but not phagocytosis, were enhanced during AMI, again changes of PMN did not correlate with the extension of infarction. In contrast, leukocyte migration inhibition in vitro revealed that only patients with extensive AMI have developed positive reaction during the first 14 days after the onset of the disease, while leukocyte inhibition reaction appeared in patients with nonextensive AMI not earlier than the 21st day after the infarction. These findings demonstrate generation of immune reactivity during AMI and indicate that humoral immune response seems more likely to be an epiphenomenon related to tissue necrosis, while cell-mediated immune reactions could influence the extensiveness of cardiac damage.

  1. Arterial damages in acute elbow dislocations: which diagnostic tests are required?

    PubMed

    Lutter, Christoph; Pfefferkorn, Ronny; Schoeffl, Volker

    2016-07-19

    Blunt vessel injuries of peripheral arteries caused by a direct trauma are rare. Studies have described the frequency of arterial ruptures following closed elbow dislocations in 0.3-1.7% of all cases. However, arterial damage does not always necessarily appear as a complete rupture of the vessel with a loss of peripheral circulation and ischaemic symptoms; a relatively strong periarticular system of collaterals can maintain circulation. Furthermore, the traumatic dislocation can also cause intimal tears, arterial dissections and aneurysms or thrombosis. In all cases of vessel injury, including total disruption, a peripheral pulse might still be palpable. 3 weeks after an acute elbow dislocation, we have diagnosed a patient with a long-segment stenosis of the brachial artery and a thrombosis of the radial artery. Therefore, the close anatomic proximity to the neurovascular structures should always be considered in cases of elbow dislocations, even if peripheral pulses are traceable.

  2. SU-E-T-168: Evaluation of Normal Tissue Damage in Head and Neck Cancer Treatments

    SciTech Connect

    Ai, H; Zhang, H

    2014-06-01

    Purpose: To evaluate normal tissue toxicity in patients with head and neck cancer by calculating average survival fraction (SF) and equivalent uniform dose (EUD) for normal tissue cells. Methods: 20 patients with head and neck cancer were included in this study. IMRT plans were generated using EclipseTM treatment planning system by dosimetrist following clinical radiotherapy treatment guidelines. The average SF for three different normal tissue cells of each concerned structure can be calculated from dose spectrum acquired from differential dose volume histogram (DVH) using linear quadratic model. The three types of normal tissues include radiosensitive, moderately radiosensitive and radio-resistant that represents 70%, 50% and 30% survival fractions, respectively, for a 2-Gy open field. Finally, EUDs for three types of normal tissue of each structure were calculated from average SF. Results: The EUDs of the brainstem, spinal cord, parotid glands, brachial plexus and etc were calculated. Our analysis indicated that the brainstem can absorb as much as 14.3% of prescription dose to the tumor if the cell line is radiosensitive. In addition, as much as 16.1% and 18.3% of prescription dose were absorbed by the brainstem for moderately radiosensitive and radio-resistant cells, respectively. For the spinal cord, the EUDs reached up to 27.6%, 35.0% and 42.9% of prescribed dose for the three types of radiosensitivities respectively. Three types of normal cells for parotid glands can get up to 65.6%, 71.2% and 78.4% of prescription dose, respectively. The maximum EUDs of brachial plexsus were calculated as 75.4%, 76.4% and 76.7% of prescription for three types of normal cell lines. Conclusion: The results indicated that EUD can be used to quantify and evaluate the radiation damage to surrounding normal tissues. Large variation of normal tissue EUDs may come from variation of target volumes and radiation beam orientations among the patients.

  3. Effects of Intracoronary Administration of Autologous Adipose Tissue-Derived Stem Cells on Acute Myocardial Infarction in a Porcine Model

    PubMed Central

    Lee, Hye Won; Park, Jong Ha; Kim, Bo Won; Ahn, Jinhee; Kim, Jin Hee; Park, Jin Sup; Oh, Jun-Hyok; Choi, Jung Hyun; Cha, Kwang Soo; Hong, Taek Jong; Park, Tae Sik; Kim, Sang-Pil; Song, Seunghwan; Kim, Ji Yeon; Park, Mi Hwa; Jung, Jin Sup

    2015-01-01

    Purpose Adipose-derived stem cells (ADSCs) are known to be potentially effective in regeneration of damaged tissue. We aimed to assess the effectiveness of intracoronary administration of ADSCs in reducing the infarction area and improving function after acute transmural myocardial infarction (MI) in a porcine model. Materials and Methods ADSCs were obtained from each pig's abdominal subcutaneous fat tissue by simple liposuction. After 3 passages of 14-days culture, 2 million ADSCs were injected into the coronary artery 30 min after acute transmural MI. At baseline and 4 weeks after the ADSC injection, 99mTc methoxyisobutylisonitrile-single photon emission computed tomography (MIBI-SPECT) was performed to evaluate the left ventricular volume, left ventricular ejection fraction (LVEF; %), and perfusion defects as well as the myocardial salvage (%) and salvage index. At 4 weeks, each pig was sacrificed, and the heart was extracted and dissected. Gross and microscopic analyses with specific immunohistochemistry staining were then performed. Results Analysis showed improvement in the perfusion defect, but not in the LVEF in the ADSC group (n=14), compared with the control group (n=14) (perfusion defect, -13.0±10.0 vs. -2.6±12.0, p=0.019; LVEF, -8.0±15.4 vs. -15.9±14.8, p=0.181). There was a tendency of reducing left ventricular volume in ADSC group. The ADSCs identified by stromal cell-derived factor-1 (SDF-1) staining were well co-localized by von Willebrand factor and Troponin T staining. Conclusion Intracoronary injection of cultured ADSCs improved myocardial perfusion in this porcine acute transmural MI model. PMID:26446632

  4. Genotoxic Evaluation of Mikania laevigata Extract on DNA Damage Caused by Acute Coal Dust Exposure

    SciTech Connect

    Freitas, T.P.; Heuser, V.D.; Tavares, P.; Leffa, D.D.; da Silva, G.A.; Citadini-Zanette, V.; Romao, P.R.T.; Pinho, R.A.; Streck, E.L.; Andrade,V.M.

    2009-06-15

    We report data on the possible antigenotoxic activity of Mikania laevigata extract (MLE) after acute intratracheal instillation of coal dust using the comet assay in peripheral blood, bone marrow, and liver cells and the micronucleus test in peripheral blood of Wistar rats. The animals were pretreated for 2 weeks with saline solution (groups 1 and 2) or MLE (100 mg/kg) (groups 3 and 4). On day 15, the animals were anesthetized with ketamine (80 mg/kg) and xylazine (20 mg/kg), and gross mineral coal dust (3 mg/0.3 mL saline) (groups 2 and 4) or saline solution (0.3 mL) (groups 1 and 3) was administered directly in the lung by intratracheal administration. Fifteen days after coal dust or saline instillation, the animals were sacrificed, and the femur, liver, and peripheral blood were removed. The results showed a general increase in the DNA damage values at 8 hours for all treatment groups, probably related to surgical procedures that had stressed the animals. Also, liver cells from rats treated with coal dust, pretreated or not with MLE, showed statistically higher comet assay values compared to the control group at 14 days after exposure. These results could be expected because the liver metabolizes a variety of organic compounds to more polar by-products. On the other hand, the micronucleus assay results did not show significant differences among groups. Therefore, our data do not support the antimutagenic activity of M. laevigata as a modulator of DNA damage after acute coal dust instillation.

  5. Biomechanics and histology of bovine claw suspensory tissue in early acute laminitis.

    PubMed

    Danscher, A M; Toelboell, T H; Wattle, O

    2010-01-01

    Weakening of the suspensory tissue supporting the pedal bone is the central issue in the theory of acute bovine laminitis, but this aspect has never been tested. The objective of this study was to investigate the effect of laminitis on the suspensory tissue. The hypothesis was that clinical and histological signs of acute laminitis are associated with decreased strength of the suspensory tissue of the bovine claw. Nonpregnant dairy heifers (n=10) received oral oligofructose overload (17 g/kg of body weight) and were killed 24 (n=4) and 72h (n=6) after overload. Control heifers (n=6) received tap water and were killed at 72 or 96h. Clinical, orthopedic, and histological examinations were carried out to confirm the occurrence of laminitis. After euthanasia, 2 adjacent tissue samples including the horn wall, lamellar layer, dermis, and pedal bone were cut from the dorso-abaxial aspect of each claw. Tissue samples were kept on ice until mounted on a mechanical testing frame, fixed by horn and bone, and loaded to failure. A stress displacement curve was generated and measurements of physiological support (force needed to displace 1mm beyond first resistance) and maximal support (force needed to break the tissue) were recorded. Heifers treated with oligofructose developed clinical signs consistent with ruminal and systemic acidosis after treatment as well as acute laminitis, characterized by weight shifting (35% of observations vs. 6% in controls), moderate lameness (100 vs. 17%, score of 3 out of 5 at 72h), and reaction to hoof testing (30 and 50% at 48 and 72h, respectively, vs. 0% in controls). Histological examination of claws from heifers killed 72h after overload showed changes consistent with acute laminitis, including stretched lamellae, wider basal cells with low chromatin density, and a thick, wavy, and blurry appearance of the basement membrane. Biomechanical results showed no effect of oligofructose overload on physiological support of the suspensory tissue

  6. Effect of decellularized tissue powders on a rat model of acute myocardial infarction.

    PubMed

    Tabuchi, Masaki; Negishi, Jun; Yamashita, Akitatsu; Higami, Tetsuya; Kishida, Akio; Funamoto, Seiichi

    2015-11-01

    Many research groups are currently investigating new treatment modalities for myocardial infarction. Numerous aspects need to be considered for the clinical application of these therapies, such as low cell integration and engraftment rates of cell injection techniques. Decellularized tissues are considered good materials for promoting regeneration of traumatic tissues. The properties of the decellularized tissues are sustained after processing to powder form. In this study, we examined the use of decellularized tissue powder in a rat model of acute myocardial infarction. The decellularized tissue powders, especially liver powder, promoted cell integration and neovascularization both in vitro and in vivo. Decellularized liver powder induced neovascularization in the infarct area, resulting in the suppression of myocardial necrosis. The results of this study suggest that decellularized liver powder has good potential for application as a blood supply material for the treatment of myocardial infarction.

  7. Acute DNA damage activates the tumour suppressor p53 to promote radiation-induced lymphoma

    PubMed Central

    Lee, Chang-Lung; Castle, Katherine D.; Moding, Everett J.; Blum, Jordan M.; Williams, Nerissa; Luo, Lixia; Ma, Yan; Borst, Luke B.; Kim, Yongbaek; Kirsch, David G.

    2015-01-01

    Genotoxic cancer therapies, such as chemoradiation, cause haematological toxicity primarily by activating the tumour suppressor p53. While inhibiting p53-mediated cell death during cancer therapy ameliorates haematologic toxicity, whether it also impacts carcinogenesis remains unclear. Here we utilize a mouse model of inducible p53 short hairpin RNA (shRNA) to show that temporarily blocking p53 during total-body irradiation (TBI) not only ameliorates acute toxicity, but also improves long-term survival by preventing lymphoma development. Using KrasLA1 mice, we show that TBI promotes the expansion of a rare population of thymocytes that express oncogenic KrasG12D. However, blocking p53 during TBI significantly suppresses the expansion of KrasG12D-expressing thymocytes. Mechanistically, bone marrow transplant experiments demonstrate that TBI activates p53 to decrease the ability of bone marrow cells to suppress lymphoma development through a non-cell-autonomous mechanism. Together, our results demonstrate that the p53 response to acute DNA damage promotes the development of radiation-induced lymphoma. PMID:26399548

  8. Soft tissue impact characterisation kit (STICK) for ex situ investigation of heart rhythm responses to acute mechanical stimulation.

    PubMed

    Cooper, Patricia J; Epstein, Avi; Macleod, Iain A; Schaaf, Sarah T M; Sheldon, Judith; Boulin, Christian; Kohl, Peter

    2006-01-01

    Both mechanical induction and mechanical termination of arrhythmias have been reported in man. Examples include pre-cordial impacts by sports implements (baseballs, pucks) that can trigger arrhythmias, including ventricular fibrillation, or via the so-called pre-cordial thump, used as an emergency resuscitation measure to convert arrhythmias to normal sinus node rhythm. These interventions have been partially reproduced in experimental studies on whole animals. Relating observations at the system's level to underlying mechanisms has been difficult, however, largely because of: (i) a deficit in efficient and affordable pharmacological agents to selectively target (sub-)cellular responses in whole animal studies, and (ii) the lack of suitable experimental models to study the above responses at intermediate levels of functional and structural integration, such as the isolated heart or cardiac tissue. This paper presents a soft tissue impact characterisation kit (STICK), suitable for quantitative investigations into the effects of acute mechanical stimulation on cardiac electro-mechanical function in rodent isolated heart or tissue preparations. The STICK offers independent control over a range of relevant biophysical parameters, such as impact location and energy, pre-impact projectile speed and contact area, as well as over the timing of a mechanical stimulus relative to the cardiac cycle (monitored via electrocardiogram, ECG, here recorded directly from the cardiac surface). Projectile deceleration upon interaction with the tissue is monitored, contact-free, with a resolution of 175 microm, providing information on tissue deformation dynamics, force, pressure and work of the mechanical intervention. In order to study functional effects of cardiac mechanical stimulation in the absence of tissue damage, impacts must be limited (for juvenile Guinea pig heart) to 2-2.5 mJ in the slack left ventricle (diastolic impact) and 5-10 mJ in contracture (systolic impact), as

  9. Ca2+ toxicity and mitochondrial damage in acute pancreatitis: translational overview

    PubMed Central

    Maléth, József; Hegyi, Péter

    2016-01-01

    Acute pancreatitis (AP) is a leading cause of hospitalization among non-malignant gastrointestinal disorders. The mortality of severe AP can reach 30–50%, which is most probably owing to the lack of specific treatment. Therefore, AP is a major healthcare problem, which urges researchers to identify novel drug targets. Studies from the last decades highlighted that the toxic cellular Ca2+ overload and mitochondrial damage are key pathogenic steps in the disease development affecting both acinar and ductal cell functions. Moreover, recent observations showed that modifying the cellular Ca2+ signalling might be beneficial in AP. The inhibition of Ca2+ release from the endoplasmic reticulum or the activity of plasma membrane Ca2+ influx channels decreased the severity of AP in experimental models. Similarly, inhibition of mitochondrial permeability transition pore (MPTP) opening also seems to improve the outcome of AP in in vivo animal models. At the moment MPTP blockers are under detailed clinical investigation to test whether interventions in MPTP openings and/or Ca2+ homeostasis of the cells can be specific targets in prevention or treatment of cell damage in AP. This article is part of the themed issue ‘Evolution brings Ca2+ and ATP together to control life and death’. PMID:27377719

  10. Acute skin sun damage in children and its consequences in adults.

    PubMed

    Pustisek, Nives; Sikanić-Dugić, Nives; Hirsl-Hećej, Vlasta; Domljan, Mislav Luka

    2010-04-01

    Children spend more time outdoors than adults and there is compelling evidence that childhood is a particularly vulnerable time for the photocarcinogenic effects of the sun. The negative effects of solar radiation are accumulated during the entire lifetime; however 80% of total lifetime sun exposure is taking place before the age of 18 years. Child skin is more sensitive than adult skin because natural defense mechanisms are not fully developed. A short exposure to midday sun will result in sunburns. Epidemiologic studies show a higher incidence of malignant melanoma in persons with a history of sunburns during childhood and adolescence. Sun exposure among infants and pre-school children is largely dependent on the discretion of adult care providers. Sun protective habits of mothers may predict the level of sun exposure in children. It is very important to transfer the knowledge and positive habits of proper sun protection to children. The purpose of sun-safety behavior is not to avoid outdoor activities, but rather to protect the skin from detrimental sun effects. Proper sun protection of children includes protection from excessive sun exposure, sunburns and other forms of skin damage caused by sun, which may lead to the future development of skin cancers. This paper reviews acute skin reactivity to sun in childhood and adolescence that causes damage in skin structure and function and produces undesirable chronic changes in adults.

  11. Disaccharides Protect Antigens from Drying-Induced Damage in Routinely Processed Tissue Sections.

    PubMed

    Boi, Giovanna; Scalia, Carla Rossana; Gendusa, Rossella; Ronchi, Susanna; Cattoretti, Giorgio

    2016-01-01

    Drying of the tissue section, partial or total, during immunostaining negatively affects both the staining of tissue antigens and the ability to remove previously deposited antibody layers, particularly during sequential rounds of de-staining and re-staining for multiple antigens. The cause is a progressive loss of the protein-associated water up to the removal of the non-freezable water, a step which abolishes the immunoavailability of the epitope. In order to describe and prevent these adverse effects, we tested, among other substances, sugars, which are known to protect unicellular organisms from freezing and dehydration, and stabilize drugs and reagents in solid state form in medical devices. Disaccharides (lactose, sucrose) prevented the air drying-induced antigen masking and protected tissue-bound antigens and antibodies from air drying-induced damage. Complete removal of the bound antibody layers by chemical stripping was permitted if lactose was present during air drying. Lactose, sucrose and other disaccharides prevent air drying artifacts, allow homogeneous, consistent staining and the reuse of formalin-fixed, paraffin-embedded tissue sections for repeated immunostaining rounds by guaranteeing constant staining quality in suboptimal hydration conditions.

  12. Using autopsy brain tissue to study alcohol-related brain damage in the genomic age.

    PubMed

    Sutherland, Greg T; Sheedy, Donna; Kril, Jillian J

    2014-01-01

    The New South Wales Tissue Resource Centre at the University of Sydney, Australia, is one of the few human brain banks dedicated to the study of the effects of chronic alcoholism. The bank was affiliated in 1994 as a member of the National Network of Brain Banks and also focuses on schizophrenia and healthy control tissue. Alcohol abuse is a major problem worldwide, manifesting in such conditions as fetal alcohol syndrome, adolescent binge drinking, alcohol dependency, and alcoholic neurodegeneration. The latter is also referred to as alcohol-related brain damage (ARBD). The study of postmortem brain tissue is ideally suited to determining the effects of long-term alcohol abuse, but it also makes an important contribution to understanding pathogenesis across the spectrum of alcohol misuse disorders and potentially other neurodegenerative diseases. Tissue from the bank has contributed to 330 peer-reviewed journal articles including 120 related to alcohol research. Using the results of these articles, this review chronicles advances in alcohol-related brain research since 2003, the so-called genomic age. In particular, it concentrates on transcriptomic approaches to the pathogenesis of ARBD and builds on earlier reviews of structural changes (Harper et al. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:951) and proteomics (Matsumoto et al. Expert Rev Proteomics 2007;4:539).

  13. Disaccharides Protect Antigens from Drying-Induced Damage in Routinely Processed Tissue Sections.

    PubMed

    Boi, Giovanna; Scalia, Carla Rossana; Gendusa, Rossella; Ronchi, Susanna; Cattoretti, Giorgio

    2016-01-01

    Drying of the tissue section, partial or total, during immunostaining negatively affects both the staining of tissue antigens and the ability to remove previously deposited antibody layers, particularly during sequential rounds of de-staining and re-staining for multiple antigens. The cause is a progressive loss of the protein-associated water up to the removal of the non-freezable water, a step which abolishes the immunoavailability of the epitope. In order to describe and prevent these adverse effects, we tested, among other substances, sugars, which are known to protect unicellular organisms from freezing and dehydration, and stabilize drugs and reagents in solid state form in medical devices. Disaccharides (lactose, sucrose) prevented the air drying-induced antigen masking and protected tissue-bound antigens and antibodies from air drying-induced damage. Complete removal of the bound antibody layers by chemical stripping was permitted if lactose was present during air drying. Lactose, sucrose and other disaccharides prevent air drying artifacts, allow homogeneous, consistent staining and the reuse of formalin-fixed, paraffin-embedded tissue sections for repeated immunostaining rounds by guaranteeing constant staining quality in suboptimal hydration conditions. PMID:26487185

  14. Intestinal nutrient uptake measurements and tissue damage: validating the everted sleeves method.

    PubMed

    Starck, J M; Karasov, W H; Afik, D

    2000-01-01

    The reliability of methods for nutrient uptake measurements across the intestinal epithelium relies on the integrity of the mucosal epithelium and the enterocytes. We tested effects of tissue handling during the "everted sleeves method" on the length of intestinal villi, the surface magnification, the circumference of the gut, and the thickness of the muscle layer in sunbirds (Nectarinia osea), chicken (Gallus gallus), and mice (Mus domesticus). The sunbird has thin and delicate intestinal villi that are greatly affected by the everted sleeves method. After eversion and incubation, villi lost 30% of their original length. The severe tissue damage coincides with uptake measurements for glucose that were an order of magnitude lower than in other nectar-feeding (nectarivorous) birds of similar body size. Tissue handling during the everted sleeves method had significant effects on morphometric parameters of chicken and mouse intestines, but on a light-microscopical level, the tissue integrity and the cytology of the enterocytes were not altered. Therefore, we think that the everted sleeves method renders reliable and reproducible measurements of nutrient uptake in those species. We conclude that a histological evaluation is necessary to assess the reliability of the method before it is applied to adults or to the developmental stage of any species.

  15. Transcriptional alterations of ET-1 axis and DNA damage in lung tissue of a rat obesity model.

    PubMed

    Del Ry, Silvia; Cabiati, Manuela; Salvadori, Costanza; Guiducci, Letizia; Caselli, Chiara; Prescimone, Tommaso; Facioni, Maria Sole; Azzarà, Alessia; Chiaramonte, Anna; Mazzoni, Stefano; Bruschi, Fabrizio; Giannessi, Daniela; Scarpato, Roberto

    2015-03-01

    Obesity has been implicated in the development of many cancers. This can lead to genome damage, especially in the form of double-strand break, the presence of which is now easily detected through nuclear phosphorylation of histone H2AX (γ-H2AX) focus assay. Recently, the endothelin (ET) axis has also been shown to have a role in the growth and progression of several tumors, including lung cancer. The aim of this study was to evaluate the ET-1 system transcriptional alterations and γ-H2AX in lung tissue of Zucker rats subdivided into obese (O, n=22) and controls (CO, n=18) rats: under either fasting conditions (CO(fc)-O(fc)) or acute hyperglycemia (CO(AH)-O(AH)). Significantly higher prepro-ET-1 (p=0.05) and ET-converting enzyme (ECE)-2 mRNA expression was observed in O with respect to CO. A significant positive association was observed between prepro-ET-1 and ET-A in the whole rat population (p=0.009) or in the obese group alone (p=0.007). The levels of γ-H2AX in O and in O(AH) rats were significantly higher (p=0.019) than in the corresponding CO and CO(AH) rats (p=0.038). The study shows an inappropriate secretion of ET-1 in O animals with a parallel DNA damage in their lungs, providing novel mechanisms by which ET receptor antagonist may exert organ protection.

  16. Gastroprotective Effects of PMK-S005 against Ethanol-Induced Acute Gastric Damage in Rats

    PubMed Central

    Choi, Yoon Jeong; Kim, Nayoung; Lee, Ju Yup; Nam, Ryoung Hee; Seo, Ji Hyung; Lee, Seonmin; Kim, Hee Jin; Choi, Yoon Jin; Lee, Hye Seung; Lee, Dong Ho

    2016-01-01

    Background/Aims This study aimed to examine the gastroprotective effects of PMK-S005, which is a synthetic S-allyl-l-cysteine (SAC; a sulfur-containing amino acid), against acute ethanol-induced gastric damage in rats. Methods Sprague-Dawley rats were divided into six groups, including a nonethanol group, groups treated with absolute ethanol 1 hour after pretreatment with various doses of PMK-S005 (1, 5, and 10 mg/kg) or rebamipide (50 mg/kg), and an absolute ethanol-only group. Ethanol-induced gross ulcer and mucus levels were measured. Myeloperoxidase, tumor necrosis factor α, interleukin 1β, PGE2, LTB4, cPLA2, COX-1, and COX-2 levels were estimated by enzyme-linked immunosorbent assay or Western blot analysis. Furthermore, the protein expression levels of antioxidant enzymes, including heme oxygenase-1 (HO-1), NAD(P)H:quinine oxidoreductase 1 (NQO-1), GCLC, and GCLM, were assessed. Results PMK-S005 significantly attenuated the ethanol-induced gastric damage; it reduced mucosal inflammatory cytokine production and increased mucus levels. The expression levels of cPLA2, COX-1, and COX-2 were decreased by PMK-S005. PMK-S005 did not affect PGE2 synthesis, but LTB4 production was significantly suppressed. In addition, long-term administration of PMK-S005 significantly increased the expression of HO-1, NQO-1, GCLC, and GCLM. Conclusions These results strongly suggest that PMK-S005 prevents gastric mucosal damage and that these gastroprotective activities are due to anti-inflammatory effects and enhancement of the gastric defense system, including antioxidant enzymes. PMID:26347516

  17. Genetic damage induced by lead chloride in different tissues of fresh water climbing perch Anabas testudineus (Bloch).

    PubMed

    Ahmed, Md Kawser; Parvin, Elora; Arif, Mohammad; Islam, Md Monirul; Akter, Mosammat Salma; Khan, Mohammad Shahneawz

    2011-11-01

    The present investigation was undertaken to study the induction of DNA damage by lead chloride (PbCl(2)) in freshwater climbing perch Anabas testudineus using alkaline single cell gel electrophoresis (comet assay). Based on the LC(50) values of lead chloride of A. testudineus three different concentrations viz., 0.1, 1.0 and 2.0 mg/L were selected to expose fish. The DNA damage was observed in the gill, kidney and liver tissue as the percentage of DNA in comet tails and comet heads in the tissue of the exposed fish. DNA damage at different concentrations showed sensitivity to particular tissue. The liver tissue exhibited significantly (p < 0.01) higher DNA damage, followed by kidney and gill. However, the DNA damage was found to be dose dependent; at 2 mg/L of PbCl(2) the tail and head DNA of liver tissue were 57.84% and 39.49%, in kidney tissue the values were 52.36% and 44.97% whereas in gill tissue the values were 48.86% and 48.96% respectively. The current study explored the utility of the comet assay for in vivo laboratory studies using A. testudineus species for screening the genotoxic potential of lead chloride.

  18. Effects of acute and chronic administration of fenproporex on DNA damage parameters in young and adult rats.

    PubMed

    Gonçalves, Cinara L; Rezin, Gislaine T; Ferreira, Gabriela K; Jeremias, Isabela C; Cardoso, Mariane R; Valvassori, Samira S; Munhoz, Bruna J P; Borges, Gabriela D; Bristot, Bruno N; Leffa, Daniela D; Andrade, Vanessa M; Quevedo, João; Streck, Emilio L

    2013-08-01

    Obesity is a chronic and multifactorial disease, whose prevalence is increasing in many countries. Pharmaceutical strategies for the treatment of obesity include drugs that regulate food intake, thermogenesis, fat absorption, and fat metabolism. Fenproporex is the second most commonly consumed amphetamine-based anorectic worldwide; this drug is rapidly converted in vivo into amphetamine, which is associated with neurotoxicity. In this context, the present study evaluated DNA damage parameters in the peripheral blood of young and adult rats submitted to an acute administration and chronic administration of fenproporex. In the acute administration, both young and adult rats received a single injection of fenproporex (6.25, 12.5 or 25 mg/kg i.p.) or vehicle. In the chronic administration, both young and adult rats received one daily injection of fenproporex (6.25, 12.5, or 25 mg/kg i.p.) or Tween for 14 days. 2 h after the last injection, the rats were killed by decapitation and their peripheral blood removed for evaluation of DNA damage parameters by alkaline comet assay. Our study showed that acute administration of fenproporex in young and adult rats presented higher levels of damage index and frequency in the DNA. However, chronic administration of fenproporex in young and adult rats did not alter the levels of DNA damage in both parameters of comet assay. The present findings showed that acute administration of fenproporex promoted damage in DNA, in both young and adult rats. Our results are consistent with other reports which showed that other amphetamine-derived drugs also caused DNA damage. We suggest that the activation of an efficient DNA repair mechanism may occur after chronic exposition to fenproporex. Our results are consistent with other reports that showed some amphetamine-derived drugs also caused DNA damage. PMID:23636618

  19. Single-pixel hyperspectral imaging for real-time cancer detection: detecting damage in ex vivo porcine tissue samples

    NASA Astrophysics Data System (ADS)

    Peller, Joseph; Farahi, Faramarz; Trammell, Susan R.

    2016-03-01

    We are developing a single-pixel hyperspectral imaging system based on compressive sensing that acquires spatial and spectral information simultaneously. Our spectral imaging system uses autofluorescencent emission from collagen (400 nm) and NAD(P)H (475 nm), as well as, differences in the optical reflectance spectra as diagnostics for differentiating between healthy and diseased tissue. In this study, we demonstrate the ability of our imaging system to discriminate between healthy and damaged porcine epidermal tissue. Healthy porcine epidermal tissue samples (n=11) were imaged ex vivo using our hyperspectral system. The amount of NAD(P)H emission and the reflectance properties were approximately constant across the surface of healthy tissue samples. The tissue samples were then thermally damaged using an 1850 nm thulium fiber laser and re-imaged after laser irradiation. The damaged regions were clearly visible in the hyperspectral images as the thermal damage altered the fluorescent emission of NAD(P)H and changed the scattering properties of the tissue. The extent of the damaged regions was determined based on the hyperspectral images and these estimates were compared to damage extents measured in white light images acquired with a traditional camera. The extent of damage determined via hyperspectral imaging was in good agreement with estimates based on white light imaging indicating that our system is capable of differentiating between healthy and damaged tissue. Possible applications of our single pixel hyperspectral imaging system range from real-time determination of tumor margins during surgery to the use of this technique in the pathology lab to aid with cancer diagnosis and staging.

  20. Exposure to cigarette smoke causes DNA damage in oropharyngeal tissue in dogs.

    PubMed

    Pérez, Natalia; Berrío, Alina; Jaramillo, Jairo Enrique; Urrego, Rodrigo; Arias, María Patricia

    2014-07-15

    More than 40 mutagenic and carcinogenic agents present in cigarette smoke have been identified as causative factors of human cancer, but no relation has been clearly documented in companion animals. In dogs, in addition to smoke inhalation and transdermic absorption, exposure to smoke includes oral ingestion of particles adhered to the animal's fur. This study evaluates the presence and type of histological alterations and DNA integrity in oropharyngeal tissue in dogs exposed and non-exposed to household cigarette smoke by means of histopathology and comet assay studies on biopsy and swab samples. A non-probabilistic convenience sample of 12 dogs were selected and classified in two groups: exposed and non-exposed to cigarette smoke. Non-parametric Kruskal-Wallis test was carried out on biopsy and swab data and a Chi(2) test was performed on the information obtained by histopathology. A significance level was set at P<0.05. Statistically significant differences were found between groups in comet assays carried out on biopsy samples. No differences (P>0.05) were found between groups based on comet assays swab samples and histopathology assessment. In conclusion, exposure to cigarette smoke causes DNA damage in dog oropharyngeal tissue. The use of dogs as sentinels for early DNA damage caused by exposure to environmental genotoxic agents like cigarette smoke is reported for the first time.

  1. Inflammation drives wound hyperpigmentation in zebrafish by recruiting pigment cells to sites of tissue damage.

    PubMed

    Lévesque, Mathieu; Feng, Yi; Jones, Rebecca A; Martin, Paul

    2013-03-01

    In humans, skin is the largest organ and serves as a barrier between our body and the outside world. Skin protects our internal organs from external pathogens and other contaminants, and melanocytes within the skin protect the body from damage by ultraviolet light. These same pigment cells also determine our skin colour and complexion. Skin wounding triggers a repair response that includes a robust recruitment of inflammatory cells, which function to kill invading microbes and clear away cell and matrix debris. Once at the wound site, these innate immune cells release a barrage of cytokines that direct the activities of other cells during the repair process. Tissue damage and repair also frequently lead to alterations in skin pigmentation, in particular to wound hyperpigmentation. In this study, we describe a model of wound hyperpigmentation in the translucent zebrafish larva, where we can live-image the recruitment of melanocytes and their precursors, melanoblasts, to the wound site. We show that these pigment cells are drawn in after the initial recruitment of innate immune cells and that the inflammatory response is essential for wound hyperpigmentation. This new model will allow us to uncover the molecular link between immune and pigment cells during tissue repair and to screen for potential therapeutics to dampen wound hyperpigmentation.

  2. The alterations in the extracellular matrix composition guide the repair of damaged liver tissue.

    PubMed

    Klaas, Mariliis; Kangur, Triin; Viil, Janeli; Mäemets-Allas, Kristina; Minajeva, Ave; Vadi, Krista; Antsov, Mikk; Lapidus, Natalia; Järvekülg, Martin; Jaks, Viljar

    2016-01-01

    While the cellular mechanisms of liver regeneration have been thoroughly studied, the role of extracellular matrix (ECM) in liver regeneration is still poorly understood. We utilized a proteomics-based approach to identify the shifts in ECM composition after CCl4 or DDC treatment and studied their effect on the proliferation of liver cells by combining biophysical and cell culture methods. We identified notable alterations in the ECM structural components (eg collagens I, IV, V, fibronectin, elastin) as well as in non-structural proteins (eg olfactomedin-4, thrombospondin-4, armadillo repeat-containing x-linked protein 2 (Armcx2)). Comparable alterations in ECM composition were seen in damaged human livers. The increase in collagen content and decrease in elastic fibers resulted in rearrangement and increased stiffness of damaged liver ECM. Interestingly, the alterations in ECM components were nonhomogenous and differed between periportal and pericentral areas and thus our experiments demonstrated the differential ability of selected ECM components to regulate the proliferation of hepatocytes and biliary cells. We define for the first time the alterations in the ECM composition of livers recovering from damage and present functional evidence for a coordinated ECM remodelling that ensures an efficient restoration of liver tissue. PMID:27264108

  3. The alterations in the extracellular matrix composition guide the repair of damaged liver tissue

    PubMed Central

    Klaas, Mariliis; Kangur, Triin; Viil, Janeli; Mäemets-Allas, Kristina; Minajeva, Ave; Vadi, Krista; Antsov, Mikk; Lapidus, Natalia; Järvekülg, Martin; Jaks, Viljar

    2016-01-01

    While the cellular mechanisms of liver regeneration have been thoroughly studied, the role of extracellular matrix (ECM) in liver regeneration is still poorly understood. We utilized a proteomics-based approach to identify the shifts in ECM composition after CCl4 or DDC treatment and studied their effect on the proliferation of liver cells by combining biophysical and cell culture methods. We identified notable alterations in the ECM structural components (eg collagens I, IV, V, fibronectin, elastin) as well as in non-structural proteins (eg olfactomedin-4, thrombospondin-4, armadillo repeat-containing x-linked protein 2 (Armcx2)). Comparable alterations in ECM composition were seen in damaged human livers. The increase in collagen content and decrease in elastic fibers resulted in rearrangement and increased stiffness of damaged liver ECM. Interestingly, the alterations in ECM components were nonhomogenous and differed between periportal and pericentral areas and thus our experiments demonstrated the differential ability of selected ECM components to regulate the proliferation of hepatocytes and biliary cells. We define for the first time the alterations in the ECM composition of livers recovering from damage and present functional evidence for a coordinated ECM remodelling that ensures an efficient restoration of liver tissue. PMID:27264108

  4. Damage to apparel layers and underlying tissue due to hand-gun bullets.

    PubMed

    Carr, Debra; Kieser, Jules; Mabbott, Alexander; Mott, Charlotte; Champion, Stephen; Girvan, Elizabeth

    2014-01-01

    Ballistic damage to the clothing of victims of gunshot wounds to the chest can provide useful forensic evidence. Anyone shot in the torso will usually be wearing clothing which will be damaged by the penetrating impact event and can reportedly be the source of some of the debris in the wound. Minimal research has previously been reported regarding the effect of bullets on apparel fabrics and underlying tissue. This paper examines the effect of ammunition (9 mm full metal jacket [FMJ] DM11 A1B2, 8.0 g; and soft point flat nose Remington R357M3, 10.2 g) on clothing layers that cover the torso (T-shirt, T-shirt plus hoodie, T-shirt plus denim jacket) and underlying structures represented by porcine thoracic wall (skin, underlying tissue, ribs). Impacts were recorded using a Phantom V12 high speed camera. Ejected bone debris was collected before wound tracts were dissected and measured; any debris found was recovered for further analysis. Size and mass of bony debris was recorded; fibre debris recovered from the wound and impact damage to fabrics were imaged using scanning electron microscopy (SEM). Remington R357M3 ammunition was characteristically associated with stellate fabric damage; individual fibres were less likely to show mushrooming. In contrast, 9 mm FMJ ammunition resulted in punch-out damage to fabric layers, with mushrooming of individual fibres being more common. Entry wound sizes were similar for both types of ammunition and smaller than the diameter of the bullet that caused them. In this work, the Remington R357M3 ammunition resulted in larger exit wounds due to the bullet construction which mushroomed. That fabric coverings did not affect the amount of bony debris produced is interesting, particularly given there was some evidence that apparel layers affected the size of the wound. Recent work has suggested that denim (representative of jeans) can exacerbate wounding caused by high-velocity bullet impacts to the thigh when the bullet does not

  5. Freezing/Thawing without Cryoprotectant Damages Native but not Decellularized Porcine Renal Tissue.

    PubMed

    Poornejad, Nafiseh; Frost, Timothy S; Scott, Daniel R; Elton, Brinden B; Reynolds, Paul R; Roeder, Beverly L; Cook, Alonzo D

    2015-01-01

    Whole organ decellularization of porcine renal tissue and recellularization with a patient's own cells would potentially overcome immunorejection, which is one of the most significant problems with allogeneic kidney transplantation. However, there are obstacles to achieving this goal, including preservation of the decellularized extracellular matrix (ECM), identifying the proper cell types, and repopulating the ECM before transplantation. Freezing biological tissue is the best option to avoid spoilage; however, it may damage the structure of the tissue or disrupt cellular membranes through ice crystal formation. Cryoprotectants have been used to repress ice formation during freezing, although cell toxicity can still occur. The effect of freezing/thawing on native (n = 10) and decellularized (n = 10) whole porcine kidneys was studied without using cryoprotectants. Results showed that the elastic modulus of native kidneys was reduced by a factor of 22 (P < 0.0001) by freezing/thawing or decellularization, while the elastic modulus for decellularized ECM was essentially unchanged by the freezing/thawing process (p = 0.0636). Arterial pressure, representative of structural integrity, was also reduced by a factor of 52 (P < 0.0001) after freezing/thawing for native kidneys, compared to a factor of 43 (P < 0.0001) for decellularization and a factor of 4 (P < 0.0001) for freezing/thawing decellularized structures. Both freezing/thawing and decellularization reduced stiffness, but the reductions were not additive. Investigation of the microstructure of frozen/thawed native and decellularized renal tissues showed increased porosity due to cell removal and ice crystal formation. Orcein and Sirius staining showed partial damage to elastic and collagen fibers after freezing/thawing. It was concluded that cellular damage and removal was more responsible for reducing stiffness than fibril destruction. Cell viability and growth were demonstrated on decellularized frozen

  6. Freezing/Thawing without Cryoprotectant Damages Native but not Decellularized Porcine Renal Tissue

    PubMed Central

    Poornejad, Nafiseh; Frost, Timothy S; Scott, Daniel R; Elton, Brinden B; Reynolds, Paul R; Roeder, Beverly L; Cook, Alonzo D

    2015-01-01

    abstract Whole organ decellularization of porcine renal tissue and recellularization with a patient's own cells would potentially overcome immunorejection, which is one of the most significant problems with allogeneic kidney transplantation. However, there are obstacles to achieving this goal, including preservation of the decellularized extracellular matrix (ECM), identifying the proper cell types, and repopulating the ECM before transplantation. Freezing biological tissue is the best option to avoid spoilage; however, it may damage the structure of the tissue or disrupt cellular membranes through ice crystal formation. Cryoprotectants have been used to repress ice formation during freezing, although cell toxicity can still occur. The effect of freezing/thawing on native (n = 10) and decellularized (n = 10) whole porcine kidneys was studied without using cryoprotectants. Results showed that the elastic modulus of native kidneys was reduced by a factor of 22 (P < 0.0001) by freezing/thawing or decellularization, while the elastic modulus for decellularized ECM was essentially unchanged by the freezing/thawing process (p = 0.0636). Arterial pressure, representative of structural integrity, was also reduced by a factor of 52 (P < 0.0001) after freezing/thawing for native kidneys, compared to a factor of 43 (P < 0.0001) for decellularization and a factor of 4 (P < 0.0001) for freezing/thawing decellularized structures. Both freezing/thawing and decellularization reduced stiffness, but the reductions were not additive. Investigation of the microstructure of frozen/thawed native and decellularized renal tissues showed increased porosity due to cell removal and ice crystal formation. Orcein and Sirius staining showed partial damage to elastic and collagen fibers after freezing/thawing. It was concluded that cellular damage and removal was more responsible for reducing stiffness than fibril destruction. Cell viability and growth were demonstrated on decellularized frozen

  7. Morphology of tissue damage caused by permanent occlusion of middle cerebral artery in mice.

    PubMed

    Mennel, H D; El-Abhar, H; Schilling, M; Bausch, J; Krieglstein, J

    2000-10-01

    In two series of experimental occlusion of the middle cerebral artery (MCA) in mice, the time course and the evolution of morphological changes were followed. Both series comprised control animals used in experiments for the screening of neuroprotective and therapeutic effects after focal ischemia. In both series the left MCA was permanently occluded and the animals were sacrificed by perfusion fixation at certain time intervals following occlusion. In the first series the follow up was continued until the 30th day after ischemia. In the second, the observation period was extended to two months. The general question was addressed, whether or not such experimental settings can contribute to the understanding of cellular (necrosis vs apoptosis) and tissue (resorption vs scar) reaction. In the two series the technical procedures were only slightly different. Nevertheless, the development of morphological sequelae was at variance. Differences in tissue reaction in both sets revealed features that were rarely observed in previous protocols. In the first series, infarct areas were different in size, often a central part near the meninges was preserved and gave rise to a prominent mesenchymal reaction. In the second series, infarcts had almost constant size and mesenchymal reaction changes were minimal. The end product in both series, however, was a shallow groove much smaller than the primary well-demarcated defect. We conclude that minor technical variations of MCA occlusion in the mouse demonstrate the variability of occlusion sequelae due to collateral irrigation known from human cerebral pathology. On the cellular level, neuronal death is obviously completed during the first 24 hours in the infarct core. Thus, the mechanism of neuronal damage can only be best observed by morphology at the transition between completed territorial necrosis and unchanged tissue: shrunken neuronal perikarya develop into pycnotic nuclei, that may be interpreted as apoptosis. A second area

  8. Tissue underlying the intestinal epithelium elicits proliferation of intestinal stem cells following cytotoxic damage

    PubMed Central

    Seiler, Kristen M; Schenhals, Erica L; von Furstenberg, Richard J; Allena, Bhavya K; Smith, Brian J; Scaria, Denny; Bresler, Michele N; Dekaney, Christopher M; Henning, Susan J

    2015-01-01

    The goals of this study were to document the proliferative response of intestinal stem cells (ISCs) during regeneration after damage from doxorubicin (DXR) and to characterize the signals responsible for ISC activation. To this end, jejuni from DXR-treated mice were harvested for histology, assessment of ISC numbers and proliferation by flow cytometry, crypt culture, and RNA analyses. Histology showed that crypt depth and width were increased 4 days after DXR. At this time point, flow cytometry on tissue collected 1 hour after EdU administration revealed increased numbers of CD24loUEA− ISCs and increased percentage of ISCs cycling. In culture, crypts harvested from DXR-treated mice were equally proliferative as those of control mice. Addition of subepithelial intestinal tissue (SET) collected 4 days after DXR elicited increased budding (1.4 ± 0.3 vs. 5.1 ± 1.0 buds per enteroid). Microarray analysis of SET collected 4 days after DXR revealed 1,030 differentially expressed transcripts. Cross comparison of Gene Ontology terms considered relevant to ISC activation pointed to 10 candidate genes. Of these the epidermal growth factor (EGF) family member amphiregulin and the BMP antagonist chordin-like 2 were chosen for further study. In crypt culture, amphiregulin alone did not elicit significant budding, but amphiregulin in combination with BMP antagonism showed marked synergism (yielding 6.3 ± 0.5 buds per enteroid). These data suggest a critical role for underlying tissue in regulating ISC behavior after damage, and point to synergism between amphiregulin and chordin-like 2 as factors which may account for activation of ISCs in the regenerative phase. PMID:25693894

  9. Prostaglandin E2 and reactive oxygen metabolite damage in the cecum in a pony model of acute colitis

    PubMed Central

    McConnico, Rebecca S.; Argenzio, Robert A.; Roberts, Malcolm C.

    2002-01-01

    The objective of this project was to determine early tissue biochemical events associated with increased colonic secretion during the acute stage of castor-oil-induced colitis by measuring cecal mucosal and submucosal malondialdehyde (MDA) and prostaglandin E2 (PGE2), levels in ponies. Intestinal tissue (inflamed or healthy) samples were obtained from 4 age- and sex-matched Shetland ponies. Biochemical methods were used to determine MDA and PGE2 levels in intestinal tissue samples from inflamed and healthy equine intestine. Inflamed tissue MDA and PGE2 levels increased with time after castor oil challenge and correlated with granulocyte infiltration, as determined by myeloperoxidase levels in a companion study. Elevated intestinal tissue MDA levels suggest that lipid peroxidation could be attributed to reactive oxygen metabolites (ROM) released from stimulated, recruited, and resident granulocytes. Tissue levels of MDA and PGE2 suggest a role for granulocyte-derived mediators of intestinal inflammation in the massive secretory response in cases of acute equine colitis. Tissue MDA and PGE2 levels may be useful laboratory tools to quantify and characterize intestinal secretory inflammatory responses in acute inflammatory conditions in the equine colon. PMID:11858649

  10. [Characteristics of brain tissue damage in kaolin-induced infantile rat hydrocephalus].

    PubMed

    Okuyama, T; Hashi, K; Okada, T; Sasaki, S

    1986-01-01

    Experimental hydrocephalus was induced by an intracisternal injection of 4% or 40% kaolin suspension in 2 days old Wistar rats. They were examined histologically and microangiographically 2 weeks after the injection of kaolin. Hydrocephalic rats were classified into 2 groups, severe hydrocephalic group A and mild hydrocephalic group B. In group A, a marked enlargement of the entire ventricular system with a thinning of the cerebral mantle was observed. On the other hand, the dilatation of the fourth ventricle was more pronounced compared with the other ventricles in group B. In group A, a spongy appearance of brain tissue was observed in the periventricular white matter accompanied with an intracerebral cavity. In these edematous areas, the lack of carbon black perfusion was apparent indicating an occurrence of microcirculatory disturbances. These microcirculatory disturbances and mechanical compression to the cerebral parenchyma may produce defective brain tissue (intracerebral cavity formation). The ependymal cell walls and subependymal glial cell layers were well preserved in spite of the damaged periventricular white matter. In group A, kaolin was present in the fourth ventricle and Sylvian aqueduct. Subependymal gliosis containing macrophages and newly produced blood vessels were observed in the region between the periventricular brain tissue and kaolin granules. These findings indicate that kaolin may produce changes in the ependymal cell and cerebral parenchyma as well as fibrosis and meningitis in the subarachnoid space. PMID:3964487

  11. Metformin Ameliorates Podocyte Damage by Restoring Renal Tissue Podocalyxin Expression in Type 2 Diabetic Rats

    PubMed Central

    Zhai, Limin; Gu, Junfei; Yang, Di; Wang, Wei; Ye, Shandong

    2015-01-01

    Podocalyxin (PCX) is a signature molecule of the glomerular podocyte and of maintaining integrity of filtration function of glomerulus. The aim of this study was to observe the effect of different doses of metformin on renal tissue PCX expression in type 2 diabetic rats and clarify its protection on glomerular podocytes. Type 2 diabetic Sprague-Dawley (SD) rats in which diabetes was induced by high-fat diet/streptozotocin (HFD-STZ) were treated with different doses of metformin (150, 300, and 500 mg/kg per day, resp.) for 8 weeks. Various biochemical parameters, kidney histopathology, and renal tissue PCX expression levels were examined. In type 2 diabetic rats, severe hyperglycemia and hyperlipidemia were developed. Urinary albumin and PCX were markedly increased. Diabetes induced significant alterations in renal glomerular structure. In addition, protein and mRNA expression of renal tissue PCX were highly decreased. However, treatment of rats with different doses of metformin restored all these changes to a varying degree. These results suggested that metformin can ameliorate glomerular podocyte damage in type 2 diabetic rats, which may be partly associated with its role in restoring PCX expression and inhibiting urinary excretion of PCX with dose dependence. PMID:26075281

  12. A mechanistic description of radiation-induced damage to normal tissue and its healing kinetics

    NASA Astrophysics Data System (ADS)

    Hanin, Leonid; Zaider, Marco

    2013-02-01

    We introduce a novel mechanistic model of the yield of tissue damage at the end of radiation treatment and of the subsequent healing kinetics. We find explicit expressions for the total number of functional proliferating cells as well as doomed (functional but non-proliferating) cells as a function of time post treatment. This leads to the possibility of estimating—for any given cohort of patients undergoing radiation therapy—the probability distribution of those kinetic parameters (e.g. proliferation rates) that determine times to injury onset and ensuing resolution. The model is suitable for tissues with simple duplication organization, meaning that functionally competent cells are also responsible for tissue renewal or regeneration following injury. An extension of the model to arbitrary temporal patterns of dose rate is presented. To illustrate the practical utility of the model, as well as its limitations, we apply it to data on the time course of urethral toxicity following fractionated radiation treatment and brachytherapy for prostate cancer.

  13. A novel fluorinated stilbene exerts hepatoprotective properties in CCl(4)-induced acute liver damage.

    PubMed

    Rivera, Horacio; Morales-Ríos, Martha S; Bautista, Wendy; Shibayama, Mineko; Tsutsumi, Víctor; Muriel, Pablo; Pérez-Álvarez, Víctor

    2011-10-01

    There has been a recently increase in the development of novel stilbene-based compounds with in vitro anti-inflamatory properties. For this study, we synthesized and evaluated the anti-inflammatory properties of 2 fluorinated stilbenes on carbon tetrachloride (CCl₄)-induced acute liver damage. To achieve this, CCl₄ (4 g·kg(-1), per os) was administered to male Wistar rats, followed by either 2-fluoro-4'-methoxystilbene (FME) or 2,3-difluoro-4'-methoxystilbene (DFME) (10 mg·kg(-1), per os). We found that although both of the latter compounds prevented cholestatic damage (γ-glutamyl transpeptidase activity), only DFME showed partial but consistent results in the prevention of necrosis, as assessed by both alanine aminotransferase activity and histological analysis. Since inflammatory responses are mediated by cytokines, mainly tumour necrosis factor α (TNF-α), we used the Western blot technique to determine the action of FME and DFME on the expression level of this cytokine. The observed increase in the level of TNF-α caused by CCl₄ administration was only prevented by treatment with DFME, in agreement with our biochemical findings. This result was confirmed by measuring interleukin-6 (IL-6) levels, since the expression of this protein depends on the level of TNF-α. In this case, DFME completely blocked the CCl₄-induced increase of IL-6. Our results suggest that DFME possesses greater anti-inflammatory properties in vivo than FME. DFME constitutes a possible therapeutic agent for liver disease and could serve as a template for structure optimization.

  14. Calcium Imaging of AM Dyes Following Prolonged Incubation in Acute Neuronal Tissue

    PubMed Central

    Morley, John W.; Tapson, Jonathan; Breen, Paul P.; van Schaik, André

    2016-01-01

    Calcium-imaging is a sensitive method for monitoring calcium dynamics during neuronal activity. As intracellular calcium concentration is correlated to physiological and pathophysiological activity of neurons, calcium imaging with fluorescent indicators is one of the most commonly used techniques in neuroscience today. Current methodologies for loading calcium dyes into the tissue require prolonged incubation time (45–150 min), in addition to dissection and recovery time after the slicing procedure. This prolonged incubation curtails experimental time, as tissue is typically maintained for 6–8 hours after slicing. Using a recently introduced recovery chamber that extends the viability of acute brain slices to more than 24 hours, we tested the effectiveness of calcium AM staining following long incubation periods post cell loading and its impact on the functional properties of calcium signals in acute brain slices and wholemount retinae. We show that calcium dyes remain within cells and are fully functional >24 hours after loading. Moreover, the calcium dynamics recorded >24 hrs were similar to the calcium signals recorded in fresh tissue that was incubated for <4 hrs. These results indicate that long exposure of calcium AM dyes to the intracellular cytoplasm did not alter the intracellular calcium concentration, the functional range of the dye or viability of the neurons. This data extends our previous work showing that a custom recovery chamber can extend the viability of neuronal tissue, and reliable data for both electrophysiology and imaging can be obtained >24hrs after dissection. These methods will not only extend experimental time for those using acute neuronal tissue, but also may reduce the number of animals required to complete experimental goals. PMID:27183102

  15. Acute pergolide exposure stiffens engineered valve interstitial cell tissues and reduces contractility in vitro.

    PubMed

    Capulli, Andrew K; MacQueen, Luke A; O'Connor, Blakely B; Dauth, Stephanie; Parker, Kevin Kit

    2016-01-01

    Medications based on ergoline-derived dopamine and serotonin agonists are associated with off-target toxicities that include valvular heart disease (VHD). Reports of drug-induced VHD resulted in the withdrawal of appetite suppressants containing fenfluramine and phentermine from the US market in 1997 and pergolide, a Parkinson's disease medication, in 2007. Recent evidence suggests that serotonin receptor activity affected by these medications modulates cardiac valve interstitial cell activation and subsequent valvular remodeling, which can lead to cardiac valve fibrosis and dysfunction similar to that seen in carcinoid heart disease. Failure to identify these risks prior to market and continued use of similar drugs reaffirm the need to improve preclinical evaluation of drug-induced VHD. Here, we present two complimentary assays to measure stiffness and contractile stresses generated by engineered valvular tissues in vitro. As a case study, we measured the effects of acute (24 h) pergolide exposure to engineered porcine aortic valve interstitial cell (AVIC) tissues. Pergolide exposure led to increased tissue stiffness, but it decreased both basal and active contractile tone stresses generated by AVIC tissues. Pergolide exposure also disrupted AVIC tissue organization (i.e., tissue anisotropy), suggesting that the mechanical properties and contractile functionality of these tissues are governed by their ability to maintain their structure. We expect further use of these assays to identify off-target drug effects that alter the phenotypic balance of AVICs, disrupt their ability to maintain mechanical homeostasis, and lead to VHD. PMID:27174867

  16. Ultra-rapid manufacturing of engineered epicardial substitute to regenerate cardiac tissue following acute ischemic injury.

    PubMed

    Serpooshan, Vahid; Ruiz-Lozano, Pilar

    2014-01-01

    Considering the impaired regenerative capacity of adult mammalian heart tissue, cardiovascular tissue engineering aims to create functional substitutes that can restore the structure and function of the damaged cardiac tissue. The success of cardiac regenerative therapies has been limited mainly due to poor control on the structure and properties of the tissue substitute, lack of vascularization, and immunogenicity. In this study we introduce a new approach to rapidly engineer dense biomimetic scaffolds consisting of type I collagen, to protect the heart against severe ischemic injury. Scaffold biomechanical properties are adjusted to mimic embryonic epicardium which is shown to be optimal to support cardiomyocyte contractile work. Moreover, the designed patch can serve as a delivery device for targeted, controlled release of cells or therapeutic macromolecules into the lesion area.

  17. Effects of copper vapor laser (CVL) on mice skin: histologic evaluation of damage and tissue stimulation

    NASA Astrophysics Data System (ADS)

    Nunes, Syllene; Moreno, E.; Oliveira, H.; Osaka, J.; Salvador, G.; Michalany, N.; Tolosa, E.

    2002-10-01

    This study was to evaluate the effects of the CVL with low energy and short pulse widths. 18 female mice, C57BL/6 (9-11 weeks old) were distributed into four groups. The control group (CG) wasn't exposed to laser beam . Group L1 had 2 laser expositions with 24 hours gap between them (0.5W). Group L2 had 3 expositions (0.5W and 0.25W) and group L3 had 4 expositions (0.25 W). It was used a CVL prototype (5lOnm, 13 Khz, pulse width of 20 ms and spot size of 0.8cm). 7 days after last laser pulse no groups presented actinic keratosis, tumors or collagen changes. CVL had effective action on pilosebaceous units. High energy with few short pulses induced hair follicles proliferation while low energy with many repetitive short pulses showed increased and specific tissue damage besides hair plugging.

  18. Tissue damage and nutritional factors in experimental respiratory tract (Co-)carcinogenesis.

    PubMed

    Reuzel, P G; Feron, V J; Spit, B J; Beems, R B; Kroes, R

    1983-04-01

    Cofactors involved in respiratory tract carcinogenesis were studied in Syrian golden hamsters or in rats using benzo(a)pyrene as the carcinogenic agent. These factors included severe tissue damage induced by electro-coagulation, glass fibers administered by intratracheal instillation, acetaldehyde as irritant vapor, food restriction, and nutrients such as vitamin A and saturated and unsaturated fats. In addition, the effects of a combined exposure to four different major gaseous cigarette smoke components--methyl nitrate, isoprene, methyl chloride and acetaldehyde--and to one solid cigarette smoke component--norharman--were examined in short- and long-term inhalation studies. An interesting finding was the carcinogenicity of acetaldehyde, of which the possible mechanism is briefly discussed. Another conspicuous observation was the substantial increase in number and size of lipid droplets in alveolar fibroblasts of hamsters fed a high vitamin A diet. PMID:6307680

  19. Tissue damage and nutritional factors in experimental respiratory tract (Co-)carcinogenesis.

    PubMed

    Reuzel, P G; Feron, V J; Spit, B J; Beems, R B; Kroes, R

    1983-04-01

    Cofactors involved in respiratory tract carcinogenesis were studied in Syrian golden hamsters or in rats using benzo(a)pyrene as the carcinogenic agent. These factors included severe tissue damage induced by electro-coagulation, glass fibers administered by intratracheal instillation, acetaldehyde as irritant vapor, food restriction, and nutrients such as vitamin A and saturated and unsaturated fats. In addition, the effects of a combined exposure to four different major gaseous cigarette smoke components--methyl nitrate, isoprene, methyl chloride and acetaldehyde--and to one solid cigarette smoke component--norharman--were examined in short- and long-term inhalation studies. An interesting finding was the carcinogenicity of acetaldehyde, of which the possible mechanism is briefly discussed. Another conspicuous observation was the substantial increase in number and size of lipid droplets in alveolar fibroblasts of hamsters fed a high vitamin A diet.

  20. Syzigium cumini seed extracts reduce tissue damage in diabetic rat brain.

    PubMed

    Stanely Mainzen Prince, P; Kamalakkannan, N; Menon, Venugopal P

    2003-02-01

    Syzigium cumini commonly known as Jamun, is widely used in different parts of India for the treatment of diabetes mellitus. Oral administration of an aqueous Jamun seed extract (JSEt) for 6 weeks caused a significant decrease in lipids, thiobarbituric acid reactive substances (TBARS) and an increase in catalase and superoxide dismutase in the brain of alloxan induced diabetic rats. Oral administration of an alcoholic JSEt for 6 weeks brought back all the parameters to near normal. The effect of alcoholic JSEt (100 mg/kg) was better than aqueous JSEt (5 g/kg). The effect of both these extracts was better than glibenclamide (600 microg/kg). Thus, our study shows that S. cumini seed extracts reduce tissue damage in diabetic rat brain. PMID:12648817

  1. Acute and chronic watercress supplementation attenuates exercise-induced peripheral mononuclear cell DNA damage and lipid peroxidation.

    PubMed

    Fogarty, Mark C; Hughes, Ciara M; Burke, George; Brown, John C; Davison, Gareth W

    2013-01-28

    Pharmacological antioxidant vitamins have previously been investigated for a prophylactic effect against exercise-induced oxidative stress. However, large doses are often required and may lead to a state of pro-oxidation and oxidative damage. Watercress contains an array of nutritional compounds such as β-carotene and α-tocopherol which may increase protection against exercise-induced oxidative stress. The present randomised controlled investigation was designed to test the hypothesis that acute (consumption 2 h before exercise) and chronic (8 weeks consumption) watercress supplementation can attenuate exercise-induced oxidative stress. A total of ten apparently healthy male subjects (age 23 (SD 4) years, stature 179 (SD 10) cm and body mass 74 (SD 15) kg) were recruited to complete the 8-week chronic watercress intervention period (and then 8 weeks of control, with no ingestion) of the experiment before crossing over in order to compete the single-dose acute phase (with control, no ingestion). Blood samples were taken at baseline (pre-supplementation), at rest (pre-exercise) and following exercise. Each subject completed an incremental exercise test to volitional exhaustion following chronic and acute watercress supplementation or control. The main findings show an exercise-induced increase in DNA damage and lipid peroxidation over both acute and chronic control supplementation phases (P< 0.05 v. supplementation), while acute and chronic watercress attenuated DNA damage and lipid peroxidation and decreased H₂O₂ accumulation following exhaustive exercise (P< 0.05 v. control). A marked increase in the main lipid-soluble antioxidants (α-tocopherol, γ-tocopherol and xanthophyll) was observed following watercress supplementation (P< 0.05 v. control) in both experimental phases. These findings suggest that short- and long-term watercress ingestion has potential antioxidant effects against exercise-induced DNA damage and lipid peroxidation.

  2. Protective effects of different antioxidants against cadmium induced oxidative damage in rat testis and prostate tissues.

    PubMed

    Jahan, Sarwat; Zahra, Asia; Irum, Umaira; Iftikhar, Natasha; Ullah, Hizb

    2014-08-01

    The present study was performed to determine the effects of different antioxidants on testicular histopathology and oxidative damage induced by cadmium (Cd) in rat testis and prostate. Twenty five rats were equally divided into five groups (n = 5/group). The control group was injected subcutaneously with saline while the Cd alone treated group received a subcutaneous injection of 0.2 mg/kg CdCl(2). Other groups were treated with sulphoraphane (25 µg/rat), vitamin E (75 mg/kg), and Ficus Religiosa plant extract (100 mg/kg) orally along with subcutaneous injections of 0.2 mg/kg CdCl(2) for fifteen days. Oxidative damage in the testicular and prostate tissues were assessed by the estimation of catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and glutathione reductase (GSR) activity. Lipid peroxidation (TBARS), protein estimation, and histomorphology were also assessed. Cadmium exposure caused a significant decrease in antioxidant enzymes like CAT, POD, SOD, GSR, protein concentrations, and a marked increase in TBARS activity in rat testis and prostate. Histological examination of adult male rat testes showed a disruption in the arrangement of seminiferous tubules along with a reduction in the number of germ cells, Leydig cells, tunica albuginea thickness, diameter of seminiferous tubules, and height of germinal epithelium. Co-treatment with vitamin E, sulphoraphane, and Ficus religiosa were found to be effective in reversing Cd induced toxicity, representing potential therapeutic options to protect the reproductive tissues from the detrimental effects of Cd toxicity. PMID:24758558

  3. Gcsf-Chr19 promotes neutrophil migration to damaged tissue through blood vessels in zebrafish.

    PubMed

    Galdames, Jorge A; Zuñiga-Traslaviña, Constanza; Reyes, Ariel E; Feijóo, Carmen G

    2014-07-01

    G-CSF is an essential cytokine that regulates proliferation and differentiation of granulocytes from hematopoietic stem and progenitor cells. In mammals G-CSF has been identified as a key factor that promotes the release of neutrophils from the bone marrow into the blood circulation. In silico analysis indicates that zebrafish has two gcsf genes, gcsf-chr12 in chromosome 12 and gcsf-chr19 in chromosome 19. Gcsf-Chr12 participates in emergency myelopoiesis, but, in contrast to its mammalian orthologue, is not involved in neutrophil migration toward damaged tissue. In turn, the function of Gcsf-Chr19 has not been examined yet. In this study, we analyzed the role of Gcsf-Chr19 in regulating neutrophil migration toward the wound. Our results indicated that during the first h after caudal fin transection, neutrophils migrate from the hematopoietic tissue toward the injury, using the extracellular matrix as a substrate. Later, between 3 and 4 h postdamage, the recruitment mainly occurs through the bloodstream, and only a few neutrophils still use the extracellular matrix to migrate. During this process, the transcriptional levels of gcsf-chr19 are considerably increased, reaching a peak 1 h postdamage. The knockdown of Gcsf-chr19 indicated that the percentage of neutrophils that reach the wound decreased after the first h postinjury, suggesting that the knockdown specifically affects neutrophils that travel to the wound through blood vessels. Together, our data provide novel information about the regulation of neutrophil migration in zebrafish, positioning Gcsf-Chr19 as a key signal during the course of an inflammatory process triggered by severe damage.

  4. Severe tissue damage in Atlantic cod larvae under increasing ocean acidification

    NASA Astrophysics Data System (ADS)

    Frommel, Andrea Y.; Maneja, Rommel; Lowe, David; Malzahn, Arne M.; Geffen, Audrey J.; Folkvord, Arild; Piatkowski, Uwe; Reusch, Thorsten B. H.; Clemmesen, Catriona

    2012-01-01

    Ocean acidification, caused by increasing atmospheric concentrations of CO2 (refs , , ), is one of the most critical anthropogenicthreats to marine life. Changes in seawater carbonate chemistry have the potential to disturb calcification, acid-base regulation, blood circulation and respiration, as well as the nervous system of marine organisms, leading to long-term effects such as reduced growth rates and reproduction. In teleost fishes, early life-history stages are particularly vulnerable as they lack specialized internal pH regulatory mechanisms. So far, impacts of relevant CO2 concentrations on larval fish have been found in behaviour and otolith size, mainly in tropical, non-commercial species. Here we show detrimental effects of ocean acidification on the development of a mass-spawning fish species of high commercial importance. We reared Atlantic cod larvae at three levels of CO2, (1) present day, (2) end of next century and (3) an extreme, coastal upwelling scenario, in a long-term ( months) mesocosm experiment. Exposure to CO2 resulted in severe to lethal tissue damage in many internal organs, with the degree of damage increasing with CO2 concentration. As larval survival is the bottleneck to recruitment, ocean acidification has the potential to act as an additional source of natural mortality, affecting populations of already exploited fish stocks.

  5. γ-Oryzanol protects against acute cadmium-induced oxidative damage in mice testes.

    PubMed

    Spiazzi, Cristiano C; Manfredini, Vanusa; Barcellos da Silva, Fabiana E; Flores, Erico M M; Izaguirry, Aryele P; Vargas, Laura M; Soares, Melina B; Santos, Francielli W

    2013-05-01

    Cadmium is a non-essential heavy metal that is present at low levels mainly in food and water and also in cigar smoke. The present study evaluated the testicular damage caused by acute cadmium exposure and verified the protective role of γ-oryzanol (ORY). Mice were administrated with a single dose of 2.5mg/kg of CdCl2, and then treated with ORY (50mM in canola oil, 5mL/kg). Testes were removed after 24h and tested for lipid peroxidation (TBARS), protein carbonylation, DNA breakage, ascorbic acid, cadmium and non-proteic thiols contents, and for the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST) and δ-aminolevulic acid dehydratase (δ-ALA-D). Cadmium presented a significant alteration in all parameters, except GPx and CAT activities. Therapy reduced in a slight degree cadmium concentration in testes (around 23%). ORY restored SOD and GST activities as well as TBARS production to the control levels. Furthermore, ORY partially recovered δ-ALA-D activity inhibited by cadmium. This study provides the first evidence on the therapeutic properties of ORY in protecting against cadmium-induced testicular toxicity. PMID:23395783

  6. Tissue damage in kidney, adrenal glands and diaphragm following extracorporeal shock wave lithotripsy.

    PubMed

    Gecit, Ilhan; Kavak, Servet; Oguz, Elif Kaval; Pirincci, Necip; Günes, Mustafa; Kara, Mikail; Ceylan, Kadir; Kaba, Mehmet; Tanık, Serhat

    2014-10-01

    This study was designed to investigate whether exposure to short-term extracorporeal shock wave lithotripsy (ESWL) produces histologic changes or induces apoptosis in the kidney, adrenal glands or diaphragm muscle in rats. The effect of shock waves on the kidney of male Wistar rats (n = 12) was investigated in an experimental setting using a special ESWL device. Animals were killed at 72 h after the last ESWL, and the tissues were stained with an in situ Cell Death Detection Kit, Fluorescein. Microscopic examination was performed by fluorescent microscopy. Apoptotic cell deaths in the renal tissue were not observed in the control group under fluorescent microscopy. In the ESWL group, local apoptotic changes were observed in the kidney in the area where the shock wave was focused. The apoptotic cell deaths observed in the adrenal gland of the control group were similar to those observed in the ESWL groups, and apoptosis was occasionally observed around the capsular structure. Apoptotic cell deaths in the diaphragm muscle were infrequently observed in the control group. Apoptosis in the ESWL group was limited to the mesothelial cells. This study demonstrated that serious kidney, adrenal gland and diaphragm muscles damage occurred following ESWL, which necessitated the removal of the organ in the rat model. It is recognized that the ESWL complications related to the kidney, adrenal gland and diaphragm muscles are rare and may be managed conservatively.

  7. Characterization of acute renal allograft rejection by proteomic analysis of renal tissue in rat.

    PubMed

    Chen, Gang; Huang, Jing-Bin; Mi, Jie; He, Yun-Feng; Wu, Xiao-Hou; Luo, Chun-Li; Liang, Si-Min; Li, Jia-Bing; Tang, Ya-Xiong; Li, Jie

    2012-02-01

    Rapid and reliable biomarkers of renal allograft rejection have not been available. This study aimed to investigate biomarkers in renal allograft tissue using proteomic analysis. Orthotopic kidney transplantations were performed using Fisher (F344) or Lewis rats as donors and Lewis rats as recipients. Syngenic control group (Group I) constituted F344-to-F344 orthotopic kidney allo-transplantations (n = 8); and allogenic group (Group II) consisted of F344-to-Lewis orthotopic kidney allo-transplantations (n = 8). Renal tissues were harvested 7 days after transplantation. Samples were analyzed using 2-D electrophoresis and matrix assisted laser desorption ionization-time of flight mass spectrometry. 6 differentially expressed proteins were identified between allogenic group and syngenic control group. A rat model of acute renal allograft rejection was successfully set up. Differentially expressed proteins in renal allograft tissue of rat were detected using proteomic analysis and might serve as novel diagnostic and therapeutic targets in human. Quantitative proteomics, using MALDL-TOF-MS methodology has the potential to provide a profiling and a deeper understanding of acute renal rejection.

  8. Optically based-indentation technique for acute rat brain tissue slices and thin biomaterials

    PubMed Central

    Lee, S. J.; Sun, J.; Flint, J. J.; Guo, S.; Xie, H. K.; King, M. A.; Sarntinoranont, M.

    2011-01-01

    Currently, micro-indentation testing of soft biological materials is limited in its capability to test over long time scales due to accumulated instrumental drift errors. As a result, there is a paucity of measures for mechanical properties such as the equilibrium modulus. In this study, indentation combined with optical coherence tomography (OCT) was used for mechanical testing of thin tissue slices. OCT was used to measure the surface deformation profiles by placing spherical beads onto submerged test samples. Agarose-based hydrogels at low-concentrations (w/v, 0.3–0.6 %) and acute rat brain tissue slices were tested using this technique over a 30 min time window. To establish that tissue slices maintained cell viability, allowable testing times were determined by measuring neuronal death or degeneration as a function of incubation time with Fluor-Jade C (FJC) staining. Since large deformations at equilibrium were measured, displacements of surface beads were compared with finite element elastic contact simulations to predict the equilibrium modulus, μ∞. Values of μ∞ for the low- concentration hydrogels ranged from 0.07–1.8 kPa, and μ∞ for acute rat brain tissue slices was 0.13 ± 0.04 kPa for the cortex and 0.09 ± 0.015 kPa for the hippocampus (for Poisson ratio=0.35). This indentation technique offers a localized, real-time, and high resolution method for long-time scale mechanical testing of very soft materials. This test method may also be adapted for viscoelasticity, for testing of different tissues and biomaterials, and for analyzing changes in internal structures with loading. PMID:21290586

  9. Korean red ginseng ameliorates acute 3-nitropropionic acid-induced cochlear damage in mice.

    PubMed

    Tian, Chunjie; Kim, Young Ho; Kim, Young Chul; Park, Kyung Tae; Kim, Seung Won; Kim, Youn Ju; Lim, Hye Jin; Choung, Yun-Hoon

    2013-01-01

    3-Nitropropionic acid (3-NP), a mitochondrial toxin, has been reported to induce an acute cochlear damage. Korean red ginseng (KRG) is known to have protective effects from some types of hearing loss. This study aimed to observe the protective effect of KRG in an ototoxic animal model using 3-NP intratympanic injection. BALB/c mice were classified into 5 groups (n=15) and dose-dependent toxic effects after intratympanic injection with 3-NP (300-5000 mM) on the left ear were investigated to determine the appropriate toxicity level of 3-NP. For observation of the protective effects of KRG, 23 mice were grouped into 3-NP (500 mM, n=12) and KRG+3-NP groups (300 mg/kg KRG for 7 days before 500 mM 3-NP administration, n=11). Auditory brain response (ABR) and cochlear morphological evaluations were performed before and after drug administration. The ABR thresholds in the 800-5000 mM groups exceeded the maximum recording limit at 16 and 32 kHz 1 day after 3-NP administration. The ABR threshold in the 500 mM 3-NP+KRG group was significantly lower than that in the 500 mM 3-NP group from post 1 week to 1 month. The mean type II fibrocyte counts significantly differed between the control and 3-NP groups and between the 3-NP and 3-NP+KRG groups. Spiral ganglion cell degeneration in the 3-NP group was more severe than that in the 3-NP+KRG group. This animal model exhibited a dose-dependent hearing loss with histological changes. KRG administration ameliorated the deterioration of hearing by 3-NP. PMID:23164932

  10. Investigations of the damage mechanisms during ultrashort pulse laser ablation of dental tissue

    NASA Astrophysics Data System (ADS)

    Domke, Matthias; Wick, Sebastian; Laible, Maike; Rapp, Stephan; Kuznetsova, Julia; Homann, Christian; Huber, Heinz P.; Sroka, Ronald

    2015-07-01

    Several investigations of dental tissue ablation with ultrashort pulsed lasers suggest that these lasers enable precise and selective material removal and reduce the formation of micro cracks and thermal effects, when compared to ns-pulses. In this study, two damage mechanisms are presented occurring during ablation of dentin using a laser emitting pulses of a duration of 380 fs at a wavelength of 1040 nm. First, it was found that nano cracks appear around the craters after single fs-pulse ablation. These cracks are directed to the crater and cross the dentinal tubules. Transient investigation of the single fs-pulse ablation process by pump-probe microscopy suggest that the driving mechanism could be a pressure wave that is released after stress confinement. Second, squared ablation holes were created by moving the laser focus at scan speeds between 0.5 mm/s and 2.0 m/s and fluences up to 14 J/cm2. It was found that deep cracks appear at the edges of the squared holes, if the scan speed is about 0.5 m/s. The fluence has only a minor impact on the crack formation. The crack propagation was investigated in the depth using x-ray micro tomography and optical coherence tomography. It was found that these cracks appear in the depth down to the dental pulp. These findings suggest that fast scanning of the laser beam is the key for damage free processing using ultrashort pulse lasers. Then, ablation rates of about 2.5 - 3.5 mm3/min/W can be achieved in dentine with pulse durations of 380 fs.

  11. Microbeam Radiation-Induced Tissue Damage Depends on the Stage of Vascular Maturation

    SciTech Connect

    Sabatasso, Sara; Laissue, Jean Albert; Hlushchuk, Ruslan; Graber, Werner; Bravin, Alberto; Braeuer-Krisch, Elke; Corde, Stephanie; Blattmann, Hans; Gruber, Guenther; Djonov, Valentin

    2011-08-01

    Purpose: To explore the effects of microbeam radiation (MR) on vascular biology, we used the chick chorioallantoic membrane (CAM) model of an almost pure vascular system with immature vessels (lacking periendothelial coverage) at Day 8 and mature vessels (with coverage) at Day 12 of development. Methods and Materials: CAMs were irradiated with microplanar beams (width, {approx}25 {mu}m; interbeam spacing, {approx}200 {mu}m) at entrance doses of 200 or 300 Gy and, for comparison, with a broad beam (seamless radiation [SLR]), with entrance doses of 5 to 40 Gy. Results: In vivo monitoring of Day-8 CAM vasculature 6 h after 200 Gy MR revealed a near total destruction of the immature capillary plexus. Conversely, 200 Gy MR barely affected Day-12 CAM mature microvasculature. Morphological evaluation of Day-12 CAMs after the dose was increased to 300 Gy revealed opened interendothelial junctions, which could explain the transient mesenchymal edema immediately after irradiation. Electron micrographs revealed cytoplasmic vacuolization of endothelial cells in the beam path, with disrupted luminal surfaces; often the lumen was engorged with erythrocytes and leukocytes. After 30 min, the capillary plexus adopted a striated metronomic pattern, with alternating destroyed and intact zones, corresponding to the beam and the interbeam paths within the array. SLR at a dose of 10 Gy caused growth retardation, resulting in a remarkable reduction in the vascular endpoint density 24 h postirradiation. A dose of 40 Gy damaged the entire CAM vasculature. Conclusions: The effects of MR are mediated by capillary damage, with tissue injury caused by insufficient blood supply. Vascular toxicity and physiological effects of MR depend on the stage of capillary maturation and appear in the first 15 to 60 min after irradiation. Conversely, the effects of SLR, due to the arrest of cell proliferation, persist for a longer time.

  12. Involvement of tissue plasminogen activator in stress responsivity during acute cocaine withdrawal in mice.

    PubMed

    Zhou, Yan; Maiya, Rajani; Norris, Erin H; Kreek, Mary Jeanne; Strickland, Sidney

    2010-11-01

    There is evidence that increased release of corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) contributes to stress responsivity during cocaine withdrawal (WD). Recent studies suggest that tissue plasminogen activator (tPA) in the CeA is a downstream effector protein for CRF after acute "binge" cocaine administration. The purpose of this study was to determine if tPA modulates cocaine WD-induced stress responsivity. Wild-type (WT) and tPA-deficient (tPA - / - ) mice were subjected to chronic (14 days) "binge" cocaine (45 mg/kg per day) or its acute (1 day) WD. Extracellular tPA activity, CRF mRNA levels, and plasma corticosterone (CORT) levels were measured in tPA - / -  and WT mice. Extracellular tPA activity was reduced by 50% in the CeA and medial amygdala of WT mice after chronic cocaine and returned to basal levels after acute WD. Unlike WT mice, tPA - / -  mice did not display elevated amygdalar CRF mRNA levels during cocaine WD. In comparison to WT mice, tPA - / -  mice showed a blunted plasma CORT response during acute WD. These results demonstrate that tPA activity in the amygdala (Amy) is altered by chronic cocaine exposure, and further suggest an involvement of tPA in modulating amygdalar CRF stress responsive system and hypothalamic-pituitary-adrenal axis in response to acute cocaine WD.

  13. Involvement of tissue plasminogen activator in stress responsivity during acute cocaine withdrawal in mice

    PubMed Central

    Zhou, Yan; Maiya, Rajani; Norris, Erin H.; Kreek, Mary Jeanne; Strickland, Sidney

    2013-01-01

    There is evidence that increased release of corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) contributes to stress responsivity during cocaine withdrawal (WD). Recent studies suggest that tissue plasminogen activator (tPA) in the CeA is a downstream effector protein for CRF after acute “binge” cocaine administration. The purpose of this study was to determine if tPA modulates cocaine WD-induced stress responsivity. Wild-type (WT) and tPA-deficient (tPA −/−) mice were subjected to chronic (14 days) “binge” cocaine (45 mg/kg per day) or its acute (1 day) WD. Extracellular tPA activity, CRF mRNA levels, and plasma corticosterone (CORT) levels were measured in tPA −/− and WT mice. Extracellular tPA activity was reduced by 50% in the CeA and medial amygdala of WT mice after chronic cocaine and returned to basal levels after acute WD. Unlike WT mice, tPA −/− mice did not display elevated amygdalar CRF mRNA levels during cocaine WD. In comparison to WT mice, tPA −/− mice showed a blunted plasma CORT response during acute WD. These results demonstrate that tPA activity in the amygdala (Amy) is altered by chronic cocaine exposure, and further suggest an involvement of tPA in modulating amygdalar CRF stress responsive system and hypothalamic–pituitary–adrenal axis in response to acute cocaine WD. PMID:20666641

  14. Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response

    PubMed Central

    Vidi, Pierre-Alexandre; Chandramouly, Gurushankar; Gray, Matthew; Wang, Lei; Liu, Er; Kim, Joseph J.; Roukos, Vassilis; Bissell, Mina J.; Moghe, Prabhas V.; Lelièvre, Sophie A.

    2012-01-01

    Epithelial tissue morphogenesis is accompanied by the formation of a polarity axis – a feature of tissue architecture that is initiated by the binding of integrins to the basement membrane. Polarity plays a crucial role in tissue homeostasis, preserving differentiation, cell survival and resistance to chemotherapeutic drugs among others. An important aspect in the maintenance of tissue homeostasis is genome integrity. As normal tissues frequently experience DNA double-strand breaks (DSBs), we asked how tissue architecture might participate in the DNA damage response. Using 3D culture models that mimic mammary glandular morphogenesis and tumor formation, we show that DSB repair activity is higher in basally polarized tissues, regardless of the malignant status of cells, and is controlled by hemidesmosomal integrin signaling. In the absence of glandular morphogenesis, in 2D flat monolayer cultures, basal polarity does not affect DNA repair activity but enhances H2AX phosphorylation, an early chromatin response to DNA damage. The nuclear mitotic apparatus protein 1 (NuMA), which controls breast glandular morphogenesis by acting on the organization of chromatin, displays a polarity-dependent pattern and redistributes in the cell nucleus of basally polarized cells upon the induction of DSBs. This is shown using high-content analysis of nuclear morphometric descriptors. Furthermore, silencing NuMA impairs H2AX phosphorylation – thus, tissue polarity and NuMA cooperate to maintain genome integrity. PMID:22331358

  15. The ability of low level laser therapy to prevent muscle tissue damage induced by snake venom.

    PubMed

    Doin-Silva, Rosany; Baranauskas, Vitor; Rodrigues-Simioni, Lea; da Cruz-Höfling, Maria Alice

    2009-01-01

    Antivenom therapy has been ineffective in neutralizing the severe local fast developing tissue damage following snakebite envenoming. Herein, some effects of in situ helium neon (HeNe) laser irradiation on rat nerve-muscle preparation injected with Bothrops jararacussu venom are described. The tibialis anterior muscle was injected with venom diluted in 0.9% saline solution (60 microg/0.02 mL) or saline solution alone. Sixty minutes after venom injection, laser (HeNe) treatment was administered at three incident energy densities: dose 1, a single exposure of 3.5 J cm(-2); dose 2, three exposures of 3.5 J cm(-2); dose 3, a single exposure of 10.5 J cm(-2). Muscle function was assessed through twitch tension recordings whereas muscle damage was evaluated through histopathologic analysis, morphometry of area of tissue affected and creatine kinase (CK) serum levels, and compared to unirradiated muscles. Laser application at the dose of 3.5 J cm(-2) reduced the area of injury by 64% (15.9 +/- 1.5%vs 44.2 +/- 5.7%), decreased the neuromuscular blockade (NMB) by 62% (11.5 +/- 2.5%vs 30.4 +/- 5.2%) and reduced CK levels by 58% (from 455 +/- 4.5% to 190.3 +/- 23.4%) when compared with unirradiated controls. Dose 2 showed a poorer benefit than dose 1, and dose 3 was ineffective in preventing the venom effects. Measurements of the absorbance of unirradiated and irradiated venom solution showed no difference in absorption spectra. In addition, no difference in the intensity of partial NMB in nerve-muscle preparation was shown by unirradiated and irradiated venom. The results indicate that the laser light did not alter venom toxicity. We conclude that HeNe laser irradiation at a dosage of 3.5 J cm(-2) effectively reduces myonecrosis and the neuromuscular transmission blocking effect caused by B. jararacussu snake venom. Thus, low level laser therapy may be a promising tool to minimize the severity of some of the local effects of snake envenoming. PMID:18643907

  16. Absence of acute ocular damage in humans after prolonged exposure to intense RF EMF.

    PubMed

    Adibzadeh, F; van Rhoon, G C; Verduijn, G M; Naus-Postema, N C; Paulides, M M

    2016-01-21

    The eye is considered to be a critical organ when determining safety standards for radio frequency (RF) radiation. Experimental data obtained using animals showed that RF heating of the eye, particularly over a specific threshold, can induce cataracts. During the treatment of cancer in the head and neck by hyperthermia, the eyes receive a considerable dose of RF radiation due to stray radiation from the prolonged (60 min) and intense exposure at 434 MHz of this region. In the current study, we verified the exposure guidelines for humans by determining the association between the electromagnetic and thermal dose in the eyes with the reported ocular effects. We performed a simulation study to retrospectively assess the specific absorption rate (SAR) and temperature increase in the eyes of 16 selected patients (encompassing a total of 74 treatment sessions) whose treatment involved high power delivery as well as a minimal distance between the tumor site and the eye. Our results show that the basic restrictions on the peak 10 g spatial-averaged SAR (10 W kg(-1)) and peak tissue temperature increase (1 °C) are exceeded by up to 10.4 and 4.6 times, on average, and by at least 6.2 and 1.8 times when considering the lower limit of the 95% confidence interval. Evaluation of the acute effects according to patients' feedback (all patients), the common toxicity criteria scores (all patients) and an ophthalmology investigation (one patient with the highest exposure) revealed no indication of any serious acute ocular effect, even though the eyes were exposed to high electromagnetic fields, leading to a high thermal dose. We also found that, although there is a strong correlation (R (2) =  0.88) between the predicted induced SAR and temperature in the eye, there are large uncertainties regarding the temperature-SAR relationship. Given this large uncertainty (129%) compared with the uncertainty of 3D temperature simulations (61%), we recommend using temperature simulations as a

  17. Absence of acute ocular damage in humans after prolonged exposure to intense RF EMF

    NASA Astrophysics Data System (ADS)

    Adibzadeh, F.; van Rhoon, G. C.; Verduijn, G. M.; Naus-Postema, N. C.; Paulides, M. M.

    2016-01-01

    The eye is considered to be a critical organ when determining safety standards for radio frequency (RF) radiation. Experimental data obtained using animals showed that RF heating of the eye, particularly over a specific threshold, can induce cataracts. During the treatment of cancer in the head and neck by hyperthermia, the eyes receive a considerable dose of RF radiation due to stray radiation from the prolonged (60 min) and intense exposure at 434 MHz of this region. In the current study, we verified the exposure guidelines for humans by determining the association between the electromagnetic and thermal dose in the eyes with the reported ocular effects. We performed a simulation study to retrospectively assess the specific absorption rate (SAR) and temperature increase in the eyes of 16 selected patients (encompassing a total of 74 treatment sessions) whose treatment involved high power delivery as well as a minimal distance between the tumor site and the eye. Our results show that the basic restrictions on the peak 10 g spatial-averaged SAR (10 W kg-1) and peak tissue temperature increase (1 °C) are exceeded by up to 10.4 and 4.6 times, on average, and by at least 6.2 and 1.8 times when considering the lower limit of the 95% confidence interval. Evaluation of the acute effects according to patients’ feedback (all patients), the common toxicity criteria scores (all patients) and an ophthalmology investigation (one patient with the highest exposure) revealed no indication of any serious acute ocular effect, even though the eyes were exposed to high electromagnetic fields, leading to a high thermal dose. We also found that, although there is a strong correlation (R 2  =  0.88) between the predicted induced SAR and temperature in the eye, there are large uncertainties regarding the temperature-SAR relationship. Given this large uncertainty (129%) compared with the uncertainty of 3D temperature simulations (61%), we recommend using temperature

  18. Ameliorative effect of statin therapy on oxidative damage in heart tissue of hypercholesterolemic rabbits.

    PubMed

    Sozer, Volkan

    2015-12-01

    The aim of this study was to investigate the effects of a high-cholesterol diet in the presence and absence of statin on Cu-Zn-superoxide dismutase (Cu,Zn-SOD), malondialdehyde (MDA), protein carbonyl (PCO), and nitric oxide (NO) of blood and heart tissue, the antioxidant activity of serum paraoxonase-1 (PON-1), and on the blood lipid profile of rabbits. The animals were divided into four groups each of which included 10 rabbits. Rabbits in group 1 received a regular rabbit chow diet (normal diet) for 8 weeks; those in group 2 received atorvastatin (0.3 mg atorvastatin per day/kg body weight) for 8 weeks; those in group 3 received high-cholesterol diet for 8 weeks; and those in group 4 received high-cholesterol diet for 4 weeks, a high-cholesterol diet + atorvastatin (0.3 mg atorvastatin per day/kg body weight) for 8 weeks. The parameters were measured by spectrophotometric methods. As expected, the atherogenic diet caused a pronounced increase in lipid profile (not HDL) parameters. Rabbits in group 3 showed higher PCO, MDA, and NO levels in circulating and heart tissue compared to the rabbits in group 1. Atorvastatin has prevented or limited LDL oxidation and has showed constitutively beneficial effects in group 4. Increased LDL-C, PCO, MDA, and NO levels leading to decreasing PON-1 activity thus create a predisposition to atherogenesis in this model. But atorvastatin administration partly ameliorated oxidative damage in heart injury of hypercholesterolemic rabbits. Atorvastatin which functions as a potent antioxidant agent may inhibit this LDL-C oxidation by increasing PON-1 activity in atherogenesis.

  19. DNA damage and metal accumulation in four tissues of feral Octopus vulgaris from two coastal areas in Portugal.

    PubMed

    Raimundo, Joana; Costa, Pedro M; Vale, Carlos; Costa, Maria Helena; Moura, Isabel

    2010-10-01

    The alkaline comet assay has been employed for the first time to estimate the basal DNA damage in the digestive gland, gills, kidney and gonads of Octopus vulgaris. Octopuses were captured in two coastal areas adjacent to the cities of Matosinhos (N) and Olhão (S), Portugal. The area of Matosinhos is influenced by discharges of the Douro River, city of Porto, industries and intensive agriculture, while Olhão is an important fisheries port. Previous works point to contrasting metal availability in the two coastal areas. Among the analysed tissues digestive gland presented the highest levels of Zn, Cu, Cd and Pb. Tissues of specimens from Matosinhos exhibited high levels of Cd and from Olhão enhanced Pb concentrations. The DNA damages in digestive gland, gills and kidney were more accentuated in specimens from Matosinhos than from Olhão, suggesting a stronger effect of contaminants. Elevated strand breakages were registered in digestive gland, recognised for its ability to store and detoxify accumulated metals. The DNA damages in kidney, gills and gonads were lower, reflecting reduced metal accumulation or efficient detoxification. The broad variability of damages in the three tissues may also mirror tissue function, specific defences to genotoxicants and cell-cycle turnover.

  20. Tissue Damage Markers after a Spinal Manipulation in Healthy Subjects: A Preliminary Report of a Randomized Controlled Trial

    PubMed Central

    Achalandabaso, A.; Plaza-Manzano, G.; Lomas-Vega, R.; Martínez-Amat, A.; Camacho, M. V.; Gassó, M.; Hita-Contreras, F.; Molina, F.

    2014-01-01

    Spinal manipulation (SM) is a manual therapy technique frequently applied to treat musculoskeletal disorders because of its analgesic effects. It is defined by a manual procedure involving a directed impulse to move a joint past its physiologic range of movement (ROM). In this sense, to exceed the physiologic ROM of a joint could trigger tissue damage, which might represent an adverse effect associated with spinal manipulation. The present work tries to explore the presence of tissue damage associated with SM through the damage markers analysis. Thirty healthy subjects recruited at the University of Jaén were submitted to a placebo SM (control group; n = 10), a single lower cervical manipulation (cervical group; n = 10), and a thoracic manipulation (n = 10). Before the intervention, blood samples were extracted and centrifuged to obtain plasma and serum. The procedure was repeated right after the intervention and two hours after the intervention. Tissue damage markers creatine phosphokinase (CPK), lactate dehydrogenase (LDH), C-reactive protein (CRP), troponin-I, myoglobin, neuron-specific enolase (NSE), and aldolase were determined in samples. Statistical analysis was performed through a 3 × 3 mixed-model ANOVA. Neither cervical manipulation nor thoracic manipulation did produce significant changes in the CPK, LDH, CRP, troponin-I, myoglobin, NSE, or aldolase blood levels. Our data suggest that the mechanical strain produced by SM seems to be innocuous to the joints and surrounding tissues in healthy subjects. PMID:25609853

  1. Acute acidic exposure induces p53-mediated oxidative stress and DNA damage in tilapia (Oreochromis niloticus) blood cells.

    PubMed

    Mai, Wei-jun; Yan, Jun-lun; Wang, Lei; Zheng, Ying; Xin, Yu; Wang, Wei-na

    2010-11-01

    Acid rain and inputs of acidic effluent can result in increased acidity in aquatic ecosystems, where it is known to have a significant impact and possibly, to cause the decline of some populations of aquatic organisms. In previous studies, intracellular acid-induced oxidative stress has been shown to cause DNA damage, and cooperatively activate the expression of the p53 gene. The acute effects of acidic environments on shrimp and fish have been widely studied. However, the molecular mechanism of acid-induced injury remains largely unknown. In this study, we examined the cellular responses of tilapia to acidic exposure-induced oxidative stress and antioxidant enzyme gene expression. Furthermore, we determined how acute acid stress activates the ATM-p53 signal pathway. We measured the upregulation of reactive oxygen species (ROS) production, the intracellular Ca(2)(+) concentration ([Ca(2)(+)](i)), the tail DNA values, the malondialdehyde (MDA) level in the blood cells and the percentage of dead and damaged blood cells. Our results suggest that oxidative stress and DNA damage occurred in tilapia in conditions where the pH was 5.3. Apoptosis was detected by Hoechst staining, which was mainly associated with changes in cell viability. The parameters that we measured were related to acid-induced DNA damage, and all parameters changed in the blood cells through time. The effects of acute acid exposure (pH 5.3) on the expression of ATM, p53, p21, Bax, manganese superoxide dismutase (MnSOD), glutathione peroxidase (GPx) were investigated in tilapia blood cells. The results showed that acute acid stress induced upregulation of ATM, p53 and p21, associated with increasing of DNA damage and apoptosis in blood cells. Additionally, the expression of Bax was slightly increased. Moreover, consensus p53-binding sequences were identified in tilapia MnSOD and GPx gene promoter regions and increased levels of ROS in the blood cells coincided with increased mRNA expression of p53, Mn

  2. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus.

    PubMed

    Villanueva, Eneida; Yalavarthi, Srilakshmi; Berthier, Celine C; Hodgin, Jeffrey B; Khandpur, Ritika; Lin, Andrew M; Rubin, Cory J; Zhao, Wenpu; Olsen, Stephen H; Klinker, Matthew; Shealy, David; Denny, Michael F; Plumas, Joel; Chaperot, Laurence; Kretzler, Matthias; Bruce, Allen T; Kaplan, Mariana J

    2011-07-01

    An abnormal neutrophil subset has been identified in the PBMC fractions from lupus patients. We have proposed that these low-density granulocytes (LDGs) play an important role in lupus pathogenesis by damaging endothelial cells and synthesizing increased levels of proinflammatory cytokines and type I IFNs. To directly establish LDGs as a distinct neutrophil subset, their gene array profiles were compared with those of autologous normal-density neutrophils and control neutrophils. LDGs significantly overexpress mRNA of various immunostimulatory bactericidal proteins and alarmins, relative to lupus and control neutrophils. In contrast, gene profiles of lupus normal-density neutrophils do not differ from those of controls. LDGs have heightened capacity to synthesize neutrophils extracellular traps (NETs), which display increased externalization of bactericidal, immunostimulatory proteins, and autoantigens, including LL-37, IL-17, and dsDNA. Through NETosis, LDGs have increased capacity to kill endothelial cells and to stimulate IFN-α synthesis by plasmacytoid dendritic cells. Affected skin and kidneys from lupus patients are infiltrated by netting neutrophils, which expose LL-37 and dsDNA. Tissue NETosis is associated with increased anti-dsDNA in sera. These results expand the potential pathogenic roles of aberrant lupus neutrophils and suggest that dysregulation of NET formation and its subsequent responses may play a prominent deleterious role.

  3. Fluorescence Diagnosis of Damage to Tumor Tissues During Photodynamic Therapy with the Photosensitizer Photolon®

    NASA Astrophysics Data System (ADS)

    Samtsov, M. P.; Tarasau, D. S.; Kaplevsky, K. N.; Voropay, E. S.; Petrov, P. T.; Istomin, Yu. P.

    2016-03-01

    We have studied the feasibility of using an indotricarbocyanine dye as a marker for the efficacy of photodynamic therapy (PDT) of cancers with the photosensitizer Photolon®. We have established that on exposure to laser emission at λ = 667 nm with an exposure dose of 100 J/cm2, we observe that the Photolon® concentration drops by about a factor of two in the exposed part of the tumor, while the concentration of the indotricarbocyanine dye does not change in any region of the tumor node. We have observed a correlation between the change in the shape of the fluorescence spectra of the indotricarbocyanine dye in vivo in the 780-880 nm resulting from a PDT session with the photosensitizer Photolon® and the extent of damage to the tumor tissues. Changes in the shape of the fluorescence spectrum of the dye are interpreted in terms of a model involving the appearance of absorption by different forms of hemoglobin, and changes in their ratio in the exposed part of the tumor due to consumption of molecular oxygen.

  4. Iron-induced tissue damage and cancer: the role of reactive oxygen species-free radicals.

    PubMed

    Okada, S

    1996-05-01

    Oxygen is poisonous, but we cannot live without it. The high oxidizing potential of oxygen molecules (dioxygen) is a valuable source of energy for the organism and its reactivity is low; that is, spin forbidden. However, the dioxygen itself is a 'free radical' and, especially in the presence of transition metals, it is a major promoter of radical reactions in the cell. Humans survive only by virtue of their elaborate defense mechanisms against oxygen toxicity. Iron is the most abundant transition metal in the human body. Because iron shows wide variation in redox potential with different co-ordination ligands, it may be used as a redox intermediate in many biological mechanism. However, it is precisely this redox activeness that makes iron a key participant in free radical production. The current research on the relationship between iron and cancer is briefly reviewed. Research results are reported here which indicate that iron, when bound to certain ligands, can cause free-radical mediated tissue damage and become carcinogenic. The present study also suggests that iron may also have a significant role in spontaneous human cancer. PMID:8809878

  5. Does prolonged radiofrequency radiation emitted from Wi-Fi devices induce DNA damage in various tissues of rats?

    PubMed

    Akdag, Mehmet Zulkuf; Dasdag, Suleyman; Canturk, Fazile; Karabulut, Derya; Caner, Yusuf; Adalier, Nur

    2016-09-01

    Wireless internet (Wi-Fi) providers have become essential in our daily lives, as wireless technology is evolving at a dizzying pace. Although there are different frequency generators, one of the most commonly used Wi-Fi devices are 2.4GHz frequency generators. These devices are heavily used in all areas of life but the effect of radiofrequency (RF) radiation emission on users is generally ignored. Yet, an increasing share of the public expresses concern on this issue. Therefore, this study intends to respond to the growing public concern. The purpose of this study is to reveal whether long term exposure of 2.4GHz frequency RF radiation will cause DNA damage of different tissues such as brain, kidney, liver, and skin tissue and testicular tissues of rats. The study was conducted on 16 adult male Wistar-Albino rats. The rats in the experimental group (n=8) were exposed to 2.4GHz frequency radiation for over a year. The rats in the sham control group (n=8) were subjected to the same experimental conditions except the Wi-Fi generator was turned off. After the exposure period was complete the possible DNA damage on the rat's brain, liver, kidney, skin, and testicular tissues was detected through the single cell gel electrophoresis assay (comet) method. The amount of DNA damage was measured as percentage tail DNA value. Based on the DNA damage results determined by the single cell gel electrophoresis (Comet) method, it was found that the% tail DNA values of the brain, kidney, liver, and skin tissues of the rats in the experimental group increased more than those in the control group. The increase of the DNA damage in all tissues was not significant (p>0.05). However the increase of the DNA damage in rat testes tissue was significant (p<0.01). In conclusion, long-term exposure to 2.4GHz RF radiation (Wi-Fi) does not cause DNA damage of the organs investigated in this study except testes. The results of this study indicated that testes are more sensitive organ to RF

  6. Tissue Inhibitor of Metalloproteinase-1 Deficiency Amplifies Acute Lung Injury in Bleomycin-Exposed Mice

    PubMed Central

    Kim, Kyoung-Hee; Burkhart, Kristin; Chen, Peter; Frevert, Charles W.; Randolph-Habecker, Julie; Hackman, Robert C.; Soloway, Paul D.; Madtes, David K.

    2005-01-01

    Bleomycin-induced lung injury triggers a profound and durable increase in tissue inhibitor of metalloproteinase (TIMP)-1 expression, suggesting a potential role for this antiproteinase in the regulation of lung inflammation and fibrosis. TIMP-1 protein induction is spatially restricted to areas of lung injury as determined by immunohistochemistry. Using TIMP-1 null mutation mice, we demonstrate that TIMP-1 deficiency amplifies acute lung injury as determined by exaggerated pulmonary neutrophilia, hemorrhage, and vascular permeability compared with wild-type littermates after bleomycin exposure. The augmented pulmonary neutrophilia observed in TIMP-1–deficient animals was not found in similarly treated TIMP-2–deficient mice. Using TIMP-1 bone marrow (BM) chimeric mice, we observed that the TIMP-1–deficient phenotype was abolished in wild-type recipients of TIMP-1–deficient BM but not in TIMP-1–deficient recipients of wild-type BM. Acute lung injury in TIMP-1–deficient mice was accompanied by exaggerated gelatinase-B activity in the alveolar compartment. TIMP-1 deficiency did not alter neutrophil chemotactic factor accumulation in the injured lung nor neutrophil migration in response to chemotactic stimuli in vivo or in vitro. Moreover, TIMP-1 deficiency did not modify collagen accumulation after bleomycin injury. Our results provide direct evidence that TIMP-1 contributes significantly to the regulation of acute lung injury, functioning to limit inflammation and lung permeability. PMID:15947421

  7. Space Radiation Effects on Human Cells: Modeling DNA Breakage, DNA Damage Foci Distribution, Chromosomal Aberrations and Tissue Effects

    NASA Technical Reports Server (NTRS)

    Ponomarev, A. L.; Huff, J. L.; Cucinotta, F. A.

    2011-01-01

    Future long-tem space travel will face challenges from radiation concerns as the space environment poses health risk to humans in space from radiations with high biological efficiency and adverse post-flight long-term effects. Solar particles events may dramatically affect the crew performance, while Galactic Cosmic Rays will induce a chronic exposure to high-linear-energy-transfer (LET) particles. These types of radiation, not present on the ground level, can increase the probability of a fatal cancer later in astronaut life. No feasible shielding is possible from radiation in space, especially for the heavy ion component, as suggested solutions will require a dramatic increase in the mass of the mission. Our research group focuses on fundamental research and strategic analysis leading to better shielding design and to better understanding of the biological mechanisms of radiation damage. We present our recent effort to model DNA damage and tissue damage using computational models based on the physics of heavy ion radiation, DNA structure and DNA damage and repair in human cells. Our particular area of expertise include the clustered DNA damage from high-LET radiation, the visualization of DSBs (DNA double strand breaks) via DNA damage foci, image analysis and the statistics of the foci for different experimental situations, chromosomal aberration formation through DSB misrepair, the kinetics of DSB repair leading to a model-derived spectrum of chromosomal aberrations, and, finally, the simulation of human tissue and the pattern of apoptotic cell damage. This compendium of theoretical and experimental data sheds light on the complex nature of radiation interacting with human DNA, cells and tissues, which can lead to mutagenesis and carcinogenesis later in human life after the space mission.

  8. Influence of chitosan coating on magnetic nanoparticles in endothelial cells and acute tissue biodistribution.

    PubMed

    Agotegaray, Mariela; Campelo, Adrián; Zysler, Roberto; Gumilar, Fernanda; Bras, Cristina; Minetti, Alejandra; Massheimer, Virginia; Lassalle, Verónica

    2016-08-01

    Chitosan coating on magnetic nanoparticles (MNPs) was studied on biological systems as a first step toward the application in the biomedical field as drug-targeted nanosystems. Composition of MNPs consists of magnetite functionalized with oleic acid and coated with the biopolymer chitosan or glutaraldehyde-cross-linked chitosan. The influence of the biopolymeric coating has been evaluated by in vitro and in vivo assays on the effects of these MNPs on rat aortic endothelial cells (ECs) viability and on the random tissue distribution in mice. Results were correlated with the physicochemical properties of the nanoparticles. Nitric oxide (NO) production by ECs was determined, considering that endothelial NO represents one of the major markers of ECs function. Cell viability was studied by MTT assay. Different doses of the MNPs (1, 10 and 100 μg/mL) were assayed, revealing that MNPs coated with non-cross-linked chitosan for 6 and 24 h did not affect neither NO production nor cell viability. However, a significant decrease in cell viability was observed after 36 h treatment with the highest dose of this nanocarrier. It was also revealed that the presence and dose of glutaraldehyde in the MNPs structureimpact on the cytotoxicity. The study of the acute tissue distribution was performed acutely in mice after 24 h of an intraperitoneal injection of the MNPs and sub acutely, after 28 days of weekly administration. Both formulations greatly avoided the initial clearance by the reticuloendothelial system (RES) in liver. Biological properties found for N1 and N2 in the performed assays reveal that chitosan coating improves biocompatibility of MNPs turning these magnetic nanosystems as promising devices for targeted drug delivery.

  9. Solid-extracellular fluid interaction and damage in the mechanical response of rat brain tissue under confined compression.

    PubMed

    Haslach, Henry W; Leahy, Lauren N; Riley, Peter; Gullapalli, Rao; Xu, Su; Hsieh, Adam H

    2014-01-01

    The mechanical processes that underlie mild traumatic brain injury from physical insults are not well understood. One aspect in particular that has not been examined is the tissue fluid, which is known to be critical in the mechanical function of other organs. To investigate the contributions of solid-fluid interactions to brain tissue mechanics, we performed confined compression tests, that force the extracellular fluid (ECF) to flow in the direction of the deformation, on 6.35mm diameter, 3mm long cylindrical samples excised from various regions of rat brains. Two types of tests in deformation control, (1) quasi-static, slow and moderate constant strain rate tests at 0.64×10(-5)/s, 0.001/s and 1/s to large strains and (2) several applications of slow linear deformation to 5% strain each followed by stress relaxation are employed to explore the solid-fluid interaction. At slow and moderate compressive strain rates, we observed stress peaks in the applied strain range at about 11%, whose magnitudes exhibited statistically significant dependence on strain rate. These data suggest that the ECF carries load until the tissue is sufficiently damaged to permit pathological fluid flow. Under the slow ramp rate in the ramp-relaxation cycles protocol, commonly used to estimate permeability, the stress relaxes to zero after the first cycle, rather than to a non-zero equilibrium stress corresponding to the applied strain, which further implicates mechanical damage. Magnetic resonance imaging (MRI) of changes in tissue microstructure during confined compression, before and after compression, provides further evidence of tissue damage. The solid-fluid interactions, reflected in the morphology of the stress-stretch curves and supported by the MRI data, suggest that increases in hydrostatic pressure in the ECF may contribute to mechanical damage of brain tissue.

  10. Effect of scanned quasi-cw CO2 laser irradiation on tissue thermal damage

    NASA Astrophysics Data System (ADS)

    Domankevitz, Yacov; Bua, Dominic; Chung, Jina; Hanel, Edward; Silver, Geoffrey; Nishioka, Norman S.

    1994-08-01

    Residual thermal damage produced by a scanned quasi cw CO2 laser was measured in pig skin. The effects of scan speed on thermal damage distribution for laser dwell times ranging between 1 and 150 msec were examined. Significantly larger thermal damage zones were produced along the crater wall for laser dwell times longer than 50 msec. Thermal damage along the crater base was constant independent of dwell time. The preliminary experimental results suggest that quasi cw CO2 can consistently produce less than 200 micrometers zones of thermal damage if laser parameters are carefully chosen.

  11. Endometrial cells sense and react to tissue damage during infection of the bovine endometrium via interleukin 1.

    PubMed

    Healy, Laura L; Cronin, James G; Sheldon, I Martin

    2014-11-14

    Cells generate inflammatory responses to bacteria when pattern recognition receptors bind pathogen-associated molecules such as lipopolysaccharide. Cells may also respond to tissue damage by sensing damage-associated molecules. Postpartum bacterial infections of the bovine uterus cause endometritis but the risk of disease is increased by tissue trauma triggered by dystocia. Animals that suffered dystocia had increased concentrations of inflammatory mediators IL-8, IL-1β and IL-1α in vaginal mucus 3 weeks postpartum, but they also had more bacteria than normal animals. Ex vivo organ cultures of endometrium, endometrial cells and peripheral blood monocytes did not generate inflammatory responses to prototypical damage molecules, HMGB1 or hyaluronan, or to necrotic cells; although they secreted IL-6 and IL-8 in a concentration-dependent manner when treated with IL-1α. However, necrotic endometrial cells did not accumulate intracellular IL-1α or release IL-1α, except when pre-treated with lipopolysaccharide or bacteria. Endometrial cell inflammatory responses to IL-1α were dependent on the cognate receptor IL-1R1, and the receptor adaptor protein MyD88, and the inflammatory response to IL-1α was independent of the response to lipopolysaccharide. Rather than a typical damage-associated molecule, IL-1α acts to scale the inflammatory response in recognition that there is a combination of pathogen challenge followed by endometrial cell damage.

  12. Design of endoscopic micro-robotic end effectors: safety and performance evaluation based on physical intestinal tissue damage characteristics.

    PubMed

    Kim, Young-Tae; Kim, Dae-Eun; Yang, Sungwook; Yoon, Eui-Sung

    2014-06-01

    During the last several years, legged locomotive mechanism has been considered as one of the main self-propelling mechanisms for future endoscopic microrobots due to its superior propulsion efficiency of an endoscopic microrobot inside the intestinal track. Nevertheless, its clinical application has been largely limited since the legged locomotive mechanism utilizes an end effector which has a sharp tip to generate sufficient traction by physically penetrating and interlocking with the intestinal tissue. This can cause excessive physical tissue damage or even complete perforation of the intestinal wall that can lead to abdominal inflammation. Hence, in this work two types of new end effectors, penetration-limited end effector (PLEE) and bi-material structured end effector (BMEE) were specially designed to acquire high medical safety as well as effective traction generation performance. The microscopic end effector specimens were fabricated with micro-wire electric discharge machining process. Traction generation performance of the end effectors was evaluated by direct measurement of resistance forces during contact-sliding tests using a custom-built contact-sliding tester. The safety of the end effector design was evaluated by examination of microscopic intestinal tissue damage using a scanning electron microscope (SEM). Physical damage characteristics of the intestinal tissue and related contact physics of the end effectors were discussed. From the results, the end effectors were evaluated with respect to their prospects in future medical applications as safe end effectors as well as micro-surgical tools.

  13. R-spondin3 prevents mesenteric ischemia/reperfusion-induced tissue damage by tightening endothelium and preventing vascular leakage.

    PubMed

    Kannan, Lakshmi; Kis-Toth, Katalin; Yoshiya, Kazuhisa; Thai, To-Ha; Sehrawat, Seema; Mayadas, Tanya N; Dalle Lucca, Jurandir J; Tsokos, George C

    2013-08-27

    Inflammation and vascular injury triggered by ischemia/reperfusion (I/R) represent a leading cause of morbidity and mortality in a number of clinical settings. Wnt and its homolog partners R-spondins, in addition to regulating embryonic development have recently been demonstrated to serve as wound-healing agents in inflammation-associated conditions. Here we ask whether R-spondins could prevent inflammation-associated tissue damage in ischemic disorders and thus investigate the role of R-spondin3 (R-spo3) in a mouse model of mesenteric I/R. We demonstrate that R-spo3 ameliorates mesenteric I/R-induced local intestinal as well as remote lung damage by suppressing local and systemic cytokine response and deposition of IgM and complement in intestinal tissues. We also show that decreased inflammatory response is accompanied by tightening of endothelial cell junctions and reduction in vascular leakage. We conclude that R-spo3 stabilizes endothelial junctions and inhibits vascular leakage during I/R and thereby mitigates the inflammatory events and associated tissue damage. Our findings uniquely demonstrate a protective effect of R-spo3 in I/R-related tissue injury and suggest a mechanism by which it may have these effects. PMID:23942120

  14. Impact of Reperfusion after 3 Hours of Symptom Onset on Tissue Fate in Acute Cerebral Ischemia

    PubMed Central

    Bang, Oh Young; Liebeskind, David S.; Buck, Brian H.; Yoon, Sa Rah; Alger, Jeffry R.; Ovbiagele, Bruce; Saver, Jeffrey L.

    2009-01-01

    BACKGROUND Reperfusion of penumbral tissue is a promising strategy for treatment of acute cerebral ischemia more than 3 hours from symptom onset. However, there has been only sparse direct evidence that reperfusion after 3 hours prevents infarct growth. METHODS We analyzed clinical and serial magnetic resonance imaging (MRI) data on patients who received endovascular recanalization therapy 3–12 hours after last known well time. Multimodal MRIs were acquired pretreatment, early (1–20 hours), and late (2–7 days) after treatment. Degree of recanalization was assessed on end of procedure catheter angiogram, degree of reperfusion on early posttreatment perfusion MRI, and infarct growth by analysis of diffusion lesion volumes on pretreatment and late MRIs. RESULTS Twenty-seven (12 men, 15 women) underwent endovascular recanalization procedures at 6.0 ± 2.1 hours (range, 3.0–11.5 hours) after last known well time. Immediate posttreatment perfusion lesion (Tmax ≥4 seconds) volume correlated strongly with infarct growth (r = .951, P < .001), exceeding the correlations of vessel recanalization score (r = −.198, P = .446) and pretreatment diffusion-perfusion mismatch volume (r = .518, P = .033). Without reperfusion, enlargement of DWI lesion volume was observed in all patients, and extent of enlargement depended on volume of immediate posttreatment perfusion defects. CONCLUSION Our data indicate that posttreatment reperfusion is the major determinant of threatened tissue outcome, and suggest reperfusion even after 3 hours of symptom onset can alter tissue fate over a wide range of mismatch volumes. PMID:19021836

  15. Oxidative stress, inflammation, and DNA damage in multiple organs of mice acutely exposed to amorphous silica nanoparticles

    PubMed Central

    Nemmar, Abderrahim; Yuvaraju, Priya; Beegam, Sumaya; Yasin, Javed; Kazzam, Elsadig E; Ali, Badreldin H

    2016-01-01

    The use of amorphous silica (SiO2) in biopharmaceutical and industrial fields can lead to human exposure by injection, skin penetration, ingestion, or inhalation. However, the in vivo acute toxicity of amorphous SiO2 nanoparticles (SiNPs) on multiple organs and the mechanisms underlying these effects are not well understood. Presently, we investigated the acute (24 hours) effects of intraperitoneally administered 50 nm SiNPs (0.25 mg/kg) on systemic toxicity, oxidative stress, inflammation, and DNA damage in the lung, heart, liver, kidney, and brain of mice. Lipid peroxidation was significantly increased by SiNPs in the lung, liver, kidney, and brain, but was not changed in the heart. Similarly, superoxide dismutase and catalase activities were significantly affected by SiNPs in all organs studied. While the concentration of tumor necrosis factor α was insignificantly increased in the liver and brain, its increase was statistically significant in the lung, heart, and kidney. SiNPs induced a significant elevation in pulmonary and renal interleukin 6 and interleukin-1 beta in the lung, liver, and brain. Moreover, SiNPs caused a significant increase in DNA damage, assessed by comet assay, in all the organs studied. SiNPs caused leukocytosis and increased the plasma activities of lactate dehydrogenase, creatine kinase, alanine aminotranferase, and aspartate aminotransferase. These results indicate that acute systemic exposure to SiNPs causes oxidative stress, inflammation, and DNA damage in several major organs, and highlight the need for thorough evaluation of SiNPs before they can be safely used in human beings. PMID:27022259

  16. Triphasic multinutrient supplementation during acute resistance exercise improves session volume load and reduces muscle damage in strength-trained athletes.

    PubMed

    Bird, Stephen P; Mabon, Tom; Pryde, Mitchell; Feebrey, Sarah; Cannon, Jack

    2013-05-01

    We hypothesized that triphasic multinutrient supplementation during acute resistance exercise would enhance muscular performance, produce a more favorable anabolic profile, and reduce biochemical markers of muscle damage in strength-trained athletes. Fifteen male strength-trained athletes completed two acute lower-body resistance exercise sessions to fatigue 7 days apart. After a 4-hour fast, participants consumed either a multinutrient supplement (Musashi 1-2-3 Step System, Notting Hill, Australia) (SUPP) or placebo (PLA) beverage preexercise (PRE), during (DUR), and immediately postexercise (IP). Session volume loads were calculated as kilograms × repetitions. Lower-body peak power was measured using unloaded repeated countermovement jumps, and blood samples were collected to assess biochemistry, serum hormones, and muscle damage markers at PRE, DUR, IP, 30 minutes postexercise (P30), and 24 hours postexercise (P24h). The SUPP demonstrated increased glucose concentrations at DUR and IP compared with at PRE (P < .01), whereas PLA demonstrated higher glucose at P30 compared with at PRE (P < .001). Session volume load was higher for SUPP compared with PLA (P < .05). Cortisol increased at DUR, IP, and P30 compared with at PRE in both treatments (P < .05); however, SUPP also displayed lower cortisol at P24h compared with at PRE and PLA (P < .01). The total testosterone response to exercise was higher for PLA compared with SUPP (P < .01); however, total creatine kinase and C-reactive protein responses to exercise were lower for SUPP compared with PLA (P < .05). These data indicate that although triphasic multinutrient supplementation did not produce a more favorable anabolic profile, it improved acute resistance exercise performance while attenuating muscle damage in strength-trained athletes.

  17. Modeling of long-term fatigue damage of soft tissue with stress softening and permanent set effects

    PubMed Central

    Martin, Caitlin; Sun, Wei

    2012-01-01

    One of the major failure modes of bioprosthetic heart valves is non-calcific structural deterioration due to fatigue of the tissue leaflets. Experimental methods to characterize tissue fatigue properties are complex and time-consuming. A constitutive fatigue model that could be calibrated by isolated material tests would be ideal for investigating the effects of more complex loading conditions. However, there is a lack of tissue fatigue damage models in the literature. To address these limitations, in this study, a phenomenological constitutive model was developed to describe the stress softening and permanent set effects of tissue subjected to long-term cyclic loading. The model was used to capture characteristic uniaxial fatigue data for glutaraldehyde-treated bovine pericardium and was then implemented into finite element software. The simulated fatigue response agreed well with the experimental data and thus demonstrates feasibility of this approach. PMID:22945802

  18. Protective effects of S-2-(3-aminopropylamino)ethylphosphorothioic acid against radiation damage of normal tissues and a fibrosarcoma in mice

    SciTech Connect

    Milas, L.; Hunter, N.; Reid, B.O.; Thames, H.D. Jr.

    1982-05-01

    S-2-(3-Aminopropylamino)ethylphosphorothioic acid (WR-2721) was investigated for its protective effect against radiation-produced damage of jejunum, testis, lung, hair follicles, and a fibrosarcoma of C3Hf/Kam mice. Most of these tissues were radioprotected, and the degree of radioprotection depended on the dose of WR-2721 and the time interval between administration of WR-2721 and radiation treatment. WR-2721 increased resistance of jejunal epithelial cells and spermatogenic cells to single doses of gamma-rays by factors of 1.64 and 1.54, respectively. Protection against hair loss was less pronounced; the dose-modifying factor here was 1.24. The radiation-induced acute damage of the lung expressed by the increased formation of tumor nodules in the lung was not decreased by treatment of animals with WR-2721 before radiation. In contrast, WR-2721 augmented the radiation-induced enhancement of metastasis formation in the lung. WR-2721 protected fibrosarcoma micrometastases in the lung against therapeutic effect of radiation by a factor of 1.238. In contrast, this compound had no effect on the therapy of an 8-mm fibrosarcoma growing in the legs of mice.

  19. Biochemical and histological evaluation of kidney damage after sub-acute exposure to 2,4-dichlorophenoxyacetic herbicide in rats: involvement of oxidative stress.

    PubMed

    Tayeb, Wafa; Nakbi, Amel; Trabelsi, Mounir; Miled, Abdelhedi; Hammami, Mohamed

    2012-11-01

    The present study evaluated the effects of sub-acute exposure to different doses of 2,4-dichlorophenoxyacetic acid (2,4-D) on rat kidney. Forty animals were divided into four equal groups and treated with different doses of 2,4-D: 0, 15, 75 and 150 mg/kg body weight per day via oral gavage for 28 consecutive days. Renal function, histopathology, tissue malondialdehyde and antioxidant enzyme activities were evaluated. The results showed a significant decrease (p < 0.01) in uric acid level and an increase in plasma levels of urea and creatinine (p < 0.01) in rats administered 2,4-D at the three studied doses. The activities of catalase and superoxide dismutase were significantly affected for all treated rats, while glutathione peroxidase significantly decreased in rats exposed to 2,4-D at a dose of 150 mg/kg. Through sub-acute treatment, starting from the low to the high doses of 2,4-D, there were significant increase in kidney MDA as compared to controls. The histopathological study revealed tubular damages, glomerular alterations, vascular congestion and increased number of pyknotic nuclei in kidneys of all 2,4-D treated groups. The severity of these alterations increase in a dose-dependent manner. Our findings confirm that sub-acute exposure to 2,4-D induced oxidative renal dysfunction in rats. Therefore, at higher doses, 2,4-D may be implicated in the pathogenesis of kidney failure via lipid peroxidation and oxidative stress.

  20. Efficient tissue ablation using a laser tunable in the water absorption band at 3 microns with little collateral damage

    NASA Astrophysics Data System (ADS)

    Nierlich, Alexandra; Chuchumishev, Danail; Nagel, Elizabeth; Marinova, Kristiana; Philipov, Stanislav; Fiebig, Torsten; Buchvarov, Ivan; Richter, Claus-Peter

    2014-03-01

    Lasers can significantly advance medical diagnostics and treatment. At high power, they are typically used as cutting tools during surgery. For lasers that are used as knifes, radiation wavelengths in the far ultraviolet and in the near infrared spectral regions are favored because tissue has high contents of collagen and water. Collagen has an absorption peak around 190 nm, while water is in the near infrared around 3,000 nm. Changing the wavelength across the absorption peak will result in significant differences in laser tissue interactions. Tunable lasers in the infrared that could optimize the laser tissue interaction for ablation and/or coagulation are not available until now besides the Free Electron Laser (FEL). Here we demonstrate efficient tissue ablation using a table-top mid-IR laser tunable between 3,000 to 3,500 nm. A detailed study of the ablation has been conducted in different tissues. Little collateral thermal damage has been found at a distance above 10-20 microns from the ablated surface. Furthermore, little mechanical damage could be seen in conventional histology and by examination of birefringent activity of the samples using a pair of cross polarizing filters.

  1. Mobilization of tissue cadmium in mice and calves and reversal of cadmium induced tissue damage in calves by zinc

    SciTech Connect

    Reddy, C.S.; Mohammad, F.K.; Ganjam, V.K.; Martino, M.A.; Brown, E.M.

    1987-08-01

    Earlier studies demonstrated that simultaneous dietary Zn supplementation to calves fed Cd, significantly decreased the accumulation of Cd in liver, kidney and muscle. However, studies are lacking in evaluating the effectiveness of zinc in reducing Cd-burden in animals with pre-existing tissue Cd-load, a situation encountered in chronic Cd intoxication. This study examined the effects of oral Zn (AnO) on tissue Cd levels in mice. N-acetylcysteine (NAC) and sodium sulfate (SS) were also used to evaluate the effects of providing organic and inorganic sources of sulfur on tissue Cd levels. Following demonstration of reduced Cd levels in tissues of mice receiving antidotal Zn, subsequent investigation was aimed at studying the reversal of Cd-induced changes by Zn. The authors also examined whether Cd-induced reduction in epididymal 5 ..cap alpha..-reductase activity could explain previously reported low levels of circulating dihydrotestosterone (DHT) following Cd treatment. The ability of Zn to reverse the inhibition of 5 ..cap alpha..-reductase activity by Cd was also examined.

  2. Glucose-Stimulated Calcium Dynamics in Islets of Langerhans in Acute Mouse Pancreas Tissue Slices

    PubMed Central

    Stožer, Andraž; Dolenšek, Jurij; Rupnik, Marjan Slak

    2013-01-01

    In endocrine cells within islets of Langerhans calcium ions couple cell stimulation to hormone secretion. Since the advent of modern fluorimetry, numerous in vitro studies employing primarily isolated mouse islets have investigated the effects of various secretagogues on cytoplasmic calcium, predominantly in insulin-secreting beta cells. Due to technical limitations, insights of these studies are inherently limited to a rather small subpopulation of outermost cells. The results also seem to depend on various factors, like culture conditions and duration, and are not always easily reconcilable with findings in vivo. The main controversies regard the types of calcium oscillations, presence of calcium waves, and the level of synchronized activity. Here, we set out to combine the in situ acute mouse pancreas tissue slice preparation with noninvasive fluorescent calcium labeling and subsequent confocal laser scanning microscopy to shed new light on the existing controversies utilizing an innovative approach enabling the characterization of responses in many cells from all layers of islets. Our experiments reproducibly showed stable fast calcium oscillations on a sustained plateau rather than slow oscillations as the predominant type of response in acute tissue slices, and that calcium waves are the mechanistic substrate for synchronization of oscillations. We also found indirect evidence that even a large amplitude calcium signal was not sufficient and that metabolic activation was necessary to ensure cell synchronization upon stimulation with glucose. Our novel method helped resolve existing controversies and showed the potential to help answer important physiological questions, making it one of the methods of choice for the foreseeable future. PMID:23358454

  3. Effects of selective iNOS inhibition in sepsis: evaluation of lung tissue damage and blood gases.

    PubMed

    Ceran, Sami; Erikoglu, Mehmet; Sahin, Mustafa; Sunam, Güven Sadi; Gölcük, Murat; Pasaoğlu, Hatice; Avsar, Fatih; Hücümenoglu, Sema

    2008-01-01

    NO is an important mediator in the generalized inflammatory response of the body during sepsis and septic shock. We investigated the possible effects of L-arginine and aminoguanidine on plasma NO levels and the interaction between NO levels and lung tissue damage and blood gases in sepsis. Fifty Wistar male rats were used in this study and divided into five groups: group 1, sham group; group 2, CLP (sepsis); group 3, CLP + 10 mg/kg L-arginine administration; group 4, CLP +15 mg/kg aminoguanidine administration; group 5: CLP + L-arginine + aminoguanidine given in similar doses. Sepsis was induced by cecal ligation and puncture (CLP) method. Drugs were administered at postoperative hours 4 and 12. The levels in the aminoguanidine and aminoguanidine + L-arginine groups were similar to the sham group. Lung tissue damage in the sepsis and L-arginine groups was more severe than the other groups.

  4. Muscle Tissue Damage Induced by the Venom of Bothrops asper: Identification of Early and Late Pathological Events through Proteomic Analysis

    PubMed Central

    Herrera, Cristina; Macêdo, Jéssica Kele A.; Feoli, Andrés; Escalante, Teresa; Rucavado, Alexandra; Gutiérrez, José María; Fox, Jay W.

    2016-01-01

    The time-course of the pathological effects induced by the venom of the snake Bothrops asper in muscle tissue was investigated by a combination of histology, proteomic analysis of exudates collected in the vicinity of damaged muscle, and immunodetection of extracellular matrix proteins in exudates. Proteomic assay of exudates has become an excellent new methodological tool to detect key biomarkers of tissue alterations for a more integrative perspective of snake venom-induced pathology. The time-course analysis of the intracellular proteins showed an early presence of cytosolic and mitochondrial proteins in exudates, while cytoskeletal proteins increased later on. This underscores the rapid cytotoxic effect of venom, especially in muscle fibers, due to the action of myotoxic phospholipases A2, followed by the action of proteinases in the cytoskeleton of damaged muscle fibers. Similarly, the early presence of basement membrane (BM) and other extracellular matrix (ECM) proteins in exudates reflects the rapid microvascular damage and hemorrhage induced by snake venom metalloproteinases. The presence of fragments of type IV collagen and perlecan one hour after envenoming suggests that hydrolysis of these mechanically/structurally-relevant BM components plays a key role in the genesis of hemorrhage. On the other hand, the increment of some ECM proteins in the exudate at later time intervals is likely a consequence of the action of endogenous matrix metalloproteinases (MMPs) or of de novo synthesis of ECM proteins during tissue remodeling as part of the inflammatory reaction. Our results offer relevant insights for a more integrative and systematic understanding of the time-course dynamics of muscle tissue damage induced by B. asper venom and possibly other viperid venoms. PMID:27035343

  5. Tissue-Specific B-Cell Dysfunction and Generalized Memory B-Cell Loss during Acute SIV Infection

    PubMed Central

    Peruchon, Sandrine; Chaoul, Nada; Burelout, Chantal; Delache, Benoit; Brochard, Patricia; Laurent, Pascale; Cognasse, Fabrice; Prévot, Sophie; Garraud, Olivier; Le Grand, Roger; Richard, Yolande

    2009-01-01

    Background Primary HIV-infected patients display severe and irreversible damage to different blood B-cell subsets which is not restored by highly efficient anti-retroviral therapy (HAART). Because longitudinal investigations of primary HIV-infection is limited by the availability of lymphoid organs, we studied the tissue-specific B-cell dysfunctions in acutely simian immunodeficiency virus (SIV) mac251-infected Cynomolgus macaques. Methods and Findings Experiments were performed on three groups of macaques infected for 14, 21 or 28 days and on three groups of animals treated with HAART for two-weeks either initiated at 4 h, 7 or 14 days post-infection (p.i.). We have simultaneously compared changes in B-cell phenotypes and functions and tissue organization of B-cell areas in various lymphoid organs. We showed that SIV induced a steady decline in SIgG-expressing memory (SIgD−CD27+) B-cells in spleen and lymph nodes during the first 4 weeks of infection, concomitant to selective homing/sequestration of B-cells to the small intestine and spleen. SIV non-specific Ig production was transiently increased before D14p.i., whereas SIV-specific Ig production was only detectable after D14p.i., coinciding with the presence of CD8+ T-cells and IgG-expressing plasma cells within germinal centres. Transient B-cell apoptosis on D14p.i. and commitment to terminal differentiation contributed to memory B-cell loss. HAART abrogated B-cell apoptosis, homing to the small intestine and SIV-specific Ig production but had minimal effect on early Ig production, increased B-cell proportions in spleen and loss of memory B-cells. Therefore, virus–B-cell interactions and SIV-induced inflammatory cytokines may differently contribute to early B-cell dysfunction and impaired SIV/HIV-specific antibody response. Conclusions These data establish tissue-specific impairments in B-cell trafficking and functions and a generalized and steady memory B-cell loss in secondary lymphoid organs

  6. Inhibition of the group I mGluRs reduces acute brain damage and improves long-term histological outcomes after photothrombosis-induced ischaemia

    PubMed Central

    Li, Hailong; Zhang, Nannan; Sun, Grace; Ding, Shinghua

    2013-01-01

    Group I mGluRs (metabotropic glutamate receptors), including mGluR1 and mGluR5, are GPCRs (G-protein coupled receptors) and play important roles in physiology and pathology. Studies on their role in cerebral ischaemia have provided controversial results. In this study, we used a PT (photothrombosis)-induced ischaemia model to investigate whether antagonists to the group I mGluRs may offer acute and long-term protective effects in adult mice. Our results demonstrated that administration with mGluR5 antagonist MPEP [2-methyl-6-(phenylethynyl)-pyridine] or mGluR1 antagonist LY367385 by intraperitoneal injection at 3 h after PT decreased brain infarct volume evaluated one day after ischaemia. Additive effects on infarct volume were observed upon co-injection with MPEP and LY367385. These antagonists also significantly alleviated neurodegeneration and apoptosis in the penumbra. In addition, when evaluated 2 weeks after PT, they reduced infarct volume and tissue loss, attenuated glial scar formation, and inhibited cell proliferation in the penumbra. Importantly, co-injection with MPEP and LY367385 reduced the expression levels of calpain, a Ca2+-activated protease known to mediate ischaemia-induced neuronal death. Injection of calpeptin, a calpain inhibitor, could inhibit neuronal death and brain damage after PT but injection of calpeptin together with MPEP and LY367385 did not further improve the protective effects mediated by MPEP and LY367385. These results suggest that inhibition of group I mGluRs is sufficient to protect ischaemic damage through the calpain pathway. Taken together, our results demonstrate that inhibition of group I mGluRs can mitigate PT-induced brain damage through attenuating the effects of calpain, and improve long-term histological outcomes. PMID:23772679

  7. Inhibition of pancreatic oxidative damage by stilbene derivative dihydro-resveratrol: implication for treatment of acute pancreatitis

    PubMed Central

    Tsang, Siu Wai; Guan, Yi-Fu; Wang, Juan; Bian, Zhao-Xiang; Zhang, Hong-Jie

    2016-01-01

    Trans-resveratrol is a natural stilbenoid possessing multifarious pharmacological benefits; however, when orally consumed, it is rapidly metabolised by colonic microflora and converted to dihydro-resveratrol. Thus, this microbial metabolite is of great therapeutic relevance. In the present study, upon the oral administration of dihydro-resveratrol (10–50 mg/kg), the severity of acute pancreatitis in the cerulein-treated rats was significantly ameliorated as evidenced by decreased α-amylase activities in the plasma and lessened oedema formation in the pancreatic parenchyma. In addition, the generation of intracellular reactive oxidative products, including malondialdehyde and protein carbonyls, was accordingly reduced, so as the production of pro-inflammatory cytokines. While inhibiting the activities of NADPH oxidase and myeloperoxidase, the depletion of glutathione was considerably restored. Importantly, the attenuation of pancreatic oxidative damage by dihydro-resveratrol was associated with a down-regulation of the nuclear factor-kappaB and phosphatidylinositol 3′-kinase-serine/threonine kinase signalling pathways. Furthermore, we demonstrated that the solubility of dihydro-resveratrol was at least 5 times higher than trans-resveratrol whilst exhibiting a much lower cytotoxicity. Collectively, the current findings accentuate new mechanistic insight of dihydro-resveratrol in pancreatic oxidative damage, and advocate its therapeutic potential for the management of acute pancreatitis, particularly for patients unresponsive to trans-resveratrol due to the lack of proper microbial strains. PMID:26971398

  8. The relationship between decorrelation time and sample thickness in acute rat brain tissue slices (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Brake, Joshua; Jang, Mooseok; Yang, Changhuei

    2016-03-01

    The optical opacity of biological tissue has long been a challenge in biomedical optics due to the strong scattering nature of tissue in the optical regime. While most conventional optical techniques attempt to gate out multiply scattered light and use only unscattered light, new approaches in the field of wavefront shaping exploit the time reversible symmetry of optical scattering in order to focus light inside or through scattering media. While these approaches have been demonstrated effectively on static samples, it has proven difficult to apply them to dynamic biological samples since even small changes in the relative positions of the scatterers within will cause the time symmetry that wavefront shaping relies upon to decorrelate. In this paper we investigate the decorrelation curves of acute rat brain slices for thicknesses in the range 1-3 mm (1/e decorrelation time on the order of seconds) using multi-speckle diffusing wave spectroscopy (MSDWS) and compare the results with theoretical predictions. The results of this study demonstrate that the 1/L^2 relationship between decorrelation time and thickness predicted by diffusing wave spectroscopy provides a good rule of thumb for estimating how the decorrelation of a sample will change with increasing thickness. Understanding this relationship will provide insight to guide the future development of biophotonic wavefront shaping tools by giving an estimate of how fast wavefront shaping systems need to operate to overcome the dynamic nature of biological samples.

  9. Pancreatic-derived pathfinder cells enable regeneration of critically damaged adult pancreatic tissue and completely reverse streptozotocin-induced diabetes.

    PubMed

    Stevenson, Karen; Chen, Daxin; MacIntyre, Alan; McGlynn, Liane M; Montague, Paul; Charif, Rawiya; Subramaniam, Murali; George, W D; Payne, Anthony P; Davies, R Wayne; Dorling, Anthony; Shiels, Paul G

    2011-04-01

    We demonstrate that intravenous delivery of human, or rat, pancreas-derived pathfinder (PDP) cells can totally regenerate critically damaged adult tissue and restore normal function across a species barrier. We have used a mouse model of streptozotocin (STZ)-induced diabetes to demonstrate this. Normoglycemia was restored and maintained for up to 89 days following the induction of diabetes and subsequent intravenous delivery of PDP cells. Normal pancreatic histology also appeared to be restored, and treated diabetic animals gained body weight. Regenerated tissue was primarily of host origin, with few rat or human cells detectable by fluorescent in situ hybridization (FISH). Crucially, the insulin produced by these animals was overwhelmingly murine in origin and was both types I and II, indicative of a process of developmental recapitulation. These results demonstrate the feasibility of using intravenous administration of adult cells to regenerate damaged tissue. Critically, they enhance our understanding of the mechanisms relating to such repair and suggest a means for novel therapeutic intervention in loss of tissue and organ function with age.

  10. Pathological considerations of laser-tissue interactions: light microscopic assessment of thermal damage of skin

    NASA Astrophysics Data System (ADS)

    Flotte, Thomas J.; Goetschkes, Margaret

    1992-06-01

    A variety of fixatives and stains were examined for the ability to differentially stain the extracellular matrix components of thermal damage to the skin in an attempt to provide methods for examining the extent of thermal effects. This information is important in comparing different lasers and laser parameters. Four zones of thermal damage were identified including char and three zones of less extensive damage. The lower bounds of the damage with steady state conditions for these zones were 64 - 66 degree(s)C, 80 - 85 degree(s)C, and > 100 degree(s)C. The best choices based on this study include the following: fixative: Bouin's, overall stain: H & E, inner zone stain: Pinkus' acid orcein giemsa, middle zone stain: Movat's pentachrome, and outer zone stain: the modified elastic stain presented in the appendix of this paper.

  11. Infusion of recombinant human tissue plasminogen activator through the superior mesenteric artery in the treatment of acute mesenteric venous thrombosis.

    PubMed

    da Motta Leal Filho, Joaquim Mauricio; Santos, Aline Cristine Barbosa; Carnevale, Francisco Cesar; de Oliveira Sousa, Wilson; Grillo, Luiz Sérgio Pereira; Cerri, Giovanni Guido

    2011-08-01

    Acute mesenteric venous thrombosis is an uncommon condition that is usually treated with systemic anticoagulation. Catheter-directed thrombolysis through the superior mesenteric artery may be a viable adjunct to treat this morbid condition. In the present article, we have described a case of superior mesenteric venous thrombosis treated with catheter-directed infusion of tissue plasminogen activator through the superior mesenteric artery.

  12. Biological Signatures of Brain Damage Associated with High Serum Ferritin Levels in Patients with Acute Ischemic Stroke and Thrombolytic Treatment

    PubMed Central

    Millán, Mónica; Sobrino, Tomás; Arenillas, Juan Francisco; Rodríguez-Yáñez, Manuel; García, María; Nombela, Florentino; Castellanos, Mar; de la Ossa, Natalia Pérez; Cuadras, Patricia; Serena, Joaquín; Castillo, José; Dávalos, Antoni

    2008-01-01

    Background and purpose: Increased body iron stores have been related to greater oxidative stress and brain injury in clinical and experimental cerebral ischemia and reperfusion. We aimed to investigate the biological signatures of excitotoxicity, inflammation and blood brain barrier disruption potentially associated with high serum ferritin levels-related damage in acute stroke patients treated with i.v. t-PA. Methods: Serum levels of ferritin (as index of increased cellular iron stores), glutamate, interleukin-6, matrix metalloproteinase-9 and cellular fibronectin were determined in 134 patients treated with i.v. t-PA within 3 hours from stroke onset in blood samples obtained before t-PA treatment, at 24 and 72 hours. Results: Serum ferritin levels before t-PA infusion correlated to glutamate (r = 0.59, p < 0.001) and interleukin-6 (r = 0.55, p <0.001) levels at baseline, and with glutamate (r = 0.57,p <0.001), interleukin-6 (r = 0.49,p <0.001), metalloproteinase-9 (r = 0.23, p = 0.007) and cellular fibronectin (r = 0.27, p = 0.002) levels measured at 24 hours and glutamate (r = 0.415, p < 0.001), interleukin-6 (r = 0.359, p < 0.001) and metalloproteinase-9 (r = 0.261, p = 0.004) at 72 hours. The association between ferritin and glutamate levels remained after adjustment for confounding factors in generalized linear models. Conclusions: Brain damage associated with increased iron stores in acute ischemic stroke patients treated with iv. tPA may be mediated by mechanisms linked to excitotoxic damage. The role of inflammation, blood brain barrier disruption and oxidative stress in this condition needs further research. PMID:19096131

  13. Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice.

    PubMed

    Shin, Jin A; Jeong, Sae Im; Kim, Minsuk; Yoon, Joo Chun; Kim, Hee-Sun; Park, Eun-Mi

    2015-11-01

    Visceral adipose tissue is accumulated with aging. An increase in visceral fat accompanied by low-grade inflammation is associated with several adult-onset diseases. However, the effects of visceral adipose tissue inflammation on the normal and ischemic brains of aged are not clearly defined. To examine the role of visceral adipose tissue inflammation, we evaluated inflammatory cytokines in the serum, visceral adipose tissue, and brain as well as blood-brain barrier (BBB) permeability in aged male mice (20 months) underwent sham or visceral fat removal surgery compared with the young mice (2.5 months). Additionally, ischemic brain injury was compared in young and aged mice with sham and visceral fat removal surgery. Interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels in examined organs were increased in aged mice compared with the young mice, and these levels were reduced in the mice with visceral fat removal. Increased BBB permeability with reduced expression of tight junction proteins in aged sham mice were also decreased in mice with visceral fat removal. After focal ischemic injury, aged mice with visceral fat removal showed a reduction in infarct volumes, BBB permeability, and levels of proinflammatory cytokines in the ischemic brain compared with sham mice, although the neurological outcomes were not significantly improved. In addition, further upregulated visceral adipose tissue inflammation in response to ischemic brain injury was attenuated in mice with visceral fat removal. These results suggest that visceral adipose tissue inflammation is associated with age-related changes in the brain and contributes to the ischemic brain damage in the aged mice. We suggest that visceral adiposity should be considered as a factor affecting brain health and ischemic brain damage in the aged population.

  14. Laser-induced damage in biological tissue: Role of complex and dynamic optical properties of the medium

    NASA Astrophysics Data System (ADS)

    Ahmed, Elharith M.

    Since its invention in the early 1960's, the laser has been used as a tool for surgical, therapeutic, and diagnostic purposes. To achieve maximum effectiveness with the greatest margin of safety it is important to understand the mechanisms of light propagation through tissue and how that light affects living cells. Lasers with novel output characteristics for medical and military applications are too often implemented prior to proper evaluation with respect to tissue optical properties and human safety. Therefore, advances in computational models that describe light propagation and the cellular responses to laser exposure, without the use of animal models, are of considerable interest. Here, a physics-based laser-tissue interaction model was developed to predict the spatial and temporal temperature and pressure rise during laser exposure to biological tissues. Our new model also takes into account the dynamic nature of tissue optical properties and their impact on the induced temperature and pressure profiles. The laser-induced retinal damage is attributed to the formation of microbubbles formed around melanosomes in the retinal pigment epithelium (RPE) and the damage mechanism is assumed to be photo-thermal. Selective absorption by melanin creates these bubbles that expand and collapse around melanosomes, destroying cell membranes and killing cells. The Finite Element (FE) approach taken provides suitable ground for modeling localized pigment absorption which leads to a non-uniform temperature distribution within pigmented cells following laser pulse exposure. These hot-spots are sources for localized thermo-elastic stresses which lead to rapid localized expansions that manifest themselves as microbubbles and lead to microcavitations. Model predictions for the interaction of lasers at wavelengths of 193, 694, 532, 590, 1314, 1540, 2000, and 2940 nm with biological tissues were generated and comparisons were made with available experimental data for the retina

  15. Radioprotection by WR-151327 against the late normal tissue damage in mouse hind legs from gamma ray radiation

    SciTech Connect

    Matsushita, Satoru; Ando, Koichi; Koike, Sachiko

    1994-11-15

    To evaluate the protective effect of WR-151327 on late radiation-induced damaged to normal tissues in mice, the right hind legs of mice with or without WR-151327 administration (400 mg/kg) were irradiated with {sup 137}Cs gamma rays. Leg contracture and skin shrinkage assays were performed at 380 days after irradiation. The mice were killed on day 400 postirradiation and histological sections of the legs were made. The thickness of the dermis, epidermis, and skin (dermis plus epidermis) was measured. The muscular area of the legs and the posterior knee angle between the femur and tibia were also measured. The left hind legs were similarly assessed as nonirradiated controls. Group means and standard deviations were calculated and dose-response curves were drawn for every endpoint. Then, the dose modifying factor (DMF) for each endpoint and the correlations among endpoints were determined. Latae damage assayed by leg contracture and skin shrinkage progressed with increasing radiation dose. However, it was reduced by drug treatment. The significant effect was indicated for skin shrinkage by a DMF of 1.8 at 35%. The DMF for leg contracture was 1.3 at 6 mm. In the irradiated legs, epidermal hyperplasia and dermal fibrosis in the skin, muscular atrophy, and extension disturbance of the knee joint were observed. These changes progressed with increasing radiation dose. Skin damage assayed by the present endpoints was also reduced by drug treatment by DMFs of 1.4 to 1.7. However, DMFs for damage to the muscle and knee were not determined because no isoeffect was observed. There were good correlations between leg contracture or skin shrinkage and the other endpoints in both untreated and drug-treated mice. WR-151327 has the potential to protect against radiation-induced late normal tissue damage. 17 refs., 6 figs., 2 tabs.

  16. Proliferation of Multiple Cell Types in the Skeletal Muscle Tissue Elicited by Acute p21 Suppression.

    PubMed

    Biferi, Maria Grazia; Nicoletti, Carmine; Falcone, Germana; Puggioni, Eleonora M R; Passaro, Nunzia; Mazzola, Alessia; Pajalunga, Deborah; Zaccagnini, Germana; Rizzuto, Emanuele; Auricchio, Alberto; Zentilin, Lorena; De Luca, Gabriele; Giacca, Mauro; Martelli, Fabio; Musio, Antonio; Musarò, Antonio; Crescenzi, Marco

    2015-05-01

    Although in the last decades the molecular underpinnings of the cell cycle have been unraveled, the acquired knowledge has been rarely translated into practical applications. Here, we investigate the feasibility and safety of triggering proliferation in vivo by temporary suppression of the cyclin-dependent kinase inhibitor, p21. Adeno-associated virus (AAV)-mediated, acute knockdown of p21 in intact skeletal muscles elicited proliferation of multiple, otherwise quiescent cell types, notably including satellite cells. Compared with controls, p21-suppressed muscles exhibited a striking two- to threefold expansion in cellularity and increased fiber numbers by 10 days post-transduction, with no detectable inflammation. These changes partially persisted for at least 60 days, indicating that the muscles had undergone lasting modifications. Furthermore, morphological hyperplasia was accompanied by 20% increases in maximum strength and resistance to fatigue. To assess the safety of transiently suppressing p21, cells subjected to p21 knockdown in vitro were analyzed for γ-H2AX accumulation, DNA fragmentation, cytogenetic abnormalities, ploidy, and mutations. Moreover, the differentiation competence of p21-suppressed myoblasts was investigated. These assays confirmed that transient suppression of p21 causes no genetic damage and does not impair differentiation. Our results establish the basis for further exploring the manipulation of the cell cycle as a strategy in regenerative medicine. PMID:25669433

  17. TU-F-12A-09: GLCM Texture Analysis for Normal-Tissue Toxicity: A Prospective Ultrasound Study of Acute Toxicity in Breast-Cancer Radiotherapy

    SciTech Connect

    Liu, T; Yang, X; Curran, W; Torres, M

    2014-06-15

    Purpose: To evaluate the morphologic and structural integrity of the breast glands using sonographic textural analysis, and identify potential early imaging signatures for radiation toxicity following breast-cancer radiotherapy (RT). Methods: Thirty-eight patients receiving breast RT participated in a prospective ultrasound imaging study. Each participant received 3 ultrasound scans: 1 week before RT (baseline), and at 6-week and 3-month follow-ups. Patients were imaged with a 10-MHz ultrasound on the four quadrant of the breast. A second order statistical method of texture analysis, called gray level co-occurrence matrix (GLCM), was employed to assess RT-induced breast-tissue toxicity. The region of interest (ROI) was 28 mm × 10 mm in size at a 10 mm depth under the skin. Twenty GLCM sonographic features, ratios of the irradiated breast and the contralateral breast, were used to quantify breast-tissue toxicity. Clinical assessment of acute toxicity was conducted using the RTOG toxicity scheme. Results: Ninety-seven ultrasound studies (776 images) were analyzed; and 5 out of 20 sonographic features showed significant differences (p < 0.05) among the baseline scans, the acute toxicity grade 1 and 2 groups. These sonographic features quantified the degree of tissue damage through homogeneity, heterogeneity, randomness, and symmetry. Energy ratio value decreased from 108±0.05 (normal) to 0.99±0.05 (Grade 1) and 0.84±0.04 (Grade 2); Entropy ratio value increased from 1.01±0.01 to 1.02±0.01 and 1.04±0.01; Contrast ratio value increased from 1.03±0.03 to 1.07±0.06 and 1.21±0.09; Variance ratio value increased from 1.06±0.03 to 1.20±0.04 and 1.42±0.10; Cluster Prominence ratio value increased from 0.98±0.02 to 1.01±0.04 and 1.25±0.07. Conclusion: This work has demonstrated that the sonographic features may serve as imaging signatures to assess radiation-induced normal tissue damage. While these findings need to be validated in a larger cohort, they suggest

  18. Dexrazoxane Diminishes Doxorubicin-Induced Acute Ovarian Damage and Preserves Ovarian Function and Fecundity in Mice

    PubMed Central

    Ringelstetter, Ashley; Khatib, Hasan; Abbott, David H.; Salih, Sana M.

    2015-01-01

    Advances in cancer treatment utilizing multiple chemotherapies have dramatically increased cancer survivorship. Female cancer survivors treated with doxorubicin (DXR) chemotherapy often suffer from an acute impairment of ovarian function, which can persist as long-term, permanent ovarian insufficiency. Dexrazoxane (Dexra) pretreatment reduces DXR-induced insult in the heart, and protects in vitro cultured murine and non-human primate ovaries, demonstrating a drug-based shield to prevent DXR insult. The present study tested the ability of Dexra pretreatment to mitigate acute DXR chemotherapy ovarian toxicity in mice through the first 24 hours post-treatment, and improve subsequent long-term fertility throughout the reproductive lifespan. Adolescent CD-1 mice were treated with Dexra 1 hour prior to DXR treatment in a 1:1 mg or 10:1 mg Dexra:DXR ratio. During the acute injury period (2–24 hours post-injection), Dexra pretreatment at a 1:1 mg ratio decreased the extent of double strand DNA breaks, diminished γH2FAX activation, and reduced subsequent follicular cellular demise caused by DXR. In fertility and fecundity studies, dams pretreated with either Dexra:DXR dose ratio exhibited litter sizes larger than DXR-treated dams, and mice treated with a 1:1 mg Dexra:DXR ratio delivered pups with birth weights greater than DXR-treated females. While DXR significantly increased the “infertility index” (quantifying the percentage of dams failing to achieve pregnancy) through 6 gestations following treatment, Dexra pretreatment significantly reduced the infertility index following DXR treatment, improving fecundity. Low dose Dexra not only protected the ovaries, but also bestowed a considerable survival advantage following exposure to DXR chemotherapy. Mouse survivorship increased from 25% post-DXR treatment to over 80% with Dexra pretreatment. These data demonstrate that Dexra provides acute ovarian protection from DXR toxicity, improving reproductive health in a mouse

  19. Oral Supplementation of Glucosamine Fails to Alleviate Acute Kidney Injury in Renal Ischemia-Reperfusion Damage.

    PubMed

    Johnsen, Marc; Späth, Martin Richard; Denzel, Martin S; Göbel, Heike; Kubacki, Torsten; Hoyer, Karla Johanna Ruth; Hinze, Yvonne; Benzing, Thomas; Schermer, Bernhard; Antebi, Adam; Burst, Volker; Müller, Roman-Ulrich

    2016-01-01

    Acute kidney injury is a leading contributor to morbidity and mortality in the ageing population. Proteotoxic stress response pathways have been suggested to contribute to the development of acute renal injury. Recent evidence suggests that increased synthesis of N-glycan precursors in the hexosamine pathway as well as feeding of animals with aminosugars produced in the hexosamine pathway may increase stress resistance through reducing proteotoxic stress and alleviate pathology in model organisms. As feeding of the hexosamine pathway metabolite glucosamine to aged mice increased their life expectancy we tested whether supplementation of this aminosugar may also protect mice from acute kidney injury after renal ischemia and reperfusion. Animals were fed for 4 weeks ad libitum with standard chow or standard chow supplemented with 0.5% N-acetylglucosamine. Preconditioning with caloric restriction for four weeks prior to surgery served as a positive control for protective dietary effects. Whereas caloric restriction demonstrated the known protective effect both on renal function as well as survival in the treated animals, glucosamine supplementation failed to promote any protection from ischemia-reperfusion injury. These data show that although hexosamine pathway metabolites have a proven role in enhancing protein quality control and survival in model organisms oral glucosamine supplementation at moderate doses that would be amenable to humans does not promote protection from ischemia-reperfusion injury of the kidney. PMID:27557097

  20. Oral Supplementation of Glucosamine Fails to Alleviate Acute Kidney Injury in Renal Ischemia-Reperfusion Damage

    PubMed Central

    Johnsen, Marc; Späth, Martin Richard; Denzel, Martin S.; Göbel, Heike; Kubacki, Torsten; Hoyer, Karla Johanna Ruth; Hinze, Yvonne; Benzing, Thomas; Schermer, Bernhard; Antebi, Adam; Burst, Volker; Müller, Roman-Ulrich

    2016-01-01

    Acute kidney injury is a leading contributor to morbidity and mortality in the ageing population. Proteotoxic stress response pathways have been suggested to contribute to the development of acute renal injury. Recent evidence suggests that increased synthesis of N-glycan precursors in the hexosamine pathway as well as feeding of animals with aminosugars produced in the hexosamine pathway may increase stress resistance through reducing proteotoxic stress and alleviate pathology in model organisms. As feeding of the hexosamine pathway metabolite glucosamine to aged mice increased their life expectancy we tested whether supplementation of this aminosugar may also protect mice from acute kidney injury after renal ischemia and reperfusion. Animals were fed for 4 weeks ad libitum with standard chow or standard chow supplemented with 0.5% N-acetylglucosamine. Preconditioning with caloric restriction for four weeks prior to surgery served as a positive control for protective dietary effects. Whereas caloric restriction demonstrated the known protective effect both on renal function as well as survival in the treated animals, glucosamine supplementation failed to promote any protection from ischemia-reperfusion injury. These data show that although hexosamine pathway metabolites have a proven role in enhancing protein quality control and survival in model organisms oral glucosamine supplementation at moderate doses that would be amenable to humans does not promote protection from ischemia-reperfusion injury of the kidney. PMID:27557097

  1. Common micro-RNA signature in skeletal muscle damage and regeneration induced by Duchenne muscular dystrophy and acute ischemia.

    PubMed

    Greco, Simona; De Simone, Marco; Colussi, Claudia; Zaccagnini, Germana; Fasanaro, Pasquale; Pescatori, Mario; Cardani, Rosanna; Perbellini, Riccardo; Isaia, Eleonora; Sale, Patrizio; Meola, Giovanni; Capogrossi, Maurizio C; Gaetano, Carlo; Martelli, Fabio

    2009-10-01

    The aim of this work was to identify micro-RNAs (miRNAs) involved in the pathological pathways activated in skeletal muscle damage and regeneration by both dystrophin absence and acute ischemia. Eleven miRNAs were deregulated both in MDX mice and in Duchenne muscular dystrophy patients (DMD signature). Therapeutic interventions ameliorating the mdx-phenotype rescued DMD-signature alterations. The significance of DMD-signature changes was characterized using a damage/regeneration mouse model of hind-limb ischemia and newborn mice. According to their expression, DMD-signature miRNAs were divided into 3 classes. 1) Regeneration miRNAs, miR-31, miR-34c, miR-206, miR-335, miR-449, and miR-494, which were induced in MDX mice and in DMD patients, but also in newborn mice and in newly formed myofibers during postischemic regeneration. Notably, miR-206, miR-34c, and miR-335 were up-regulated following myoblast differentiation in vitro. 2) Degenerative-miRNAs, miR-1, miR-29c, and miR-135a, that were down-modulated in MDX mice, in DMD patients, in the degenerative phase of the ischemia response, and in newborn mice. Their down-modulation was linked to myofiber loss and fibrosis. 3) Inflammatory miRNAs, miR-222 and miR-223, which were expressed in damaged muscle areas, and their expression correlated with the presence of infiltrating inflammatory cells. These findings show an important role of miRNAs in physiopathological pathways regulating muscle response to damage and regeneration.

  2. Protective Effect of Hydroalcoholic Extract of Tribulus Terrestris on Cisplatin Induced Renal Tissue Damage in Male Mice

    PubMed Central

    Raoofi, Amir; Khazaei, Mozafar; Ghanbari, Ali

    2015-01-01

    Background: According beneficial effects of Tribulus terrestris (TT) extract on tissue damage, the present study investigated the influence of hydroalcoholic extract of TT plant on cisplatin (CIS) (EBEWE Pharma, Unterach, Austria) induced renal tissue damage in male mice. Methods: Thirty mice were divided into five groups (n = 6). The first group (control) was treated with normal saline (0.9% NaCl) and experimental groups with CIS (E1), CIS + 100 mg/kg extract of TT (E2), CIS + 300 mg/kg extract of TT (E3), CIS + 500 mg/kg extract of TT (E4) intraperitoneally. The kidneys were removed after 4 days of injections, and histological evaluations were performed. Results: The data were analyzed using one-way analysis of variance followed by Tukey's post-hoc test, paired-sample t-test, Kruskal–Wallis and Mann–Whitney tests. In the CIS treated group, the whole kidney tissue showed an increased dilatation of Bowman's capsule, medullar congestion, and dilatation of collecting tubules and a decreased in the body weight and kidney weight. These parameters reached to the normal range after administration of fruit extracts of TT for 4 days. Conclusions: The results suggested that the oral administration of TT fruit extract at dose 100, 300 and 500 mg/kg body weight provided protection against the CIS induced toxicity in the mice. PMID:25789143

  3. Alterations in antioxidant enzyme activities and oxidative damage in alcoholic rat tissues: protective role of Thespesia populnea.

    PubMed

    Pandanaboina, Sahitya Chetan; Kondeti, Shanmugam Ramudu; Rajbanshi, Sangeetha Lakshmi; Kunala, Pavan Nagavenkata; Pandanaboina, Saritha; Pandanaboina, Murali Mohan; Wudayagiri, Rajendra

    2012-05-01

    Recent advances in our understanding of the pathogenesis of alcohol-induced hepato-renal injury and the development of new approaches to its treatment have been reported in various works. This study involves alcohol-induced oxidative stress linked to the metabolism of ethanol involving both mitochondrial and peroxisomal fractions of liver and kidney. Alcohol treatment resulted in the depletion of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), Glutathione-S-Transferase (GST) activities, and reduced glutathione (GSH) content, higher level of malondialdehyde (MDA) and lower levels of protein carbonyls (PC) causing malfunction of hepatic and renal tissues, when compared to control rats. Thespesia populnea (TP) leaf extracts, administered to chronic alcohol ingested rats, were envisaged to possess significant antioxidant defence properties and help in the recovery of tissues from alcohol-induced oxidative damage. The results showed that degenerative changes in hepatic and renal cells of alcoholic groups were minimized by the administration of TP leaf extracts as also revealed by histopathological examination. The current findings indicate that treatment with TP extracts reduces alcohol-induced oxidative stress, thereby protecting the hepatic and renal tissue from alcohol-induced damage.

  4. Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance.

    PubMed

    Miska, Jason; Abdulreda, Midhat H; Devarajan, Priyadharshini; Lui, Jen Bon; Suzuki, Jun; Pileggi, Antonello; Berggren, Per-Olof; Chen, Zhibin

    2014-03-10

    Real-time imaging studies are reshaping immunological paradigms, but a visual framework is lacking for self-antigen-specific T cells at the effector phase in target tissues. To address this issue, we conducted intravital, longitudinal imaging analyses of cellular behavior in nonlymphoid target tissues to illustrate some key aspects of T cell biology. We used mouse models of T cell-mediated damage and protection of pancreatic islet grafts. Both CD4(+) and CD8(+) effector T (Teff) lymphocytes directly engaged target cells. Strikingly, juxtaposed β cells lacking specific antigens were not subject to bystander destruction but grew substantially in days, likely by replication. In target tissue, Foxp3(+) regulatory T (Treg) cells persistently contacted Teff cells with or without involvement of CD11c(+) dendritic cells, an observation conciliating with the in vitro "trademark" of Treg function, contact-dependent suppression. This study illustrates tolerance induction by contact-based immune cell interaction in target tissues and highlights potentials of tissue regeneration under antigenic incognito in inflammatory settings.

  5. Gamma-Glutamyl Cysteine Attenuates Tissue Damage and Enhances Tissue Regeneration in a rat Model of Lead-Induced Nephrotoxicity.

    PubMed

    Salama, Samir A; Arab, Hany H; Maghrabi, Ibrahim A; Hassan, Memy H; AlSaeed, Mohammed S

    2016-09-01

    Lead is a biohazardous metal that is commonly involved in human illness including renal injury. Although it is a non-redox reactive metal, lead-induced renal injury is largely based on oxidative stress. The current work aimed at exploring the possible protective effect of γ-glutamyl cysteine (γGC) against lead-induced renal injury. Rats were allocated to normal and γGC control groups, lead-treated group, and lead and γGC-treated group. γGC alleviated lead-induced renal injury as evidenced by attenuation of histopathological aberration, amelioration of oxidative injury as demonstrated by significant reduction in lipid and protein oxidation, elevation of total antioxidant capacity, and glutathione level. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) was significantly elevated. γGC significantly decreased levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β and the activity of the apoptotic marker caspase-3. In addition, γGC reduced kidney lead content, enhanced weight gain, and improved renal function as demonstrated by reduced serum levels of urea and creatinine. Importantly, γGC upregulated proliferating cell nuclear antigen (PCNA) expression, denoting enhanced renal regenerative capacity. Together, our findings highlight evidence for alleviating effects of γGC against lead-induced renal injury that is potentially mediated through diminution of oxidative tissue injury, reduction of inflammatory response, attenuation of apoptosis, and enhancement of renal regenerative capacity.

  6. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation

    PubMed Central

    Keleku-Lukwete, Nadine; Suzuki, Mikiko; Otsuki, Akihito; Tsuchida, Kouhei; Katayama, Saori; Hayashi, Makiko; Naganuma, Eriko; Moriguchi, Takashi; Tanabe, Osamu; Engel, James Douglas; Imaizumi, Masue; Yamamoto, Masayuki

    2015-01-01

    Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells’ hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage. PMID:26371321

  7. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation.

    PubMed

    Keleku-Lukwete, Nadine; Suzuki, Mikiko; Otsuki, Akihito; Tsuchida, Kouhei; Katayama, Saori; Hayashi, Makiko; Naganuma, Eriko; Moriguchi, Takashi; Tanabe, Osamu; Engel, James Douglas; Imaizumi, Masue; Yamamoto, Masayuki

    2015-09-29

    Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells' hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage.

  8. Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: Protection by melatonin and cranberry flavonoids

    SciTech Connect

    Cheshchevik, V.T.; Lapshina, E.A.; Dremza, I.K.; Zabrodskaya, S.V.; Reiter, R.J.; Prokopchik, N.I.; Zavodnik, I.B.

    2012-06-15

    In current societies, the risk of toxic liver damage has markedly increased. The aim of the present work was to carry out further research into the mechanism(s) of liver mitochondrial damage induced by acute (0.8 g/kg body weight, single injection) or chronic (1.6 g/ kg body weight, 30 days, biweekly injections) carbon tetrachloride – induced intoxication and to evaluate the hepatoprotective potential of the antioxidant, melatonin, as well as succinate and cranberry flavonoids in rats. Acute intoxication resulted in considerable impairment of mitochondrial respiratory parameters in the liver. The activity of mitochondrial succinate dehydrogenase (complex II) decreased (by 25%, p < 0.05). Short-term melatonin treatment (10 mg/kg, three times) of rats did not reduce the degree of toxic mitochondrial dysfunction but decreased the enhanced NO production. After 30-day chronic intoxication, no significant change in the respiratory activity of liver mitochondria was observed, despite marked changes in the redox-balance of mitochondria. The activities of the mitochondrial enzymes, succinate dehydrogenase and glutathione peroxidase, as well as that of cytoplasmic catalase in liver cells were inhibited significantly. Mitochondria isolated from the livers of the rats chronically treated with CCl{sub 4} displayed obvious irreversible impairments. Long-term melatonin administration (10 mg/kg, 30 days, daily) to chronically intoxicated rats diminished the toxic effects of CCl{sub 4}, reducing elevated plasma activities of alanine aminotransferase and aspartate aminotransferase and bilirubin concentration, prevented accumulation of membrane lipid peroxidation products in rat liver and resulted in apparent preservation of the mitochondrial ultrastructure. The treatment of the animals by the complex of melatonin (10 mg/kg) plus succinate (50 mg/kg) plus cranberry flavonoids (7 mg/kg) was even more effective in prevention of toxic liver injury and liver mitochondria damage

  9. Effects of acute resistance exercise on muscle damage and perceptual measures between men who are lean and obese.

    PubMed

    Comstock, Brett A; Thomas, Gwendolyn A; Dunn-Lewis, Courtenay; Volek, Jeff S; Szivak, Tunde K; Hooper, David R; Kupchak, Brian R; Flanagan, Shawn D; Denegar, Craig R; Kraemer, William J

    2013-12-01

    The purpose of this investigation was to assess indices of muscle damage and psychological stress between young, untrained, lean, and obese men. Using a between-subject design, 19 young men (9 lean men [age, 20.1 ± 2.1 years; body mass, 71.7 ± 5.8 kg; height, 177.8 ± 8.7 cm; body fat (BF), 14.7 ± 3.5%], 5 World Health Organization [WHO] class 1 obese men [age, 21.6 ± 2.5 years; body mass, 97.8 ± 8.6 kg; height, 176.3 ± 3.7 cm; BF, 34.7 ± 3.0%], and 5 WHO class 2 or 3 men [age, 20.0 ± 1.4 years; body mass, 120.8 ± 10.5 kg; height, 177.7 ± 5.2 cm; BF, 40.5 ± 5.8%]) volunteered and completed an acute resistance exercise (RE) protocol (6 exercises performed for 3 sets of 10 repetitions at an intensity of 85-95% of a 10 repetition maximum). Plasma myoglobin and serum creatine kinase were obtained before and immediately after exercise, and in recovery (at +110 minutes and +24 hours). Perceptual measures including rating of perceived exertion, pain and soreness, fatigue, and general soreness were assessed at different time points (during exercise for rating of perceived exertion, and for the fatigue and soreness measures before, immediately after, and at 24 hours of recovery from exercise). The primary findings of this investigation were that lean and obese, sedentary, young men do not significantly differ from each other in terms of indirect, humoral measures of muscle damage, or perceptual scales in response to a moderate-intensity acute RE bout, despite using significantly more exercise volume relative to fat mass (FM). We conclude that excess FM during daily activities of life provides a protective effect for muscle damage. When strength training individuals who are obese, practitioners should be aware of how excess FM affects muscle damage and total volume. But these considerations do not preclude individuals who are obese from using well-designed RE workouts which use free-weight, multijoint movements that stimulate all of the major muscle groups.

  10. Beyond Tissue Injury—Damage-Associated Molecular Patterns, Toll-Like Receptors, and Inflammasomes Also Drive Regeneration and Fibrosis

    PubMed Central

    2014-01-01

    Tissue injury initiates an inflammatory response through the actions of immunostimulatory molecules referred to as damage-associated molecular patterns (DAMPs). DAMPs encompass a group of heterogenous molecules, including intracellular molecules released during cell necrosis and molecules involved in extracellular matrix remodeling such as hyaluronan, biglycan, and fibronectin. Kidney-specific DAMPs include crystals and uromodulin released by renal tubular damage. DAMPs trigger innate immunity by activating Toll-like receptors, purinergic receptors, or the NLRP3 inflammasome. However, recent evidence revealed that DAMPs also trigger re-epithelialization upon kidney injury and contribute to epithelial-mesenchymal transition and, potentially, to myofibroblast differentiation and proliferation. Thus, these discoveries suggest that DAMPs drive not only immune injury but also kidney regeneration and renal scarring. Here, we review the data from these studies and discuss the increasingly complex connection between DAMPs and kidney diseases. PMID:24762401

  11. Acute ZnO nanoparticles exposure induces developmental toxicity, oxidative stress and DNA damage in embryo-larval zebrafish.

    PubMed

    Zhao, Xuesong; Wang, Shutao; Wu, Yuan; You, Hong; Lv, Lina

    2013-07-15

    Nano-scale zinc oxide (nano-ZnO) is widely used in various industrial and commercial applications. However, the available toxicological information was inadequate to assess the potential ecological risk of nano-ZnO to aquatic organisms and the publics. In this study, the developmental toxicity, oxidative stress and DNA damage of nano-ZnO embryos were investigated in the embryo-larval zebrafish, the toxicity of Zn(2+) releasing from nano-ZnO were also investigated to ascertain the relationship between the nano-ZnO and corresponding Zn(2+). Zebrafish embryos were exposed to 1, 5, 10, 20, 50, and 100mg/L nano-ZnO and 0.59, 2.15, 3.63, 4.07, 5.31, and 6.04 mg/L Zn(2+) for 144 h post-fertilisation (hpf), respectively. Up to 144 hpf, activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and malondialdehyde (MDA) contents, the genes related to oxidative damage, reactive oxygen species (ROS) generation and DNA damage in zebrafish embryos were measured. The nano-ZnO was found to exert a dose-dependent toxicity to zebrafish embryos and larvae, reducing the hatching rate and inducing malformation and the acute toxicity to zebrafish embryos was greater than that of the Zn(2+) solution. The generation of ROS was significantly increased at 50 and 100mg/L nano-ZnO. DNA damage of zebrafish embryo was evaluated by single-cell gel electrophoresis and was enhanced with increasing nano-ZnO concentration. Moreover, the transcriptional expression of mitochondrial inner membrane genes related to ROS production, such as Bcl-2, in response to oxidative damage, such as Nqo1, and related to antioxidant response element such as Gstp2 were significantly down-regulated in the nano-ZnO treatment groups. However, the nano-ZnO up-regulated the transcriptional expression of Ucp2-related to ROS production. In conclusion, nano-ZnO induces developmental toxicity, oxidative stress and DNA damage on zebrafish embryos and the dissolved Zn(2+) only partially

  12. Acute oxidant damage promoted on cancer cells by amitriptyline in comparison with some common chemotherapeutic drugs.

    PubMed

    Cordero, Mario David; Sánchez-Alcázar, José Antonio; Bautista-Ferrufino, María Rosa; Carmona-López, María Inés; Illanes, Matilde; Ríos, María José; Garrido-Maraver, Juan; Alcudia, Ana; Navas, Plácido; de Miguel, Manuel

    2010-11-01

    Oxidative therapy is a relatively new anticancer strategy based on the induction of high levels of oxidative stress, achieved by increasing intracellular reactive oxygen species (ROS) and/or by depleting the protective antioxidant machinery of tumor cells. We focused our investigations on the antitumoral potential of amitriptyline in three human tumor cell lines: H460 (lung cancer), HeLa (cervical cancer), and HepG2 (hepatoma); comparing the cytotoxic effect of amitriptyline with three commonly used chemotherapeutic drugs: camptothecin, doxorubicin, and methotrexate. We evaluated apoptosis, ROS production, mitochondrial mass and activity, and antioxidant defenses of tumor cells. Our results show that amitriptyline produces the highest cellular damage, inducing high levels of ROS followed by irreversible serious mitochondrial damage. Interestingly, an unexpected decrease in antioxidant machinery was observed only for amitriptyline. In conclusion, based on the capacity of generating ROS and inhibiting antioxidants in tumor cells, amitriptyline emerges as a promising new drug to be tested for anticancer therapy.

  13. Neuroprotection and enhanced neurogenesis by extract from the tropical plant Knema laurina after inflammatory damage in living brain tissue.

    PubMed

    Häke, Ines; Schönenberger, Silvia; Neumann, Jens; Franke, Katrin; Paulsen-Merker, Katrin; Reymann, Klaus; Ismail, Ghazally; Bin Din, Laily; Said, Ikram M; Latiff, A; Wessjohann, Ludger; Zipp, Frauke; Ullrich, Oliver

    2009-01-01

    Inflammatory reactions in the CNS, resulting from a loss of control and involving a network of non-neuronal and neuronal cells, are major contributors to the onset and progress of several major neurodegenerative diseases. Therapeutic strategies should therefore keep or restore the well-controlled and finely-tuned balance of immune reactions, and protect neurons from inflammatory damage. In our study, we selected plants of the Malaysian rain forest by an ethnobotanic survey, and investigated them in cell-based-assay-systems and in living brain tissue cultures in order to identify anti-inflammatory and neuroprotective effects. We found that alcoholic extracts from the tropical plant Knema laurina (Black wild nutmeg) exhibited highly anti-inflammatory and neuroprotective effects in cell culture experiments, reduced NO- and IL-6-release from activated microglia cells dose-dependently, and protected living brain tissue from microglia-mediated inflammatory damage at a concentration of 30 microg/ml. On the intracellular level, the extract inhibited ERK-1/2-phosphorylation, IkB-phosphorylation and subsequently NF-kB-translocation in microglia cells. K. laurina belongs to the family of Myristicaceae, which have been used for centuries for treatment of digestive and inflammatory diseases and is also a major food plant of the Giant Hornbill. Moreover, extract from K. laurina promotes also neurogenesis in living brain tissue after oxygen-glucose deprivation. In conclusion, extract from K. laurina not only controls and limits inflammatory reaction after primary neuronal damage, it promotes moreover neurogenesis if given hours until days after stroke-like injury.

  14. The effect of interferon gamma on conventional fractionated radiation-induced damage and fibrosis in the pelvic tissue of rabbits

    PubMed Central

    Yang, Yunyi; Liu, Zi; Wang, Juan; Chai, Yanlan; Su, Jin; Shi, Fan; Wang, Jiquan; Che, Shao Min

    2016-01-01

    We aim to investigate the effect of interferon gamma (IFN-γ) on conventional fractionated radiation–induced damage and fibrosis in ureter and colorectal mucosa. Fifty-two rabbits were randomly divided into three groups comprising a conventional radiation group, an IFN-γ group, and a control group. X-rays were used to irradiate the pelvic tissues of the rabbits in the IFN-γ and conventional radiation groups. Five days after radiation exposure, the rabbits in the IFN-γ group were administered 250,000 U/kg IFN-γ intramuscularly once a week for 5 weeks. The rabbits in the conventional radiation group received 5.0 mL/kg saline. The rabbits were sacrificed at 4, 8, 12, and 16 weeks postradiation, and the rectal and ureteral tissues within the radiation areas were collected. The results showed that the morphology of rectal and ureteral tissues was changed by X-ray radiation. The degree of damage at 4, 8, and 12 weeks, but not at 16 weeks, postradiation was significantly different between the IFN-γ and conventional radiation groups. The expression of transforming growth factor beta 1 mRNA in the ureter and colorectal mucosa of the IFN-γ group was significantly lower than that in the conventional radiation group at 4, 8, 12, and 16 weeks postradiation, but it was still higher than that in the control group. There were significant differences in the expression of collagen III among the three groups. IFN-γ can inhibit the radiation-induced upregulation of transforming growth factor beta 1 mRNA and collagen III protein in the ureter and colorectal mucosa and attenuate radiation-induced damage and fibrosis. PMID:27274263

  15. Genome-wide effects of acute progressive feed restriction in liver and white adipose tissue

    SciTech Connect

    Pohjanvirta, Raimo Boutros, Paul C.; Moffat, Ivy D.; Linden, Jere; Wendelin, Dominique; Okey, Allan B.

    2008-07-01

    Acute progressive feed restriction (APFR) represents a specific form of caloric restriction in which feed availability is increasingly curtailed over a period of a few days to a few weeks. It is often used for control animals in toxicological and pharmacological studies on compounds causing body weight loss to equalize weight changes between experimental and control groups and thereby, intuitively, to also set their metabolic states to the same phase. However, scientific justification for this procedure is lacking. In the present study, we analyzed by microarrays the impact on hepatic gene expression in rats of two APFR regimens that caused identical diminution of body weight (19%) but differed slightly in duration (4 vs. 10 days). In addition, white adipose tissue (WAT) was also subjected to the transcriptomic analysis on day-4. The data revealed that the two regimens led to distinct patterns of differentially expressed genes in liver, albeit some major pathways of energy metabolism were similarly affected (particularly fatty acid and amino acid catabolism). The reason for the divergence appeared to be entrainment by the longer APFR protocol of peripheral oscillator genes, which resulted in derailment of circadian rhythms and consequent interaction of altered diurnal fluctuations with metabolic adjustments in gene expression activities. WAT proved to be highly unresponsive to the 4-day APFR as only 17 mRNA levels were influenced by the treatment. This study demonstrates that body weight is a poor proxy of metabolic state and that the customary protocols of feed restriction can lead to rhythm entrainment.

  16. Clinical features and outcome of acute exacerbation of interstitial pneumonia associated with connective tissue disease.

    PubMed

    Toyoda, Yuko; Hanibuchi, Masaki; Kishi, Jun; Kawano, Hiroshi; Morizumi, Shun; Sato, Seidai; Kondo, Mayo; Takikura, Terumi; Tezuka, Toshifumi; Goto, Hisatsugu; Nishioka, Yasuhiko

    2016-01-01

    Acute exacerbation (AE) of interstitial lung disease is reported to be developed in not only idiopathic pulmonary fibrosis but also connective tissue disease-associated interstitial pneumonia (CTD-IP). As the significance of AE of CTD-IP has not been so widely recognized, its clinical feature is not fully elucidated. In the present study, we investigated the incidence, clinical features and outcome of AE of CTD-IP. We retrospectively reviewed admitted cases in our department with medical record from 2011 to 2015. Among 155 patients with CTD-IP, 10 (6.5%) cases developed AE (6 rheumatoid arthritis, 2 polymyositis/dermatomyositis, 1 systemic lupus erythematosus, 1 Sjögren syndrome), and one died of AE within 30 days. Median survival time after the onset of AE was 169 days in all 10 patients. The treatment with immunosuppressant just before AE onset might improve the prognosis of AE. The median survival time after the onset of AE was significantly longer in patients showing good response to corticosteroid compared with those with poor response to corticosteroid (805 days and 45 days, respectively) (p <0.05), suggesting that there are some cases in CTD-IP, showing the good response to corticosteroid even when AE was complicated. J. Med. Invest. 63: 294-299, August, 2016. PMID:27644575

  17. Characterization and response of antioxidant systems in the tissues of the freshwater pond snail (Lymnaea stagnalis) during acute copper exposure.

    PubMed

    Atli, Gülüzar; Grosell, Martin

    2016-07-01

    The response of enzymatic (superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase, GPX and glutathione reductase, GR) and non-enzymatic responses (glutathione, GSH, oxidized glutathione, GSSG and GSH/GSSG) against acute Cu toxicity (2-90μg/mL for 48h) in different tissues of Lymnaea stagnalis were measured. Incubation conditions for enzymatic activity measurements were optimized for L. stagnalis tissues. Three examined tissues, the hepatopancreas, the foot muscle and the mantle, exhibited variable responses in antioxidant parameters as a function of Cu concentrations. The most responsive antioxidant enzymes were GPX and CAT while GR appeared less sensitive. In general antioxidant enzymes at higher Cu concentrations though GSH levels at lower Cu concentrations exhibited the greatest changes in hepatopancreas and foot muscle, respectively. All antioxidant enzymes except GR increased after exposure to the highest Cu concentration in mantle. Total and reduced GSH increased in hepatopancreas but decreased with GSH/GSSG ratios at all Cu concentrations in foot muscle. The present results show that antioxidants respond to acute Cu exposure at concentrations as low as 2μg Cu/L in adult L. stagnalis with variable responses in different tissues. Antioxidants both including enzymatic and non-enzymatic parameters may account, in part, for the high tolerance to acute metal exposure observed in adult L. stagnalis and could form suited biomarkers to evaluate the metal exposure and toxicity in aquatic environment even at relatively low level short term exposure. PMID:27108202

  18. Human mesenchymal stem cells attenuate early damage in a ventilated pig model of acute lung injury.

    PubMed

    Moodley, Yuben; Sturm, Marian; Shaw, Kathryn; Shimbori, Chiko; Tan, Dino B A; Kolb, Martin; Graham, Ruth

    2016-07-01

    Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a major cause of global morbidity and mortality. Mesenchymal stem cells (MSC) have shown promise in treating inflammatory lung conditions. We hypothesised that human MSC (hMSC) can improve ALI/ARDS through their anti-inflammatory actions. We subjected pigs (n=6) to intravenous oleic acid (OA) injury, ventilation and hMSC infusion, while the controls (n=5) had intravenous OA, ventilation and an infusion vehicle control. hMSC were infused 1h after the administration of OA. The animals were monitored for additional 4h. Nuclear translocation of nuclear factor-light chain enhancer of activated B cells (NF-κB), a transcription factor that mediates several inflammatory pathways was reduced in hMSC treated pigs compared to controls (p=0.04). There was no significant difference in lung injury, assessed by histological scoring in hMSC treated pigs versus controls (p=0.063). There was no difference in neutrophil counts between hMSC-treated pigs and controls. Within 4h, there was no difference in the levels of IL-10 and IL-8 pre- and post-treatment with hMSC. In addition, there was no difference in hemodynamics, lung mechanics or arterial blood gases between hMSC treated animals and controls. Subsequent studies are required to determine if the observed decrease in inflammatory transcription factors will translate into improvement in inflammation and in physiological parameters over the long term.

  19. Genotoxicity assessment of carp (Cyprinus carpio L.) fingerlings by tissue DNA damage and micronucleus test, after environmental exposure to fenitrothion.

    PubMed

    Sepici-Dincel, Aylin; Sahin, Duygu; Karasu Benli, A Caglan; Sarikaya, Rabia; Selvi, Mahmut; Erkoc, Figen; Altan, Nilgun

    2011-06-01

    The purpose of this study was to evaluate the adverse effects of sublethal doses of fenitrothion, an organophosphothionate insecticide on brain, gill, liver, and muscle tissues as a ratio of 8-OHdG to dG to indicate the DNA damage and erythrocyte micronucleus frequency for genotoxicity of carp (Cyprinus carpio L.) fingerlings. In our study, the mean weights and lengths of the fish (n = 4-12) were 31.13 ± 14.24 g and 12.53 ± 1.41, respectively. Before the experiment, fish were maintained in aerated dechlorinated tap water at 21.8 ± 1 °C and fed daily with commercial feed at a rate of 2% of their body weights. Experiments were conducted under static conditions in the aquaria. Technical grade (95%) fenitrothion was diluted in acetone to give a dosing solution of 10 mg/L. The increased lesions/10⁶ DNA bases (p < 0.05) of liver tissue of exposure group (0.49 ± 0.18) was observed when compared to control group (0.28 ± 0.30). There was not any significant differences between brain tissues, no damage were detectable in gill and muscle tissues of control groups, and in exposure groups altered levels of damage were detected for gill (0.06 ± 0.05) and muscle (0.16 ± 0.21) tissues. The increased micronucleus frequencies (%) in erythrocytes of carp following the exposure to 48 h fenitrothion (6.43 ± 3.89; p<0.05) was observed when compared to control group (1.29 ± 1.03). The available data indicate that there is still lack of well-established dose-response relationships between occupational or environmental exposures and the induction of 8-OHdG. Such biomarkers may be used in assessing adverse/toxic effects of pesticides as environmental stressors. PMID:21417631

  20. Acute Oxidative Effect and Muscle Damage after a Maximum 4 Min Test in High Performance Athletes

    PubMed Central

    Fernandes Filho, José; Fernandes, Luiz Cláudio

    2016-01-01

    The purpose of this investigation was to determine lipid peroxidation markers, physiological stress and muscle damage in elite kayakers in response to a maximum 4-min kayak ergometer test (KE test), and possible correlations with individual 1000m kayaking performances. The sample consisted of twenty-three adult male and nine adult female elite kayakers, with more than three years’ experience in international events, who voluntarily took part in this study. The subjects performed a 10-min warm-up, followed by a 2-min passive interval, before starting the test itself, which consisted of a maximum 4-min work paddling on an ergometer; right after the end of the test, an 8 ml blood sample was collected for analysis. 72 hours after the test, all athletes took part in an official race, when then it was possible to check their performance in the on site K1 1000m test (P1000m). The results showed that all lipoproteins and hematological parameters tested presented a significant difference (p≤0.05) after exercise for both genders. In addition, parameters related to muscle damage such as lactate dehydrogenase (LDH) and creatine kinase (CK) presented significant differences after stress. Uric acid presented an inverse correlation with the performance (r = -0.76), while CK presented a positive correlation (r = 0.46) with it. Based on these results, it was possible to verify muscle damage and the level of oxidative stress caused by indoor training with specific ergometers for speed kayaking, highlighting the importance of analyzing and getting to know the physiological responses to this type of training, in order to provide information to coaches and optimize athletic performance. PMID:27111088

  1. Myocardial changes in acute Trypanosoma cruzi infection. Ultrastructural evidence of immune damage and the role of microangiopathy.

    PubMed Central

    Andrade, Z. A.; Andrade, S. G.; Correa, R.; Sadigursky, M.; Ferrans, V. J.

    1994-01-01

    Histological and ultrastructural studies of the hearts of dogs sacrificed 18 to 26 days after intraperitoneal inoculation with 4 x 10(5) blood forms of the 12 SF strain of Trypanosoma cruzi/kg of body weight disclosed myocarditis characterized by parasitic invasion of some myocytes, damage and necrosis of nonparasitized myocytes, and interstitial infiltration by mononuclear cells. Nonparasitized myocytes showed alterations ranging from mild edema to severe myocytolysis. These changes often were accompanied by contacts of myocytes with lymphocytes (both granular and agranular) and macrophages. These contacts were characterized by focal loss of the myocyte basement membrane and close approximation of the plasma membranes of the two cells. Contacts between lymphocytes and capillary endothelial cells were also frequent. Platelet aggregates and fibrin microthrombi were observed in some capillaries. Our findings suggest that immune effector cells play a major role in the pathogenesis of the myocyte damage and the microangiopathy in acute Chagas' disease. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 PMID:8203476

  2. Cgnz1 allele confers kidney resistance to damage preventing progression of immune complex-mediated acute lupus glomerulonephritis.

    PubMed

    Ge, Yan; Jiang, Chao; Sung, Sun-Sang J; Bagavant, Harini; Dai, Chao; Wang, Hongyang; Kannapell, Carol C; Cathro, Helen P; Gaskin, Felicia; Fu, Shu Man

    2013-10-21

    Cgnz1 and Agnz1 on the distal region of mouse chromosome 1 are associated with chronic glomerulonephritis (cGN) and acute GN (aGN). NZM2328.Lc1R27 (R27) was generated by introgressing a C57L/J region where Cgnz1 is located to NZM2328. R27 female mice developed aGN mediated by immune complex (IC) deposition and complement activation without progression to cGN with severe proteinuria. End stage renal disease (ESRD) was not seen in R27 mice as old as 15 mo. Thus, aGN and cGN are under separate genetic control, and IC-mediated proliferative GN need not progress to cGN and ESRD. NZM2328 and R27 female mice have comparable immune and inflammatory parameters. In contrast to NZM2328, R27 mice were resistant to sheep anti-mouse GBM serum-induced nephritis, supporting the hypothesis that aGN is mediated by autoimmunity and resistance to the development of cGN is mediated by end organ resistance to damage. Thus, autoimmunity should be considered distinct from end organ damage. The Cgnz1 region has been mapped to a 1.34 MB region with 45 genes. Nine candidate genes were identified. Clinical relevance of these observations is supported by case studies. Clinical implications and the significance to human lupus and other diseases are presented.

  3. Enhanced ROS production and oxidative damage in subcutaneous white adipose tissue mitochondria in obese and type 2 diabetes subjects.

    PubMed

    Chattopadhyay, Mrittika; Khemka, Vineet Kumar; Chatterjee, Gargi; Ganguly, Anirban; Mukhopadhyay, Satinath; Chakrabarti, Sasanka

    2015-01-01

    Oxidative stress in the insulin target tissues has been implicated in the pathophysiology of type 2 diabetes. The study has examined the oxidative stress parameters in the mitochondria of subcutaneous white adipose tissue from obese and non-obese subjects with or without type 2 diabetes. An accumulation of protein carbonyls, fluorescent lipid peroxidation products, and malondialdehyde occurs in the adipose tissue mitochondria of obese type 2 diabetic, non-diabetic obese, and non-obese diabetic subjects with the maximum increase noticed in the obese type 2 diabetes patients and the minimum in non-obese type 2 diabetics. The mitochondria from obese type 2 diabetics, non-diabetic obese, and non-obese type 2 diabetics also produce significantly more reactive oxygen species (ROS) in vitro compared to those of controls, and apparently the mitochondrial ROS production rate in each group is proportional to the respective load of oxidative damage markers. Likewise, the mitochondrial antioxidant enzymes like superoxide dismutase and glutathione peroxidase show decreased activities most markedly in obese type 2 diabetes subjects and to a lesser degree in non-obese type 2 diabetes or non-diabetic obese subjects in comparison to control. The results imply that mitochondrial dysfunction with enhanced ROS production may contribute to the metabolic abnormality of adipose tissue in obesity and diabetes.

  4. Modelling the effect of repositioning on the evolution of skeletal muscle damage in deep tissue injury.

    PubMed

    Demol, Jan; Deun, Dorien Van; Haex, Bart; Oosterwyck, Hans Van; Sloten, Jos Vander

    2013-04-01

    Deep tissue injury (DTI) is a localized area of tissue necrosis that originates in the subcutaneous layers under an intact skin and tends to develop when soft tissue is compressed for a prolonged period of time. In clinical practice, DTI is particularly common in bedridden patients and remains a serious issue in todays health care. Repositioning is generally considered to be an effective preventive measure of pressure ulcers. However, limited experimental research and no computational studies have been undertaken on this method. In this study, a methodology was developed to evaluate the influence of different repositioning intervals on the location, size and severity of DTI in bedridden patients. The spatiotemporal evolution of compressive stresses and skeletal muscle viability during the first 48 h of DTI onset was simulated for repositioning schemes in which a patient is turned every 2, 3, 4 or 6 h. The model was able to reproduce important experimental findings, including the morphology and location of DTI in human patients as well as the discrepancy between the internal tissue loads and the contact pressure at the interface with the environment. In addition, the model indicated that the severity and size of DTI were reduced by shortening the repositioning intervals. In conclusion, the computational framework presented in this study provides a promising modelling approach that can help to objectively select the appropriate repositioning scheme that is effective and efficient in the prevention of DTI.

  5. Protective Role of Nuclear Factor E2-Related Factor 2 against Acute Oxidative Stress-Induced Pancreatic β -Cell Damage.

    PubMed

    Fu, Jingqi; Zheng, Hongzhi; Wang, Huihui; Yang, Bei; Zhao, Rui; Lu, Chunwei; Liu, Zhiyuan; Hou, Yongyong; Xu, Yuanyuan; Zhang, Qiang; Qu, Weidong; Pi, Jingbo

    2015-01-01

    Oxidative stress is implicated in the pathogenesis of pancreatic β-cell dysfunction that occurs in both type 1 and type 2 diabetes. Nuclear factor E2-related factor 2 (NRF2) is a master regulator in the cellular adaptive response to oxidative stress. The present study found that MIN6 β-cells with stable knockdown of Nrf2 (Nrf2-KD) and islets isolated from Nrf2-knockout mice expressed substantially reduced levels of antioxidant enzymes in response to a variety of stressors. In scramble MIN6 cells or wild-type islets, acute exposure to oxidative stressors, including hydrogen peroxide (H2O2) and S-nitroso-N-acetylpenicillamine, resulted in cell damage as determined by decrease in cell viability, reduced ATP content, morphology changes of islets, and/or alterations of apoptotic biomarkers in a concentration- and/or time-dependent manner. In contrast, silencing of Nrf2 sensitized MIN6 cells or islets to the damage. In addition, pretreatment of MIN6 β-cells with NRF2 activators, including CDDO-Im, dimethyl fumarate (DMF), and tert-butylhydroquinone (tBHQ), protected the cells from high levels of H2O2-induced cell damage. Given that reactive oxygen species (ROS) are involved in regulating glucose-stimulated insulin secretion (GSIS) and persistent activation of NRF2 blunts glucose-triggered ROS signaling and GSIS, the present study highlights the distinct roles that NRF2 may play in pancreatic β-cell dysfunction that occurs in different stages of diabetes. PMID:25949772

  6. Acute toxicity of heavy metals to Tetrahymena in an in vitro experiment and envelope damage study.

    PubMed

    Zhang, Tian; Li, Xi; Lu, Yang; Wu, Chunyun; Fang, Tingting; Liu, Peng; Zhang, Chaocan; Liang, Wei

    2013-07-01

    The toxicity of Cr³⁺, Cu²⁺ and Cd²⁺ to Tetrahymena growth metabolism was studied by microcalorimetry at 28°C, and the growth constant (k), peak time (T) and generation times (T(G)) were calculated. The metal ion concentrations that resulted in 50% inhibition (IC₅₀) of population growth were obtained through the dynamic parameters. The results indicated that the order of toxicity was Cd²⁺> Cr³⁺> Cu²⁺. Inductively coupled plasma-atomic emission spectrometry results suggested that the metal ions affected the permeability of the cell membrane. Observations of the Cd-exposed organisms by scanning electron microscopy revealed damage to the cell membrane in the form of an altered surface appearance. The cells suffered serious damage after sufficient acting time. Attenuated total reflection Fourier transform infrared spectra revealed that amide groups and PO₂⁻ of the phospholipid phospho-diester, both located in the hydrophobic end of the outer layer of the cell membrane, were most readily affected.

  7. Endothelial cells are damaged by autophagic induction before hepatocytes in Con A-induced acute hepatitis.

    PubMed

    Yang, Ming-Chen; Chang, Chih-Peng; Lei, Huan-Yao

    2010-08-01

    We have reported both T-cell-dependent and -independent hepatitis in immunocompetent and immunodeficiency mice, respectively, after intravenous injection of Con A in mice. The mode of hepatocyte cell death is different: autophagy for T-cell-independent hepatitis in contrast to apoptosis for T-cell-dependent one. In this study, we further demonstrate that liver blood vessels are the first target in both modes. The infused Con A bond to the hepatic vascular endothelial cells and cause its damage with autophagy. Before the elevation of the serum alanine aminotransferase at 6 h post-injection, the plasma leakage and hemorrhage occur at 1-3 h without inflammation. Con A induces autophagy of endothelial cells and hemorrhage that is enhanced by IFN-gamma. Using the endothelial cell line HMEC-1, a dose- and time-dependent cell death with autophagic LC3-II (microtubule-associated protein light chain 3) conversion was induced by Con A and was enhanced by IFN-gamma. In conclusion, Con A induced autophagy on hepatic endothelial cells; the damage of liver blood vessel occurs before the induction of T-cell-dependent hepatitis via apoptosis or T-cell-independent hepatitis via autophagy.

  8. Lectin from Crataeva tapia Bark Improves Tissue Damages and Plasma Hyperglycemia in Alloxan-Induced Diabetic Mice

    PubMed Central

    da Rocha, Amanda Alves; Araújo, Tiago Ferreira da Silva; da Fonseca, Caíque Silveira Martins; da Mota, Diógenes Luís; de Medeiros, Paloma Lys; Paiva, Patrícia Maria Guedes; Coelho, Luana Cassandra Breitenbach Barroso; Correia, Maria Tereza dos Santos; Lima, Vera Lúcia de Menezes

    2013-01-01

    Crataeva tapia is a plant popularly used for diabetes treatment, in Brazil. Progressive decline in renal and hepatic functions has been described in patients with diabetes mellitus, and mortality rate is increased in patients with chronic liver and renal disease. This study aimed to evaluate whether Crataeva tapia bark lectin (CrataBL) improves hyperglycemia and renal and hepatic damage in diabetic mice. CrataBL was purified by ion exchange chromatography on CM-cellulose, and intraperitoneal administration of CrataBL to alloxan-induced diabetic mice at dose of 10 mg/Kg/day and 20 mg/Kg/day for 10 days significantly reduced serum glucose levels by 14.9% and 55.9%, respectively. Serum urea, creatinine, aspartate aminotransferase, and alanine aminotransferase were also significantly reduced after treatment with both doses of CrataBL. Furthermore, histological analysis of liver, kidney, and pancreas revealed an improvement in the tissue morphology upon treatment with CrataBL. The results suggest that CrataBL has a beneficial hypoglycemic activity and improves the renal and hepatic complications of diabetes. Therefore, this lectin may be a promising agent for the treatment of diabetes, and this might be the basis for its use in the folk medicine as an alternative treatment to manage diabetes-related complications such as hyperglycemia and tissue damage. PMID:24324521

  9. Therapeutic hypothermia attenuates tissue damage and cytokine expression after traumatic brain injury by inhibiting necroptosis in the rat

    PubMed Central

    Liu, Tao; Zhao, Dong-xu; Cui, Hua; Chen, Lei; Bao, Ying-hui; Wang, Yong; Jiang, Ji-yao

    2016-01-01

    Necroptosis has been shown as an alternative form of cell death in many diseases, but the detailed mechanisms of the neuron loss after traumatic brain injury (TBI) in rodents remain unclear. To investigate whether necroptosis is induced after TBI and gets involved in the neuroprotecton of therapeutic hypothermia on the TBI, we observed the pathological and biochemical change of the necroptosis in the fluid percussion brain injury (FPI) model of the rats. We found that receptor-interacting protein (RIP) 1 and 3, and mixed lineage kinase domain-like protein (MLKL), the critical downstream mediators of necroptosis recently identified in vivo, as well as HMGB1 and the pro-inflammation cytokines TNF-α, IL-6 and IL-18, were increased at an early phase (6 h) in cortex after TBI. Posttraumatic hypothermia (33 °C) led to the decreases in the necroptosis regulators, inflammatory factors and brain tissue damage in rats compared with normothermia-treated TBI animals. Immunohistochemistry studies showed that posttraumatic hypothermia also decreased the necroptosis-associated proteins staining in injured cortex and hippocampal CA1. Therefore, we conclude that the RIP1/RIP3-MLKL-mediated necroptosis occurs after experimental TBI and therapeutic hypothermia may protect the injured central nervous system from tissue damage and the inflammatory responses by targeting the necroptosis signaling after TBI. PMID:27080932

  10. Amifostine, a radioprotectant agent, protects rat brain tissue lipids against ionizing radiation induced damage: An FTIR microspectroscopic imaging study

    SciTech Connect

    Cakmak G.; Miller L.; Zorlu, F.; Severcan, F.

    2012-03-03

    Amifostine is the only approved radioprotective agent by FDA for reducing the damaging effects of radiation on healthy tissues. In this study, the protective effect of amifostine against the damaging effects of ionizing radiation on the white matter (WM) and grey matter (GM) regions of the rat brain were investigated at molecular level. Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated at a single dose of 800 cGy, decapitated after 24 h and the brain tissues of these rats were analyzed using Fourier transform infrared microspectroscopy (FTIRM). The results revealed that the total lipid content and CH{sub 2} groups of lipids decreased significantly and the carbonyl esters, olefinic=CH and CH{sub 3} groups of lipids increased significantly in the WM and GM after exposure to ionizing radiation, which could be interpreted as a result of lipid peroxidation. These changes were more prominent in the WM of the brain. The administration of amifostine before ionizing radiation inhibited the radiation-induced lipid peroxidation in the brain. In addition, this study indicated that FTIRM provides a novel approach for monitoring ionizing radiation induced-lipid peroxidation and obtaining different molecular ratio images can be used as biomarkers to detect lipid peroxidation in biological systems.

  11. Relationship between opioid therapy, tissue-damaging procedures, and brain metabolites as measured by proton MRS in asphyxiated term neonates.

    PubMed

    Angeles, Danilyn M; Ashwal, Stephen; Wycliffe, Nathaniel D; Ebner, Charlotte; Fayard, Elba; Sowers, Lawrence; Holshouser, Barbara A

    2007-05-01

    To examine the effects of opioid and tissue-damaging procedures (TDPs) [i.e. procedures performed in the neonatal intensive care unit (NICU) known to result in pain, stress, and tissue damage] on brain metabolites, we reviewed the medical records of 28 asphyxiated term neonates (eight opioid-treated, 20 non-opioid treated) who had undergone magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) within the first month of life as well as eight newborns with no clinical findings of asphyxial injury. We found that lower creatine (Cr), myoinositol (Ins), and N-acetylaspartate (NAA)/choline (Cho) (p < or = 0.03) and higher Cho/Cr and glutamate/glutamine (Glx) Cr (p < or = 0.02) correlated with increased TDP incidence in the first 2 d of life (DOL). We also found that occipital gray matter (OGM) NAA/Cr was decreased (p = 0.03) and lactate (Lac) was present in a significantly higher amount (40%; p = 0.03) in non-opioid-treated neonates compared with opioid-treated neonates. Compared with controls, untreated neonates showed larger changes in more metabolites in basal ganglia (BG), thalami (TH), and OGM with greater significance than treated neonates. Our data suggest that TDPs affect spectral metabolites and that opioids do not cause harm in asphyxiated term neonates exposed to repetitive TDPs in the first 2-4 DOL and may provide a degree of neuroprotection.

  12. A Preliminary Investigation of Normal Pancreas and Acute Pancreatitis Elasticity Using Virtual Touch Tissue Quantification (VTQ) Imaging

    PubMed Central

    Xie, Juan; Zou, Liling; Yao, Minghua; Xu, Guang; Zhao, Lixia; Xu, Huixiong; Wu, Rong

    2015-01-01

    Background The aim of this study was to prospectively evaluate the use of elastometry in healthy volunteers and patients with acute pancreatitis using virtual touch tissue quantification (VTQ) imaging technology performed on the pancreas. Material/Methods We enrolled 210 healthy volunteers and 44 acute pancreatitis patients in the study between March 2012 and June 2013. Healthy subjects were divided into 3 groups: young (18–30 years), middle-aged (30–50 years), and elderly (>50 years). VTQ was performed on the pancreatic head and body regions to obtain shear wave velocity (SWV) measurements, which were used to evaluate the elasticity values of tissues. Results The pancreatic head SWV value in the whole healthy group was 1.18±0.23 m/s, and that in the pancreatic body was 1.21±0.20 m/s. In patients with acute pancreatitis, the mean SWV measurements at the head were 1.18±0.20 m/s, compared to 1.25±0.19 m/s in the pancreatic body. There was no statistically significant difference between whole healthy volunteers and the acute pancreatitis group. Conclusions VTQ is a new method that shows promise for the quantification of pancreatic elasticity, but further studies are warranted. PMID:26062803

  13. In vitro flubendazole-induced damage to vital tissues in adult females of the filarial nematode Brugia malayi

    PubMed Central

    O'Neill, Maeghan; Geary, James F.; Agnew, Dalen W.; Mackenzie, Charles D.; Geary, Timothy G.

    2015-01-01

    The use of a microfilaricidal drug for the control of onchocerciasis and lymphatic filariasis necessitates prolonged yearly dosing. Prospects for elimination or eradication of these diseases would be enhanced by availability of a macrofilaricidal drug. Flubendazole (FLBZ), a benzimidazole anthelmintic, is an appealing candidate macrofilaricide. FLBZ has demonstrated profound and potent macrofilaricidal effects in a number of experimental filarial rodent models and one human trial. Unfortunately, FLBZ was deemed unsatisfactory for use in mass drug administration (MDA) campaigns due to its markedly limited oral bioavailability. However, a new formulation that provided sufficient bioavailability following oral administration could render FLBZ an effective treatment for onchocerciasis and LF. This study characterized the effects of FLBZ and its reduced metabolite (FLBZ-R) on filarial nematodes in vitro to determine the exposure profile which results in demonstrable damage. Adult female Brugia malayi were exposed to varying concentrations of FLBZ or FLBZ-R (100 nM–10 μM) for up to five days, after which worms were fixed for histology. Morphological damage following exposure to FLBZ was observed prominently in the hypodermis and developing embryos at concentrations as low as 100 nM following 24 h exposure. The results indicate that damage to tissues required for reproduction and survival can be achieved at pharmacologically relevant concentrations. PMID:26288741

  14. Resident neural stem cells restrict tissue damage and neuronal loss after spinal cord injury in mice.

    PubMed

    Sabelström, Hanna; Stenudd, Moa; Réu, Pedro; Dias, David O; Elfineh, Marta; Zdunek, Sofia; Damberg, Peter; Göritz, Christian; Frisén, Jonas

    2013-11-01

    Central nervous system injuries are accompanied by scar formation. It has been difficult to delineate the precise role of the scar, as it is made by several different cell types, which may limit the damage but also inhibit axonal regrowth. We show that scarring by neural stem cell-derived astrocytes is required to restrict secondary enlargement of the lesion and further axonal loss after spinal cord injury. Moreover, neural stem cell progeny exerts a neurotrophic effect required for survival of neurons adjacent to the lesion. One distinct component of the glial scar, deriving from resident neural stem cells, is required for maintaining the integrity of the injured spinal cord.

  15. Effects of Nd:YAG laser photoradiation on intra-abdominal tissues: a histological study of tissue damage versus power density applied

    SciTech Connect

    Brackett, K.A.; Sankar, M.Y.; Joffe, S.N.

    1986-01-01

    Liver, spleen, and pancreas were subjected to laser photoradiation of 50- to 100-Watt power levels. Samples were evaluated by light microscopy at 0 hours and 7, 14, and 21 days. Four zones of cellular damage were visible in liver and pancreas: coagulum, cavitation, acidophilia, and transition. Only the first three zones were clearly visible in the spleen. Mean lateral tissue penetration was 3.1 mm in liver, 3.3 mm in spleen, and 1.0 mm in pancreas. No significant increase in lateral penetration occurred with increasing power. Normal healing was observed in liver and spleen. Pancreatitis was found in all samples at 7 days postoperatively. At power levels of 80 W or less, recovery was observed. Above 80 W, pancreatic pseudocysts and necrosis led to death of the animals.

  16. Inorganic arsenic in drinking water accelerates N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder tissue damage in mice

    SciTech Connect

    Lin, Paul-Yann; Lin, Yung-Lun; Huang, Chin-Chin; Chen, Sin-Syu; Liu, Yi-Wen

    2012-02-15

    Epidemiological studies have revealed that exposure to an arsenic-contaminated environment correlates with the incidence of bladder cancer. Bladder cancer is highly recurrent after intravesical therapy, and most of the deaths from this disease are due to invasive metastasis. In our present study, the role of inorganic arsenic in bladder carcinogenesis is characterized in a mouse model. This work provides the first evidence that inorganic arsenic in drinking water promotes N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced bladder tissue damage, including the urothelium and submucosal layer. This damage to the bladder epithelium induced by BBN includes thickening of the submucosal layer, the loss of the glycosaminoglycan layer and an increase in both the deoxyguanosine oxidation and cytosine methylation levels in the DNA. Further, when 10 ppm inorganic arsenic is combined with BBN, the number of bladder submucosal capillaries is increased. In addition, inorganic arsenic also increases the deoxyguanosine oxidation level, alters the cytosine methylation state, decreases the activities of glutathione reductase and glucose-6-phosphate dehydrogenase, decreases the protein expression of NAD(P)H quinone oxidoreductase-1 (NQO-1) and increases the protein expression of specific protein 1 (Sp1) in bladder tissues. In summary, our data reveal that inorganic arsenic in drinking water promotes the BBN-induced pre-neoplastic damage of bladder tissue in mice, and that the 8-hydroxy-2′-deoxyguanosine, 5-methylcytosine, NQO-1 protein and Sp1 protein levels may be pre-neoplastic markers of bladder tumors. -- Highlights: ► The role of inorganic arsenic in bladder carcinogenesis is characterized in mice. ► We examine the changes in the histology and biochemistry of bladder tissues. ► Inorganic arsenic enhances BBN-induced DNA oxidation while decreases BBN-induced DNA methylation in the mouse bladder. ► Inorganic arsenic alters the activities of the anti-oxidant enzymes in

  17. Imaging pheromone sensing in a mouse vomeronasal acute tissue slice preparation.

    PubMed

    Brechbühl, Julien; Luyet, Gaëlle; Moine, Fabian; Rodriguez, Ivan; Broillet, Marie-Christine

    2011-01-01

    . Here, we present an acute tissue slice preparation of the mouse VNO for performing calcium imaging investigations. This physiological approach allows observations, in the natural environment of a living tissue, of general or individual subpopulations of VSNs previously loaded with Fura-2AM, a calcium dye. This method is also convenient for studying any GFP-tagged pheromone receptor and is adaptable for the use of other fluorescent calcium probes. As an example, we use here a VG mouse line, in which the translation of the pheromone V1rb2 receptor is linked to the expression of GFP by a polycistronic strategy.

  18. Fabrication of Anti-human Cardiac Troponin I Immunogold Nanorods for Sensing Acute Myocardial Damage

    NASA Astrophysics Data System (ADS)

    Guo, Z. R.; Gu, C. R.; Fan, X.; Bian, Z. P.; Wu, H. F.; Yang, D.; Gu, N.; Zhang, J. N.

    2009-12-01

    A facile, rapid, solution-phase method of detecting human cardiac troponin I for sensing myocardial damage has been described using gold nanorods-based biosensors. The sensing is demonstrated by the distinct change of the longitudinal surface plasmon resonance wavelength of the gold nanorods to specific antibody-antigen binding events. For a higher sensitivity, the aspect ratio of gold nanorods is increased up to ca 5.5 by simply adding small amount of HCl in seed-mediated growth solution. Experimental results show that the detecting limit of the present method is 10 ng/mL. Contrast tests reveal that these gold nanorods-based plasmonic biosensors hold much higher sensitivity than that of conventionally spherical gold nanoparticles.

  19. Freezing adipose tissue grafts may damage their ability to integrate into the host.

    PubMed

    Grewal, Navanjun; Yacomotti, Luciana; Melkonyan, Vahe; Massey, Marga; Bradley, James P; Zuk, Patricia A

    2009-01-01

    In this study, the effect of freezing on the morphology, viability, and VEGF synthesis of human adipose tissue grafts is examined. Currently, storage of adipose grafts involves freezing in simple saline solutions. However, the effect of freezing on the morphology and function of adipose tissue remains unclear. As a result, this study attempts to determine whether freezing adipose grafts should be considered prior to soft-tissue augmentation. In this study, the freezing of adipose grafts in saline for only 24 hr resulted in morphological changes in vivo and affected their ability to synthesize VEGF. The use of a simple cryopreservation medium containing sucrose appeared to maintain VEGF synthetic levels by the grafts and improved both their morphology and retention in vivo. However, the benefits of this cryopreservation medium were directly linked to storage time as long-term storage did not result in any noticeable benefit to graft retention. Finally, as an alternative to freezing, adipose grafts were combined with human adipose-derived stem cells (ASCs) to determine if their presence could enhance in vivo graft structure. The presence of ASCs did appear to improve graft structure in vivo over the short term and was also capable of improving tissue morphology when combined with grafts frozen in PBS. In conclusion, the successful use of adipose grafts may require a closer examination of the graft's storage conditions and time. Specifically, it now appears that the practice of freezing in saline may not be advisable if graft viability, activity, and structure are to be maintained in vivo.

  20. Persistent DNA Damage in Spermatogonial Stem Cells After Fractionated Low-Dose Irradiation of Testicular Tissue

    SciTech Connect

    Grewenig, Angelika; Schuler, Nadine; Rübe, Claudia E.

    2015-08-01

    Purpose: Testicular spermatogenesis is extremely sensitive to radiation-induced damage, and even low scattered doses to testis from radiation therapy may pose reproductive risks with potential treatment-related infertility. Radiation-induced DNA double-strand breaks (DSBs) represent the greatest threat to the genomic integrity of spermatogonial stem cells (SSCs), which are essential to maintain spermatogenesis and prevent reproduction failure. Methods and Materials: During daily low-dose radiation with 100 mGy or 10 mGy, radiation-induced DSBs were monitored in mouse testis by quantifying 53 binding protein 1 (53BP-1) foci in SSCs within their stem cell niche. The accumulation of DSBs was correlated with proliferation, differentiation, and apoptosis of testicular germ cell populations. Results: Even very low doses of ionizing radiation arrested spermatogenesis, primarily by inducing apoptosis in spermatogonia. Eventual recovery of spermatogenesis depended on the survival of SSCs and their functional ability to proliferate and differentiate to provide adequate numbers of differentiating spermatogonia. Importantly, apoptosis-resistant SSCs resulted in increased 53BP-1 foci levels during, and even several months after, fractionated low-dose radiation, suggesting that surviving SSCs have accumulated an increased load of DNA damage. Conclusions: SSCs revealed elevated levels of DSBs for weeks after radiation, and if these DSBs persist through differentiation to spermatozoa, this may have severe consequences for the genomic integrity of the fertilizing sperm.

  1. Dynamics of wound healing signaling as a potential therapeutic target for radiation-induced tissue damage.

    PubMed

    Chung, Yih-Lin; Pui, Newman N M

    2015-01-01

    We hypothesized the histone deacetylase inhibitor phenylbutyrate (PB) has beneficial effects on radiation-induced injury by modulating the expression of DNA repair and wound healing genes. Hamsters received a radiosurgical dose of radiation (40 Gy) to the cheek and were treated with varying PB dosing regimens. Gross alteration of the irradiated cheeks, eating function, histological changes, and gene expression during the course of wound healing were compared between treatment groups. Pathological analysis showed decreased radiation-induced mucositis, facilitated epithelial cell growth, and preventing ulcerative wound formation, after short-term PB treatment, but not after vehicle or sustained PB. The radiation-induced wound healing gene expression profile exhibited a sequential transition from the inflammatory and DNA repair phases to the tissue remodeling phase in the vehicle group. Sustained PB treatment resulted in a prolonged wound healing gene expression profile and delayed the wound healing process. Short-term PB shortened the duration of inflammatory cytokine expression, triggered repeated pulsed expression of cell cycle and DNA repair-regulating genes, and promoted earlier oscillatory expression of tissue remodeling genes. Distinct gene expression patterns between sustained and short-term treatment suggest dynamic profiling of wound healing gene expression can be an important part of a biological therapeutic strategy to mitigate radiation-related tissue injury.

  2. Clinical implications of oral candidiasis: host tissue damage and disseminated bacterial disease.

    PubMed

    Kong, Eric F; Kucharíková, Sona; Van Dijck, Patrick; Peters, Brian M; Shirtliff, Mark E; Jabra-Rizk, Mary Ann

    2015-02-01

    The clinical significance of polymicrobial interactions, particularly those between commensal species with high pathogenic potential, remains largely understudied. Although the dimorphic fungal species Candida albicans and the bacterium Staphylococcus aureus are common cocolonizers of humans, they are considered leading opportunistic pathogens. Oral candidiasis specifically, characterized by hyphal invasion of oral mucosal tissue, is the most common opportunistic infection in HIV(+) and immunocompromised individuals. In this study, building on our previous findings, a mouse model was developed to investigate whether the onset of oral candidiasis predisposes the host to secondary staphylococcal infection. The findings demonstrated that in mice with oral candidiasis, subsequent exposure to S. aureus resulted in systemic bacterial infection with high morbidity and mortality. Histopathology and scanning electron microscopy of tongue tissue from moribund animals revealed massive C. albicans hyphal invasion coupled with S. aureus deep tissue infiltration. The crucial role of hyphae in the process was demonstrated using a non-hypha-producing and a noninvasive hypha-producing mutant strains of C. albicans. Further, in contrast to previous findings, S. aureus dissemination was aided but not contingent upon the presence of the Als3p hypha-specific adhesion. Importantly, impeding development of mucosal C. albicans infection by administering antifungal fluconazole therapy protected the animals from systemic bacterial disease. The combined findings from this study demonstrate that oral candidiasis may constitute a risk factor for disseminated bacterial disease warranting awareness in terms of therapeutic management of immunocompromised individuals.

  3. Clinical Implications of Oral Candidiasis: Host Tissue Damage and Disseminated Bacterial Disease

    PubMed Central

    Kong, Eric F.; Kucharíková, Sona; Peters, Brian M.; Shirtliff, Mark E.

    2014-01-01

    The clinical significance of polymicrobial interactions, particularly those between commensal species with high pathogenic potential, remains largely understudied. Although the dimorphic fungal species Candida albicans and the bacterium Staphylococcus aureus are common cocolonizers of humans, they are considered leading opportunistic pathogens. Oral candidiasis specifically, characterized by hyphal invasion of oral mucosal tissue, is the most common opportunistic infection in HIV+ and immunocompromised individuals. In this study, building on our previous findings, a mouse model was developed to investigate whether the onset of oral candidiasis predisposes the host to secondary staphylococcal infection. The findings demonstrated that in mice with oral candidiasis, subsequent exposure to S. aureus resulted in systemic bacterial infection with high morbidity and mortality. Histopathology and scanning electron microscopy of tongue tissue from moribund animals revealed massive C. albicans hyphal invasion coupled with S. aureus deep tissue infiltration. The crucial role of hyphae in the process was demonstrated using a non-hypha-producing and a noninvasive hypha-producing mutant strains of C. albicans. Further, in contrast to previous findings, S. aureus dissemination was aided but not contingent upon the presence of the Als3p hypha-specific adhesion. Importantly, impeding development of mucosal C. albicans infection by administering antifungal fluconazole therapy protected the animals from systemic bacterial disease. The combined findings from this study demonstrate that oral candidiasis may constitute a risk factor for disseminated bacterial disease warranting awareness in terms of therapeutic management of immunocompromised individuals. PMID:25422264

  4. Maternal hypertension programs increased cerebral tissue damage following stroke in adult offspring.

    PubMed

    Ventura, Nicole M; Jin, Albert Y; Tse, M Yat; Peterson, Nichole T; Andrew, R David; Mewburn, Jeffrey D; Pang, Stephen C

    2015-10-01

    The maternal system is challenged with many physiological changes throughout pregnancy to prepare the body to meet the metabolic needs of the fetus and for delivery. Many pregnancies, however, are faced with pathological stressors or complications that significantly impact maternal health. A shift in this paradigm is now beginning to investigate the implication of pregnancy complications on the fetus and their continued influence on offspring disease risk into adulthood. In this investigation, we sought to determine whether maternal hypertension during pregnancy alters the cerebral response of adult offspring to acute ischemic stroke. Atrial natriuretic peptide gene-disrupted (ANP(-/-)) mothers exhibit chronic hypertension that escalates during pregnancy. Through comparison of heterozygote offspring born from either normotensive (ANP(+/-WT)) or hypertensive (ANP(+/-KO)) mothers, we have demonstrated that offspring exposed to maternal hypertension exhibit larger cerebral infarct volumes following middle cerebral artery occlusion. Observation of equal baseline cardiovascular measures, cerebrovascular structure, and cerebral blood volumes between heterozygote offspring suggests no added influences on offspring that would contribute to adverse cerebral response post-stroke. Cerebral mRNA expression of endothelin and nitric oxide synthase vasoactive systems demonstrated up-regulation of Et-1 and Nos3 in ANP(+/-KO) mice and thus an enhanced acute vascular response compared to ANP(+/-WT) counterparts. Gene expression of Na(+)/K(+) ATPase channel isoforms, Atp1a1, Atp1a3, and Atp1b1, displayed no significant differences. These investigations are the first to demonstrate a fetal programming effect between maternal hypertension and adult offspring stroke outcome. Further mechanistic studies are required to complement epidemiological evidence of this phenomenon in the literature. PMID:26169981

  5. Ischaemia-related cell damage in extracorporeal preserved tissue – new findings with a novel perfusion model

    PubMed Central

    Taeger, Christian D; Müller-Seubert, Wibke; Horch, Raymund E; Präbst, Konstantin; Münch, Frank; Geppert, Carol I; Birkholz, Torsten; Dragu, Adrian

    2014-01-01

    Tissue undergoing free transfer in transplant or reconstructive surgery always is at high risk of ischaemia-related cell damage. This study aims at assessing different procedures using an extracorporeal perfusion and oxygenation system to investigate the expression of hypoxia inducible factor (HIF)-1-α as marker for hypoxia and of the pro-apoptotic protein Caspase-3 in skeletal muscle to elucidate potential improvements in tissue conservation. Twenty-four porcine rectus abdominis muscles were assigned to five different groups and examined after they had been extracorporeally preserved for 60 min. time. Group I was left untreated (control), group II was perfused with a cardioplegic solution, group III was flushed with 10 ml of a cardioplegic solution and then left untreated. Group IV and V were perfused and oxygenated with either an isotone crystalloid solution or a cardioplegic solution. Among others, immunohistochemistry (Caspase-3 and HIF-1-α) of muscle samples was performed. Furthermore, oxygen partial pressure in the perfusate at the arterial and venous branch was measured. Expression of Caspase-3 after 60 min. was reduced in all groups compared to the control group. Furthermore, all groups (except group III) expressed less HIF-1-α than the control group. Oxygenation leads to higher oxygen levels at the venous branch compared to groups without oxygenation. Using an extracorporeal perfusion and oxygenation system cell damage could be reduced as indicated by stabilized expressions of Caspase-3 and HIF-1-α for 60 min. of tissue preservation. Complete depletion of oxygen at the venous branch can be prevented by oxygenation of the perfusate with ambient air. PMID:24636195

  6. Severe acute oxidant exposure: morphological damage and aerobic metabolism in the lung

    SciTech Connect

    Montgomery, M.R.; Teuscher, F.; LaSota, I.; Niewoehner, D.E.

    1986-09-01

    Groups of male rats were exposed to acute doses of oxygen, ozone, or paraquat which produced equivalent mortality (25-30%) over a 28 day post-exposure period. Quantitative evaluation of morphological changes indicated the primary response to be edema and inflammation with only slight fibrosis being apparent by the end of the observation period. Aerobic pulmonary metabolism was inhibited in lungs from animals exposed to oxygen and ozone as evidenced by decreased oxygen consumption; however, this was transient and O/sub 2/ consumption returned to normal within 24 hours after removal from the exposure chamber. Conversely, treatment with paraquat caused an immediate, transient stimulation of O/sub 2/ consumption. Glucose metabolism was unaltered by the gas exposures and, as previously reported, was initially stimulated by paraquat treatment. In vitro, only paraquat altered both O/sub 2/ consumption and glucose metabolism when added to lung slice preparations; ozone had no effect. Oxygen did not alter O/sub 2/ consumption but caused a slight biphasic response in glucose metabolism. Aerobic metabolism is relatively unchanged by these doses of oxygen and ozone which result in the death of 25-30% of all treated animals. Even though paraquat produces similar morphologic changes, it may represent a more severe metabolic insult than ''equivalent'' doses of oxygen or ozone. Also, if interstitial pulmonary fibrosis is a desired result of experimental exposure, rats may not be a suitable model for oxidant induced lung injury.

  7. Kidney damage biomarkers detect acute kidney injury but only functional markers predict mortality after paraquat ingestion.

    PubMed

    Mohamed, Fahim; Buckley, Nicholas A; Jayamanne, Shaluka; Pickering, John W; Peake, Philip; Palangasinghe, Chathura; Wijerathna, Thilini; Ratnayake, Indira; Shihana, Fathima; Endre, Zoltan H

    2015-09-01

    Acute kidney injury (AKI) is common following paraquat ingestion. The diagnostic performance of injury biomarkers was investigated in serial blood and urine samples from patients from 5 Sri Lankan hospitals. Functional AKI was diagnosed using serum creatinine (sCr) or serum cystatin C (sCysC). The 95th centile in healthy subjects defined the urinary biomarker cutoffs for diagnosing structural AKI. 50 poisoned patients provided 2 or more specimens, 76% developed functional AKI [AKIN stage 1 (n=12), 2 (n=7) or 3 (n=19)]; 19/26 patients with AKIN stage 2/3 also had functional AKI by sCysC criteria (≥50% increase). Urinary cystatin C (uCysC), clusterin (uClu) and NGAL (uNGAL) increased within 24h of ingestion compared with NoAKI patients and healthy controls. Each biomarker demonstrated moderate diagnostic utility [AUC-ROC: uCysC 0.79, uNGAL 0.79, uClu 0.68] for diagnosis of functional AKI at 16h. Death occurred only in subjects with functional AKI. Structural biomarker-based definitions detected more AKI than did sCr or sCysC, but did not independently predict death. Renal injury biomarkers did not add clinical value to patients who died rapidly due to multi-organ failure. Use of injury biomarkers within 16-24h may guide early intervention for reno-protection in less severe paraquat poisoning. PMID:26071311

  8. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    PubMed Central

    González-Ponce, Herson Antonio; Martínez-Saldaña, María Consolación; Rincón-Sánchez, Ana Rosa; Sumaya-Martínez, María Teresa; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juárez, Fernando

    2016-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-l-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients and contain high levels of bioactive compounds, including antioxidants. The aim of this study was to evaluate the hepatoprotective effect of Opuntia robusta and Opuntia streptacantha extracts against APAP-induced ALF. In addition, we analyzed the antioxidant activities of these extracts. Fruit extracts (800 mg/kg/day, orally) were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally). Rat hepatocyte cultures were exposed to 20 mmol/L APAP, and necrosis was assessed by LDH leakage. Opuntia robusta had significantly higher levels of antioxidants than Opuntia streptacantha. Both extracts significantly attenuated APAP-induced injury markers AST, ALT and ALP and improved liver histology. The Opuntia extracts reversed APAP-induced depletion of liver GSH and glycogen stores. In cultured hepatocytes, Opuntia extracts significantly reduced leakage of LDH and cell necrosis, both prophylactically and therapeutically. Both extracts appeared to be superior to NAC when used therapeutically. We conclude that Opuntia extracts are hepatoprotective and can be used as a nutraceutical to prevent ALF. PMID:27782042

  9. dsRNA Released by Tissue Damage Activates TLR3 to Drive Skin Regeneration.

    PubMed

    Nelson, Amanda M; Reddy, Sashank K; Ratliff, Tabetha S; Hossain, M Zulfiquer; Katseff, Adiya S; Zhu, Amadeus S; Chang, Emily; Resnik, Sydney R; Page, Carly; Kim, Dongwon; Whittam, Alexander J; Miller, Lloyd S; Garza, Luis A

    2015-08-01

    Regeneration of skin and hair follicles after wounding--a process known as wound-induced hair neogenesis (WIHN)--is a rare example of adult organogenesis in mammals. As such, WIHN provides a unique model system for deciphering mechanisms underlying mammalian regeneration. Here, we show that dsRNA, which is released from damaged skin, activates Toll-Like Receptor 3 (TLR3) and its downstream effectors IL-6 and STAT3 to promote hair follicle regeneration. Conversely, TLR3-deficient animals fail to initiate WIHN. TLR3 activation promotes expression of hair follicle stem cell markers and induces elements of the core hair morphogenetic program, including ectodysplasin A receptor (EDAR) and the Wnt and Shh pathways. Our results therefore show that dsRNA and TLR3 link the earliest events of mammalian skin wounding to regeneration and suggest potential therapeutic approaches for promoting hair neogenesis.

  10. Metallothionein blocks oxidative DNA damage induced by acute inorganic arsenic exposure

    SciTech Connect

    Qu, Wei Waalkes, Michael P.

    2015-02-01

    We studied how protein metallothionein (MT) impacts arsenic-induced oxidative DNA damage (ODD) using cells that poorly express MT (MT-I/II double knockout embryonic cells; called MT-null cells) and wild-type (WT) MT competent cells. Arsenic (as NaAsO{sub 2}) was less cytolethal over 24 h in WT cells (LC{sub 50} = 11.0 ± 1.3 μM; mean ± SEM) than in MT-null cells (LC{sub 50} = 5.6 ± 1.2 μM). ODD was measured by the immuno-spin trapping method. Arsenic (1 or 5 μM; 24 h) induced much less ODD in WT cells (121% and 141% of control, respectively) than in MT-null cells (202% and 260%). In WT cells arsenic caused concentration-dependent increases in MT expression (transcript and protein), and in the metal-responsive transcription factor-1 (MTF-1), which is required to induce the MT gene. In contrast, basal MT levels were not detectable in MT-null cells and unaltered by arsenic exposure. Transfection of MT-I gene into the MT-null cells markedly reduced arsenic-induced ODD levels. The transport genes, Abcc1 and Abcc2 were increased by arsenic in WT cells but either showed no or very limited increases in MT-null cells. Arsenic caused increases in oxidant stress defense genes HO-1 and GSTα2 in both WT and MT-null cells, but to much higher levels in WT cells. WT cells appear more adept at activating metal transport systems and oxidant response genes, although the role of MT in these responses is unclear. Overall, MT protects against arsenic-induced ODD in MT competent cells by potential sequestration of scavenging oxidant radicals and/or arsenic. - Highlights: • Metallothionein blocks arsenic toxicity. • Metallothionein reduces arsenic-induced DNA damage. • Metallothionein may bind arsenic or radicals produced by arsenic.

  11. Quercetin, a Flavonoid Antioxidant, Ameliorated Procarbazine-Induced Oxidative Damage to Murine Tissues.

    PubMed

    Olayinka, Ebenezer Tunde; Ore, Ayokanmi; Adeyemo, Oluwatobi Adewumi; Ola, Olaniyi Solomon; Olotu, Olaoluwa Oluwaseun; Echebiri, Roseline Chinonye

    2015-01-01

    Procarbazine (PCZ) (indicated in Hodgkin's disease), is an alkylating agent known to generate free radicals in vivo, while Quercetin (QCT) is a flavonoid antioxidant with proven free radical scavenging capacity. This study investigated the protective effects of QCT on PCZ-induced oxidative damage in the rat. Male Wistar rats (160-180 g) were randomized into five groups (n = 5/group): I (control), II PCZ-treated (2 mg/kg body weight (bw) for seven days); III pre-treated with QCT (20 mg/kg bw) for seven days, followed by PCZ for seven days; IV co-treated with PCZ and QCT for seven days and V administered QCT alone for seven days. PCZ caused a significant increase in plasma total bilirubin, urea, and creatinine when compared with control (P < 0.05). Similarly, plasma activities of alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transferase (γ-GT) were significantly increased in the PCZ-treated group relative to control. Furthermore, PCZ caused a significant decrease in the activities of hepatic superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) as well as levels of ascorbic acid (AA) and glutathione (GSH). This was followed by a significant increase in hepatic malondialdehyde (MDA) content. However, QCT pre-treatment and co-treatment ameliorated the PCZ-induced changes in plasma levels of urea, creatinine, and bilirubin as well as the activities of ALP, AST, ALT, and GGT. QCT also ameliorated hepatic AA and GSH levels and the activities of SOD, CAT, and GST. This all suggests that QCT protected against PCZ-induced oxidative damage in rats. PMID:26783707

  12. Mechanisms of Vascular Damage by Hemorrhagic Snake Venom Metalloproteinases: Tissue Distribution and In Situ Hydrolysis

    PubMed Central

    Baldo, Cristiani; Jamora, Colin; Yamanouye, Norma; Zorn, Telma M.; Moura-da-Silva, Ana M.

    2010-01-01

    Background Envenoming by viper snakes constitutes an important public health problem in Brazil and other developing countries. Local hemorrhage is an important symptom of these accidents and is correlated with the action of snake venom metalloproteinases (SVMPs). The degradation of vascular basement membrane has been proposed as a key event for the capillary vessel disruption. However, SVMPs that present similar catalytic activity towards extracellular matrix proteins differ in their hemorrhagic activity, suggesting that other mechanisms might be contributing to the accumulation of SVMPs at the snakebite area allowing capillary disruption. Methodology/Principal Findings In this work, we compared the tissue distribution and degradation of extracellular matrix proteins induced by jararhagin (highly hemorrhagic SVMP) and BnP1 (weakly hemorrhagic SVMP) using the mouse skin as experimental model. Jararhagin induced strong hemorrhage accompanied by hydrolysis of collagen fibers in the hypodermis and a marked degradation of type IV collagen at the vascular basement membrane. In contrast, BnP1 induced only a mild hemorrhage and did not disrupt collagen fibers or type IV collagen. Injection of Alexa488-labeled jararhagin revealed fluorescent staining around capillary vessels and co-localization with basement membrane type IV collagen. The same distribution pattern was detected with jararhagin-C (disintegrin-like/cysteine-rich domains of jararhagin). In opposition, BnP1 did not accumulate in the tissues. Conclusions/Significance These results show a particular tissue distribution of hemorrhagic toxins accumulating at the basement membrane. This probably occurs through binding to collagens, which are drastically hydrolyzed at the sites of hemorrhagic lesions. Toxin accumulation near blood vessels explains enhanced catalysis of basement membrane components, resulting in the strong hemorrhagic activity of SVMPs. This is a novel mechanism that underlies the difference between

  13. NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

    PubMed Central

    Xiong, Wenjun; MacColl Garfinkel, Alexandra E.; Li, Yiqing; Benowitz, Larry I.; Cepko, Constance L.

    2015-01-01

    Oxidative stress contributes to the loss of neurons in many disease conditions as well as during normal aging; however, small-molecule agents that reduce oxidation have not been successful in preventing neurodegeneration. Moreover, even if an efficacious systemic reduction of reactive oxygen and/or nitrogen species (ROS/NOS) could be achieved, detrimental side effects are likely, as these molecules regulate normal physiological processes. A more effective and targeted approach might be to augment the endogenous antioxidant defense mechanism only in the cells that suffer from oxidation. Here, we created several adeno-associated virus (AAV) vectors to deliver genes that combat oxidation. These vectors encode the transcription factors NRF2 and/or PGC1a, which regulate hundreds of genes that combat oxidation and other forms of stress, or enzymes such as superoxide dismutase 2 (SOD2) and catalase, which directly detoxify ROS. We tested the effectiveness of this approach in 3 models of photoreceptor degeneration and in a nerve crush model. AAV-mediated delivery of NRF2 was more effective than SOD2 and catalase, while expression of PGC1a accelerated photoreceptor death. Since the NRF2-mediated neuroprotective effects extended to photoreceptors and retinal ganglion cells, which are 2 very different types of neurons, these results suggest that this targeted approach may be broadly applicable to many diseases in which cells suffer from oxidative damage. PMID:25798616

  14. Philometra floridensis (Nematoda: Philometridae) damages ovarian tissue without reducing host (Sciaenops ocellatus) fecundity.

    PubMed

    Bakenhaster, Micah D; Lowerre-Barbieri, Susan; Kiryu, Yasunari; Walters, Sarah; Fajer-Avila, Emma J

    2014-04-01

    The parasitic nematode Philometra floridensis infects the ovary of its only host, the economically important fish species Sciaenops ocellatus, but the factors influencing host susceptibility and potential pathogenic effects are unknown. Here we report new information on these topics from evaluations of infected and uninfected hosts collected from the northeastern Gulf of Mexico. Fish length and age were evaluated vis-à-vis nematode prevalence to check for ontogenetic differences in host susceptibility. To evaluate health and reproductive consequences of infection, we looked for effects in Fulton's condition factor (K) and batch fecundity estimates (BF), and we evaluated ovarian tissue histologically to check for oocyte atresia and other host responses. We observed localized pathological changes in fish ovarian tissue associated with female nematodes, including leucocytic exudates, granulomatous inflammation, and Langhans-type multinucleated giant cells; the hosts, however, appeared to maintain high fecundity and actually exhibited, on average, better health index scores and higher relative fecundity than did uninfected fish. These differences are likely explained by the parasite's tendency to disproportionately infect the largest, actively spawning fish and by the localization of pathogenic changes, which could have masked effects that otherwise would have been reflected in mass-based health indicators. Although we did not detect negative effects on measures of overall health or reproductive output, further research is needed to better elucidate the relationship between these parasites and other factors affecting host reproductive potential, such as egg quality. PMID:24695236

  15. Philometra floridensis (Nematoda: Philometridae) damages ovarian tissue without reducing host (Sciaenops ocellatus) fecundity.

    PubMed

    Bakenhaster, Micah D; Lowerre-Barbieri, Susan; Kiryu, Yasunari; Walters, Sarah; Fajer-Avila, Emma J

    2014-04-01

    The parasitic nematode Philometra floridensis infects the ovary of its only host, the economically important fish species Sciaenops ocellatus, but the factors influencing host susceptibility and potential pathogenic effects are unknown. Here we report new information on these topics from evaluations of infected and uninfected hosts collected from the northeastern Gulf of Mexico. Fish length and age were evaluated vis-à-vis nematode prevalence to check for ontogenetic differences in host susceptibility. To evaluate health and reproductive consequences of infection, we looked for effects in Fulton's condition factor (K) and batch fecundity estimates (BF), and we evaluated ovarian tissue histologically to check for oocyte atresia and other host responses. We observed localized pathological changes in fish ovarian tissue associated with female nematodes, including leucocytic exudates, granulomatous inflammation, and Langhans-type multinucleated giant cells; the hosts, however, appeared to maintain high fecundity and actually exhibited, on average, better health index scores and higher relative fecundity than did uninfected fish. These differences are likely explained by the parasite's tendency to disproportionately infect the largest, actively spawning fish and by the localization of pathogenic changes, which could have masked effects that otherwise would have been reflected in mass-based health indicators. Although we did not detect negative effects on measures of overall health or reproductive output, further research is needed to better elucidate the relationship between these parasites and other factors affecting host reproductive potential, such as egg quality.

  16. The natural xanthone alpha-mangostin reduces oxidative damage in rat brain tissue.

    PubMed

    Márquez-Valadez, Berenice; Lugo-Huitrón, Rafael; Valdivia-Cerda, Verónica; Miranda-Ramírez, Luis Rubén; Pérez-De La Cruz, Verónica; González-Cuahutencos, Octavio; Rivero-Cruz, Isabel; Mata, Rachel; Santamaría, Abel; Pedraza-Chaverrí, José

    2009-02-01

    The antiperoxidative properties of alpha-mangostin, a xanthone isolated from mangosteen fruit, were tested for the first time in nerve tissue exposed to different toxic insults. Two reliable biological preparations (rat brain homogenates and synaptosomal P2 fractions) were exposed to the toxic actions of a free radical generator (ferrous sulfate), an excitotoxic agent (quinolinate), and a mitochondrial toxin (3-nitropropionate). alpha-Mangostin decreased the lipoperoxidative action of FeSO(4) in both preparations in a concentration-dependent manner, and completely abolished the peroxidative effects of quinolinate, 3-nitropropionate and FeSO(4) + quinolinate at all concentrations tested. Interestingly, when tested alone in brain homogenates, alpha-mangostin significantly decreased the lipoperoxidation even below basal levels. alpha-Mangostin also prevented the decreased reductant capacity of mitochondria in synaptosomal fractions. Our results suggest that alpha-mangostin exerts a robust antiperoxidative effect in brain tissue preparations probably through its properties as a free radical scavenger. In light of these findings, this antioxidant should be tested in other neurotoxic models involving oxidative stress.

  17. G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice.

    PubMed

    Guo, Yuji; Liu, Shangming; Zhang, Xianghong; Wang, Liyan; Gao, Jiangang; Han, Aiqing; Hao, Aijun

    2015-12-01

    Granulocyte colony-stimulating factor (G-CSF) was investigated for its capacity to induce autophagy and related neuroprotective mechanisms in an acute spinal cord injury model. To accomplish this goal, we established a mouse spinal cord hemisection model to test the effects of recombinant human G-CSF. The results showed that autophagy was activated after spinal cord injury and G-CSF appears to induce a more rapid activation of autophagy within injured spinal cords as compared with that of non-treated animals. Apoptosis as induced in mechanically injured neurons with G-CSF treatment was enhanced after inhibiting autophagy by 3-methyladenine (3-MA), which partially blocked the neuroprotective effect of autophagy as induced by G-CSF. In addition, G-CSF inhibited the activity of the NF-κB signal pathway in neurons after mechanical injury. We conclude that G-CSF promotes autophagy by inhibiting the NF-κB signal pathway and protects neuronal structure after spinal cord injury. We therefore suggest that G-CSF, which rapidly induces autophagy after spinal cord injury to inhibit neuronal apoptosis, may thus provide an effective auxiliary therapeutic intervention for spinal cord injury.

  18. Association between neuroserpin and molecular markers of brain damage in patients with acute ischemic stroke

    PubMed Central

    2011-01-01

    Background Neuroserpin has shown neuroprotective effects in animal models of cerebral ischemia and has been associated with functional outcome after ischemic stroke. Our aim was to study whether neuroserpin serum levels could be associated to biomarkers of excitotoxicity, inflammation and blood brain barrier disruption. Methods We prospectively included 129 patients with ischemic stroke (58.1% male; mean age, 72.4 ± 9.6 years) not treated with tPA within 12 hours (h) of symptoms onset (mean time, 4.7 ± 2.1 h). Poor functional outcome at 3 months was considered as a modified Rankin scale score >2. Serum levels of neuroserpin, Interleukin 6 (IL-6), Intercellular adhesion molecule-1 (ICAM-1), active Matrix metalloproteinase 9 (MMP-9), and cellular fibronectin (cFn) (determined by ELISA) and glutamate (determined by HPLC) were measured on admission, 24 and 72 h. The main variable was considered the decrease of neuroserpin levels within the first 24 h. ROC analysis was used to select the best predictive value for neuroserpin to predict poor functional outcome due to a lack of linearity. Results The decrease of neuroserpin levels within the first 24 h was negatively correlated with serum levels at 24 hours of glutamate (r = -0.642), IL-6 (r = -0.678), ICAM-1 (r = -0.345), MMP-9 (r = -0.554) and cFn (r = -0.703) (all P < 0.0001). In the multivariate analysis, serum levels of glutamate (OR, 1.04; CI95%, 1.01-1.06, p = 0.001); IL-6 (OR, 1.4; CI95%, 1.1-1.7, p = 0.001); and cFn (OR, 1.3; CI95%, 1.1-1.6, p = 0.002) were independently associated with a decrease of neuroserpin levels <70 ng/mL at 24 h after adjusting for confounding factors. Conclusions These findings suggest that neuroprotective properties of neuroserpin may be related to the inhibition of excitotoxicity, inflammation, as well as blood brain barrier disruption that occur after acute ischemic stroke. PMID:21569344

  19. The effects of different fractions of Coriandrum sativum on pentylenetetrazole-induced seizures and brain tissues oxidative damage in rats

    PubMed Central

    Anaeigoudari, Akbar; Hosseini, Mahmoud; Karami, Reza; Vafaee, Farzaneh; Mohammadpour, Toktam; Ghorbani, Ahmad; Sadeghnia, Hamid Reza

    2016-01-01

    Objective: In the present work, the effects of different fractions of Coriandrum sativum (C. sativum), on pentylenetetrazole (PTZ)-induced seizures and brain tissues oxidative damage were investigated in rats. Materials and Methods: The rats were divided into the following groups: (1) vehicle, (2) PTZ (90 mg/kg), (3) water fraction (WF) of C. sativum (25 and 100 mg/kg), (4) n-butanol fraction (NBF) of C. sativum (25 and 100 mg/kg), and (5) ethyl acetate fraction (EAF) of C. sativum (25 and 100 mg/kg). Results: The first generalized tonic-clonic seizures (GTCS) latency in groups treated with 100 mg /kg of WF or EAF was significantly higher than that of PTZ group (p<0.01). In contrast to WF, the EAF and NBF were not effective in increasing the first minimal clonic seizure (MCS) latency. Malondialdehyde (MDA) levels in both cortical and hippocampal tissues of PTZ group were significantly higher than those of control animals (p<0.001). Pretreatment with WF, NBF, or EAF resulted in a significant reduction in the MDA levels of hippocampi (p<0.01 - p<0.001). Following PTZ administration, a significant reduction in total thiol groups was observed in the brain tissues (p<0.05). Pretreatment with WF and NBF significantly elevated thiol concentrations in cortical and hippocampal tissues, respectively (p<0.05). Conclusion: The present study showed that different fractions of C. sativum possess antioxidant activity in the brain and WF and EAF of this plant have anticonvulsant effects. PMID:27222836

  20. Ameliorating effects of CAPE on oxidative damage caused by pneumoperitoneum in rat lung tissue

    PubMed Central

    Davarci, Isil; Alp, Harun; Ozgur, Tumay; Karcioglu, Murat; Tuzcu, Kasim; Evliyaoglu, Osman; Motor, Sedat; Durgun Yetim, Tulin

    2014-01-01

    We investigated the biochemical and histopathological effects of caffeic acid phenethyl ester (CAPE) against oxidative stress causing lung injury induced by pneumoperitoneum. Twenty-eight rats were selected at random and seven rats were assigned to each of the following groups. The control group (S) was subjected to a sham operation without pneumoperitoneum. The other groups were subjected to CO2 pneumoperitoneum 15 mmHg for 60 min. The laparoscopy group (L) had no additional drugs administered, the laparoscopy + alcohol (LA) group had 1 ml of 70% ethyl alcohol administered 1 h before the desufflation period, and the laparoscopy + CAPE (LC) group had CAPE administered at 10 μmol/kg 1 h before the desufflation period. The total oxidative status levels of lung and plasma were significantly increased in the LA group as compared with the LC and S group. When the LC group was compared with the L group, there was a decrease in the level of total oxidant status and increase in the levels of total antioxidant status and paraoxonase in lung tissue. The level of total antioxidative status in the S group was increased compared with the L group in lung tissue and bronchoalveolar lavage fluid. TNF-α and IL-6 were found significantly elevated in the L group compared with the LC and S groups in bronchoalveolar lavage fluid. There was a similar increase in plasma levels of IL-6. These results were supported by histopathological examination. CAPE was found to considerably reduce oxidative stress and inflammation induced by pneumoperitoneum. PMID:25126167

  1. Photodynamic damage to cartilage and synovial tissue grafted on a chick's chorioallantoic membrane

    NASA Astrophysics Data System (ADS)

    Fisher, M.; Nahir, A. M.; Kimel, Sol

    1997-09-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints causing pain deformities and disability. The highly vascular inflamed synovium has aggressive and destructive characteristics, it invades, erodes and gradually destroys cartilage and underlying bone. Photodynamic therapy (PDT) was performed using the chick chorioallantoic membrane (CAM) model to investigate the vitality of synovium and cartilage implanted on the CAM. Synovium, obtained from human patients, was grafted onto the CAM; gross microscopy and histology proved its vitality 7 days post grafting. Cartilage obtained from rabbit knee joint was also maintained on the CAM for 7 days. Its vitality was demonstrated by histology and by measuring metabolic and enzymatic activity of cartilage cells (chondrocytes) as well as the collagen and proteoglycans content. Selective PDT was performed using aluminum phthalocyanine tetrasulfonate (AlPcS4), a hydrophilic compound, soluble in biological solutions, as a photosensitizer. After irradiation with a diode laser (lambda equals 670 nm, 10 mW) damage was observed in vascularized synovium grafts, whereas avascular cartilage remained intact.

  2. Effects of Regular Treadmill Exercise on a DNA Oxidative-Damage Marker and Total Antioxidant Capacity in Rat Hippocampal Tissue

    PubMed Central

    Mahjoub, Soleiman; Ghadi, Arezoo; Pourbagher, Roghayeh; Hajian-Tilaki, Karimollah

    2016-01-01

    Background and Purpose Regular exercise can result in changes in the levels of oxidative stress in the hippocampus; however, little attention has been paid to physical-activity-induced neuronal protection to exposure to lead compounds. This study investigated the effects of regular treadmill exercise on a DNA oxidative-damage marker [8-hydroxy-2'-deoxyguanosine (8-OHdG)] and the total antioxidant capacity (TAC) of hippocampal tissue in lead-acetate exposed rats. Methods This study investigated the effects of 8 weeks of regular treadmill exercise on 8-OHdG and the TAC of hippocampal tissue in lead-acetate-exposed rats. Wistar rats were randomly divided into four groups: baseline, sham (control), lead, and exercise+lead. The exercise program involved running on a treadmill with increasing intensity five times a week for 8 weeks. Animals in the lead and exercise+lead groups received lead acetate at 20 mg/kg body weight intraperitoneally three times weekly for 8 weeks. Animals in the sham group received solvent (ethyl oleate) at 30 mg/kg body weight three times weekly for 8 weeks. TAC and 8-OHdG were measured by spectrophotometric and ELISA techniques, respectively. Data were analyzed by ANOVA and Tukey's post-hoc test with a significance cutoff of p≤0.05. Results The level of 8-OHdG and the TAC were significantly higher and lower, respectively, in the lead group than in the baseline and sham groups (p<0.01). However, the 8-OHdG level and TAC value in hippocampal tissue were significantly decreased and increased, respectively, in the exercise+lead group relative to the lead group (p<0.05). Conclusions The TAC of hippocampal tissue may be directly associated with neural protection mechanisms of exercise following lead acetate injection, and the beneficial effects of regular exercise in preventing hippocampal neuronal damage could be due to decreased hippocampal oxidative stress such as reflected by a lower 8-OHdG level and increased TAC.

  3. The influence of water/air cooling on collateral tissue damage using a diode laser with an innovative pulse design (micropulsed mode)-an in vitro study.

    PubMed

    Beer, F; Körpert, W; Buchmair, A G; Passow, H; Meinl, A; Heimel, P; Moritz, A

    2013-05-01

    Since the diode laser is a good compromise for the daily use in dental offices, finding usage in numerous dental indications (e.g., surgery, periodontics, and endodontics), the minimization of the collateral damage in laser surgery is important to improve the therapeutical outcome. The aim of this study was to investigate the effect of water/air cooling on the collateral thermal soft tissue damage of 980-nm diode laser incisions. A total of 36 mechanically executed laser cuts in pork liver were made with a 980-nm diode laser in micropulsed mode with three different settings of water/air cooling and examined by histological assessment to determine the area and size of carbonization, necrosis, and reversible tissue damage as well as incision depth and width. In our study, clearly the incision depth increased significantly under water/air cooling (270.9 versus 502.3 μm-test group 3) without significant changes of incision width. In test group 2, the total area of damage was significantly smaller than in the control group (in this group, the incision depth increases by 65 %). In test group 3, the total area of damage was significantly higher (incision depth increased by 85 %), but the bigger part of it represented a reversible tissue alteration leaving the amount of irreversible damage almost the same as in the control group. This first pilot study clearly shows that water/air cooling in vitro has an effect on collateral tissue damage. Further studies will have to verify, if the reduced collateral damage we have proved in this study can lead to accelerated wound healing. Reduction of collateral thermal damage after diode laser incisions is clinically relevant for promoted wound healing.

  4. Lack of reversal of oxidative damage in renal tissues of lead acetate-treated rats.

    PubMed

    Oyagbemi, Ademola Adetokunbo; Omobowale, Temidayo Olutayo; Akinrinde, Akinleye Stephen; Saba, Adebowale Bernard; Ogunpolu, Blessing Seun; Daramola, Oluwabusola

    2015-11-01

    Removal of lead from the environment of man or otherwise, the movement of man from lead-contaminated areas has been employed as a means of abatement of the toxic effects of lead. Whether toxic effects in already-exposed individuals subside after lead withdrawal remains unanswered. To understand the reversibility of nephrotoxicity induced by lead acetate, male Wistar rats were orally exposed to 0.25, 0.5, and 1.0 mg/mL of lead acetate for 6 weeks. Activities of glutathione-s-transferase, catalase (CAT), superoxide dismutase (SOD) and the concentrations of hydrogen peroxide (H2 O2 ), and malondialdehyde increased significantly (p < 0.05) in a dose-dependent manner, whereas reduced glutathione (GSH) level and glutathione peroxidase activity were significantly reduced. The pattern of alterations in most of the oxidative stress and antioxidant parameters remained similar in rats from the withdrawal period, although CAT and SOD activities reduced, in contrast to their elevation during the exposure period. Serum creatinine levels were significantly elevated in both exposure and withdrawal experiments whereas serum blood urea nitrogen levels were not significantly different from the control in both exposure and withdrawal periods. The histological damage observed include multifocal areas of inflammation, disseminated tubular necrosis, and fatty infiltration of the kidney tubules both at exposure and withdrawal periods. The results suggest that lead acetate-induced nephrotoxicity by induction of oxidative stress and disruption of antioxidant. The aforementioned alterations were not reversed in the rats left to recover within the time course of study.

  5. [Early-onset radiation complications and tissue damage in the treatment of head and neck tumors].

    PubMed

    Isaev, P A; Medvedev, V S; Pasov, V V; Semin, D Iu; Derbugov, D N; Pol'kin, V V; Terekhov, O V

    2010-01-01

    The report discusses the results of an evaluation of the effectiveness of combined radiotherapy in 1,192 cases of head and neck tumors divided into 4 groups: distant radiotherapy in standard fractions of 1.8-2.3 Gy, 5 times a week, TTD of 60 Gy (group 1 - 486 40.8%); radiotherapy + local UHF hyperthermia + regional intraarterial chemotherapy + hyper glycemia + administrations of regional intraarterial chemotherapy + hyperglycemia + local UHF hyperthermia (group 2 - 244 20.5%); accelerated superfractition radiotherapy with variable STD of 1 and 1.5/2 Gy, TTD of 60 Gy, plus neoadjuvant polychemotherapy with cisplatin 100 mg/lm2 + 5-fluorouracil, continuous intravenous infusion of 3,000 mg for 72 h (group 3 - 204 17%1); combined photon-neutron therapy (group 4 - 258 21.6%): neutron beam therapy - 36 (3%); interstitial neutron brachytherapy with 252 Cf sources in combination with external beam gamma-therapy and chemotherapy. Overall radiation injury incidence was 1,087 (91.2%); oral mucositis grade I (WHO) - 110 (9.2%), grade II - 166(13.9%), grade III - 811 (68%), radiation dermatitis - 279 (23.4%), grade I/II - 196 (16.4%), grade III/IV - 83 (7%). Grade III/IV side effects developed in 26.7% after gamma therapy and in 72.2% - in the photon-neutron group (p < or = 0.0001). Skin damage was rare, as expected, in the photon-brachytherapy group (1.8%) (p < or = 0.0001). Hence, Cf252 neutron brachytherapy and radiotherapy with concomitant chemotherapy appeared to produce the most sparing effects. PMID:21137234

  6. Preventive supplementation with fresh and preserved peach attenuates CCl4-induced oxidative stress, inflammation and tissue damage.

    PubMed

    Gasparotto, Juciano; Somensi, Nauana; Bortolin, Rafael Calixto; Girardi, Carolina Saibro; Kunzler, Alice; Rabelo, Thallita Kelly; Schnorr, Carlos Eduardo; Moresco, Karla Suzana; Bassani, Valquiria Linck; Yatsu, Francini Kiyono Jorge; Vizzotto, Márcia; Raseira, Maria do Carmo Bassols; Zanotto-Filho, Alfeu; Moreira, José Claudio Fonseca; Gelain, Daniel Pens

    2014-12-01

    The present study was elaborated to comparatively evaluate the preventive effect of different peach-derived products obtained from preserved fruits (Syrup and Preserve Pulp Peach [PPP]) and from fresh peels and pulps (Peel and Fresh Pulp Peach [FPP]) in a model of liver/renal toxicity and inflammation induced by carbon tetrachloride (CCl4) in rats. Tissue damage (carbonyl, thiobarbituric acid reactive species and sulfhydril), antioxidant enzymes activity (catalase and superoxide dismutase) and inflammatory parameters [tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels, and receptor for advanced glycation end-products (RAGE) and nuclear factor (NF)κB-p65 immunocontent] were investigated. Our findings demonstrated that Peel, PPP and FPP (200 or 400 mg/kg) daily administration by oral gavage for 30 days conferred a significant protection against CCl4-induced antioxidant enzymes activation and, most importantly, oxidative damage to lipids and proteins as well as blocked induction of inflammatory mediators such as TNF-α, IL-1β, RAGE and NFκB. This antioxidant/anti-inflammatory effect seems to be associated with the abundance of carotenoids and polyphenols present in peach-derived products, which are enriched in fresh-fruit-derived preparations (Peel and FPP) but are also present in PPP. The Syrup - which was the least enriched in antioxidants - displayed no protective effect in our experiments. These effects cumulated in decreased levels of transaminases and lactate dehydrogenase leakage into serum and maintenance of organ architecture. Therefore, the herein presented results show evidence that supplementation with peach products may be protective against organ damage caused by oxidative stress, being interesting candidates for production of antioxidant-enriched functional foods.

  7. Ablation velocity and thermal damage of myocardial tissue using a CO2 laser for transmyocardial laser revascularization

    NASA Astrophysics Data System (ADS)

    Sachinopoulou, Anna; Beek, Johan F.; van Leeuwen, Ton G. J. M.; Beek, W. J.

    1999-02-01

    Transmyocardial Laser Revascularization (TMLR) is a new experimental method for relief of angina pectoris in patients with severe coronary artery disease. TMLR aims at revascularizing chronic hibernating myocardium by creating transmural channels. One of the working mechanism hypotheses is that the endocardial side of the channels remains open, enabling perfusion of the hibernating myocardium directly from the left ventricle. Although the working mechanism of TMLR is still unknown (perfusion through patent channels, induction of angiogenesis, relief of angina through destruction of sympatic innervation, others?), first clinical studies are successful. Currently, the Heart LaserTM and other CO2 lasers, XeCl Excimer laser and Ho:YAG laser are under investigation for TMLR. The initial attempts of TMR with needles were soon replaced by laser induced channels. Efforts were focused on developing a CO2 laser that could penetrate a beating heart during its relaxation phase. Later, the position of the beam could be fixed in the myocardial wall using lasers with fiber delivery systems and perforation was achieved within multiple cycles. Various researchers reported on both patent and non-patent channels after TMLR. Our belief is that the extent of laser induced thermal damage is one of the factors that determine the clinical outcome and the extent of angiogenesis (and, possibly, the patency of the channel). The purpose of this study is to present a simple theoretical model to predict the extent of thermal damage around a transmyocardial channel. In vitro experiments were performed on myocardial bovine tissue and damage was assessed. The results were used to determine the final parameters of the approximating theoretical equation. To evaluate our results, we compared our results to in vitro data using the Heart LaserTM from the literature. Ablation velocities were also measured and the results were compared to ablation velocity calculations using a model described by Ostegar

  8. TNF-mediated damage to glomerular endothelium is an important determinant of acute kidney injury in sepsis.

    PubMed

    Xu, Chang; Chang, Anthony; Hack, Bradley K; Eadon, Michael T; Alper, Seth L; Cunningham, Patrick N

    2014-01-01

    Severe sepsis is often accompanied by acute kidney injury (AKI) and albuminuria. Here we studied whether the AKI and albuminuria associated with lipopolysaccharide (LPS) treatment in mice reflects impairment of the glomerular endothelium with its associated endothelial surface layer. LPS treatment decreased the abundance of endothelial surface layer heparan sulfate proteoglycans and sialic acid, and led to albuminuria likely reflecting altered glomerular filtration permselectivity. LPS treatment decreased the glomerular filtration rate (GFR), while also causing significant ultrastructural alterations in the glomerular endothelium. The density of glomerular endothelial cell fenestrae was 5-fold lower, whereas the average fenestrae diameter was 3-fold higher in LPS-treated than in control mice. The effects of LPS on the glomerular endothelial surface layer, endothelial cell fenestrae, GFR, and albuminuria were diminished in TNF receptor 1 (TNFR1) knockout mice, suggesting that these LPS effects are mediated by TNF-α activation of TNFR1. Indeed, intravenous administration of TNF decreased GFR and led to loss of glomerular endothelial cell fenestrae, increased fenestrae diameter, and damage to the glomerular endothelial surface layer. LPS treatment decreased kidney expression of vascular endothelial growth factor (VEGF). Thus, our findings confirm the important role of glomerular endothelial injury, possibly by a decreased VEGF level, in the development and progression of AKI and albuminuria in the LPS model of sepsis in the mouse.

  9. Brain tissue damage in dementia with Lewy bodies: an in vivo diffusion tensor MRI study.

    PubMed

    Bozzali, M; Falini, A; Cercignani, M; Baglio, F; Farina, E; Alberoni, M; Vezzulli, P; Olivotto, F; Mantovani, F; Shallice, T; Scotti, G; Canal, N; Nemni, R

    2005-07-01

    The aim of the present study was to apply diffusion tensor MRI (DT-MRI), a quantitative MRI measure which reflects tissue organization, to dementia with Lewy bodies (DLB). DT-MRI scans were obtained from 15 patients with probable DLB and 10 sex- and age-matched healthy controls. Abnormalities were found in the corpus callosum, pericallosal areas and the frontal, parietal, occipital and, less prominently, temporal white matter of patients compared with controls. Abnormalities were also found in the caudate nucleus and the putamen. The average grey matter volume was lower in patients than in controls. These findings of concomitant grey matter atrophy and white matter abnormalities (as detected by DT-MRI) in regions with a high prevalence of long connecting fibre tracts might suggest the presence of neurodegeneration involving associative cortices. The modest involvement of the temporal lobe fits with the relative preservation of global neuropsychological measures and memory tasks in the early stage of DLB. The selective involvement of parietal, frontal and occipital lobes might explain some of the clinical and neuropsychological features of DLB, providing a possible distinctive marker for this disease. The abnormalities found in the subcortical grey matter may indicate that DLB and Parkinson's disease share a similar nigrostriatal involvement caused by common pathophysiological mechanisms.

  10. Global DNA hypomethylation: a potential mechanism in King pigeon nerve tissue damage induced by avermectin.

    PubMed

    Cao, Ye; Chen, Li-Jie; Zhang, Zi-wei; Yao, Hai-dong; Liu, Ci; Li, Shu; Xu, Shi-wen

    2014-08-01

    As an effective insecticidal and nematicidal agent, avermectin (AVM) has been widely used in agricultural production and stock farming areas. Subsequently, the residues of AVM or its active metabolites in animal manure pose a toxic threat to non-target organisms in the environment. As the most characteristic epigenetic phenomena, DNA methylation status is a useful biological signal for the toxicity assessment of environmental chemical toxicants. In this study, analyses of the overall level of genomic DNA methylation were performed, and the expression levels of DNA methyltransferases (DNMTs), as well as demethylase methyl-CpG-binding domain protein 2 (MBD2), in pigeon brain tissues after subchronic exposure (with a AVM concentration of 20 mg/kg, 40 mg/kg and 60 mg/kg, respectively) to AVM for 30, 60 and 90 days were investigated. Global DNA hypomethylation and down-regulation of DNMT mRNA expression occurred in a dose-time-dependent manner in pigeon brains. The expression level of MBD2, which functions as a demethylase, was significantly enhanced in a dose-dependent but not time-dependent manner. In addition, the elevated expression level of MBD2 had a more robust effect on genomic DNA hypomethylation compared to changes in DNMT expression. Taken together, these results suggested that subchronic dose exposures of AVM could affect the global DNA methylation status, and this mechanism is closely related to changes in the expression levels of DNMTs and MBD2.

  11. Estimate of normal tissue damage in treatment planning for stereotactic radiotherapy.

    PubMed

    Benassi, M; Begnozzi, L; Gentile, F P; Chiatti, L; Carpino, S

    1993-10-01

    A personal computer (PC) system was developed to perform treatment planning for radiosurgery and stereotactic radiotherapy. These techniques of irradiation of the brain may be accomplished with a linear accelerator by performing several non-coplanar arcs of a highly collimated beam focused at a fixed point. The PC system allows the acquisition, reconstruction and the visualization of the target volume from CT or MR images, and then it permits to calculate a three-dimensional (3-D) dose distribution due to small photon beams and to visualize it. The software calculates not only total dose distribution, administered fractionated or in single fraction, but also the NTD2 (normalized total dose) predicted to have a biological effect equivalent to the single irradiation. The choice of the best technique is supported by the dose volume histograms (DVH) calculation and by an estimate of complication probability to the brain normal tissue (NTCP). The algorithm for NTCP calculation is based on two models: the linear quadratic and the logistic. A comparison of three different dose calculations for a typical cerebral target volume is presented to demonstrate the system performances.

  12. Acute compartment syndrome of the forearm caused by calcific tendinitis of the distal biceps.

    PubMed

    Garayoa, Santiago Amillo; Romero-Muñoz, Luis M; Pons-Villanueva, Juan

    2010-12-01

    Acute compartment syndrome of the forearm requires immediate treatment to avoid damage of the soft tissues and a poor functional outcome for the forearm. Muscular and bone lesions are the main causes of acute compartment syndromes. We report a case of acute compartment syndrome of the forearm caused by a calcific tendinitis of the distal biceps.

  13. Comparison of Genotoxic Damage in Monolayer Cell Cultures and Three-Dimensional Tissue-Like Cell Assemblies

    NASA Technical Reports Server (NTRS)

    Behravesh, E.; Emami, K.; Wu, H.; Gonda, S.

    2004-01-01

    Assessing the biological risks associated with exposure to the high-energy charged particles encountered in space is essential for the success of long-term space exploration. Although prokaryotic and eukaryotic cell models developed in our laboratory and others have advanced our understanding of many aspects of genotoxicity, in vitro models are needed to assess the risk to humans from space radiation insults. Such models must be representative of the cellular interactions present in tissues and capable of quantifying I genotoxic damage. Toward this overall goal, the objectives of this study were to examine the effect of the localized microenvironment of cells, cultured as either 2-dimensional (2D) monolayers or 3-dimensional (3D) aggregates, on the rate and type of genotoxic damage resulting from exposure to iron charged particles, a significant portion of space radiation. We used rodent transgenic cell lines containing 50-70 copies of a LacI transgene to provide the enhanced sensitivity required to quantify mutational frequency and type in the 1,100-bp LacI target as well as assessment of DNA,damage to the entire 45-kbp construct. Cultured cells were exposed to high-enerir on charged particles at Brookhaven National Laboratory s Alternating Gradient Synchrotron facility for a total dose of 0, 0.1, 0.25,0.5, 1.0, or 2.0 Gy and allowed to recover for 0, 1, or 7 days, after which mutational type and frequency were evaluated. The mutational frequency was found to be higher in 3D samples than in 2D samples at all radiation doses. Mutational frequency also was higher at 7 days after irradiation than immediately after exposure. DNA sequencing of the mutant targets revealed that deletional mutations contributed an increasingly high percentage (up to 27%) of all mutations in cells as the dose was increased from 0.5 to 2 Gy. Several mutants also showed large and complex deletions in multiple locations within the Lac1 target. However, no differences in mutational type were

  14. YAP and TAZ in epithelial stem cells: A sensor for cell polarity, mechanical forces and tissue damage

    PubMed Central

    Elbediwy, Ahmed; Vincent‐Mistiaen, Zoé I.

    2016-01-01

    The YAP/TAZ family of transcriptional co‐activators drives cell proliferation in epithelial tissues and cancers. Yet, how YAP and TAZ are physiologically regulated remains unclear. Here we review recent reports that YAP and TAZ act primarily as sensors of epithelial cell polarity, being inhibited when cells differentiate an apical membrane domain, and being activated when cells contact the extracellular matrix via their basal membrane domain. Apical signalling occurs via the canonical Crumbs/CRB‐Hippo/MST‐Warts/LATS kinase cascade to phosphorylate and inhibit YAP/TAZ. Basal signalling occurs via Integrins and Src family kinases to phosphorylate and activate YAP/TAZ. Thus, YAP/TAZ is localised to the nucleus in basal stem/progenitor cells and cytoplasm in differentiated squamous cells or columnar cells. In addition, other signals such as mechanical forces, tissue damage and possibly receptor tyrosine kinases (RTKs) can influence MST‐LATS or Src family kinase activity to modulate YAP/TAZ activity. PMID:27173018

  15. Lead accumulation, oxidative damage and histopathological alteration in testes and accessory glands of freshwater crab, Sinopotamon henanense, induced by acute lead exposure.

    PubMed

    Li, Na; Hou, Yu-hua; Ma, Dan-dan; Jing, Wei-xin; Dahms, Hans-Uwe; Wang, Lan

    2015-07-01

    Lead (Pb) is one of the most toxic environmental pollutants and known to exert multiple toxic effects including gonadotoxic and spermiotoxic effects. In order to understand toxic mechanisms of lead (Pb) on the testes and the accessory glands of crabs, we investigated Pb accumulation in testes and accessory glands and the survival rate of sperms of freshwater crab, Sinopotamon henanense. The tissue damaging effects of Pb was also investigated by histopathological examination and analyses of antioxidant enzymes as well as lipid peroxidation. Crabs were exposed to different Pb concentrations (0, 3.675, 7.35, 14.7, 29.4 and 58.8 mg/L) for 3, 5 and 7 days. The results showed that Pb levels in testes and accessory glands increased significantly following Pb exposure for 5 and 7 days in almost all treated groups, and survival rate of sperm decreased with increasing Pb concentrations at 5 and 7 days. Morphological changes identified histologically were discovered in testes, including a disordered arrangement of germ cells, a decreased number of sperm in the lumina of the seminiferous tubules, extensive necrosis in the germinal layer of the seminiferous tubules, etc. At the same time, histological abnormalities were discovered in accessory glands, the wall cells were separated from the basement membrane, and wall cells were missing partly. The activities of SOD, GPx and CAT in testes showed no statistically significant changes compared to the control for 3 days, and initially increased and subsequently decreased with increasing Pb concentrations at 5 and 7 days. The antioxidant enzyme activities in accessory glands initially increased and subsequently decreased with increasing Pb concentrations and Pb exposure. This was accompanied with an increase in malondialdehyde (MDA) content in a concentration-dependent manner. These results showed that acute Pb exposure led to a reduction of survival rate of sperm and harmful effects at the cellular level of crab testes and accessory

  16. Myocardin-related transcription factor-A-overexpressing bone marrow stem cells protect cardiomyocytes and alleviate cardiac damage in a rat model of acute myocardial infarction.

    PubMed

    Zhong, Ze; Hu, Jia-Qing; Wu, Xin-Dong; Sun, Yong; Jiang, Jun

    2015-09-01

    Myocardin-related transcription factor-A (MRTF-A) can transduce biomechanical and humoral signals, which can positively modulate cardiac damage induced by acute myocardial infarction (AMI). In the clinic, bone marrow stem cell (BMSC) therapy is being increasingly utilized for AMI; however, the effects of BMSC transplantation remain to be optimized. Therefore, a novel strategy to enhance BMSC‑directed myocardial repair is particularly important. The present study was performed to assess the efficacy of MRTF‑A-overexpressing BMSCs in a rat model of AMI. Primary cardiomyocytes were prepared from neonatal Sprague-Dawley rats and BMSCs were isolated from male Sprague-Dawley rats (aged 8-12 weeks). Annexin V-phycoerythrin/7-actinomycin D staining was used to evaluate BMSC and cardiomyocyte survival after exposure to hydrogen peroxide in vitro. B-cell lymphoma 2 (Bcl-2) protein expression was measured by flow cytometric and western blot analyses. The effects of MRTF-A‑overexpressing BMSCs in a rat model of AMI were investigated by hematoxylin and eosin staining and western blot analysis of Bcl-2 expression in myocardial tissue sections. MRTF-A enhanced the migration of BMSCs, and overexpression of MRTF-A in BMSCs prevented hydrogen peroxide-induced apoptosis in primary cardiomyocytes ex vivo. In addition, co-culture of cardiomyocytes with MRTF‑A-overexpressing BMSCs inhibited hydrogen peroxide-induced apoptosis and the enhanced expression of Bcl-2. Furthermore, in vivo, enhanced cell survival was observed in the MRTF-A-modified BMSC group compared with that in the control group. These observations indicated that MRTF-A-overexpressing BMSCs have the potential to exert cardioprotective effects against hydrogen peroxide-induced injury and that treatment with MRTF‑A‑modified BMSCs is able to reverse cardiac dysfunction after AMI.

  17. Mechanistic simulation of normal-tissue damage in radiotherapy—implications for dose-volume analyses

    NASA Astrophysics Data System (ADS)

    Rutkowska, Eva; Baker, Colin; Nahum, Alan

    2010-04-01

    A radiobiologically based 3D model of normal tissue has been developed in which complications are generated when 'irradiated'. The aim is to provide insight into the connection between dose-distribution characteristics, different organ architectures and complication rates beyond that obtainable with simple DVH-based analytical NTCP models. In this model the organ consists of a large number of functional subunits (FSUs), populated by stem cells which are killed according to the LQ model. A complication is triggered if the density of FSUs in any 'critical functioning volume' (CFV) falls below some threshold. The (fractional) CFV determines the organ architecture and can be varied continuously from small (series-like behaviour) to large (parallel-like). A key feature of the model is its ability to account for the spatial dependence of dose distributions. Simulations were carried out to investigate correlations between dose-volume parameters and the incidence of 'complications' using different pseudo-clinical dose distributions. Correlations between dose-volume parameters and outcome depended on characteristics of the dose distributions and on organ architecture. As anticipated, the mean dose and V20 correlated most strongly with outcome for a parallel organ, and the maximum dose for a serial organ. Interestingly better correlation was obtained between the 3D computer model and the LKB model with dose distributions typical for serial organs than with those typical for parallel organs. This work links the results of dose-volume analyses to dataset characteristics typical for serial and parallel organs and it may help investigators interpret the results from clinical studies.

  18. Cerebral hypoperfusion detected by SPECT in patients with systemic lupus erythematosus is related to clinical activity and cumulative tissue damage.

    PubMed

    López-Longo, F J; Carol, N; Almoguera, M I; Olazarán, J; Alonso-Farto, J C; Ortega, A; Monteagudo, I; González, C Manuel; Carreño, L

    2003-01-01

    Cerebral single-photon emission computed tomography (SPECT) is a sensitive technique for the detection of central nervous system (CNS) involvement in systemic lupus erythematosus (SLE). The objective was to determine whether a relationship exists between cerebral hypoperfusion as detected by cerebral SPECT, cumulative tissue damage and the clinical activity of SLE. Cerebral technetium-99m-L,L-ethyl cysteinate dimer (99mTc-ECD) SPECT was performed in two groups of patients: 10 women with SLE (Group A) who had no previous history of major neuropsychiatric (NPS) manifestations and no minor NPS symptoms in the last six months, and 57 unselected women with SLE (Group B). In the same week that SPECT was performed, the SLE disease activity index (SLEDAI), SLICC/ACR damage index, native anti-DNA antibodies (ELISA) and erythrocyte sedimentation rate (ESR) were determined. In Group A, cerebral SPECT showed moderate or severe hypoperfusion (abnormal SPECT) in five patients without NPS symptoms, unrelated to age (mean 24.8 versus 27.8 years) or disease duration (mean 6.8 versus 9 years). Patients with significant cerebral hypoperfusion had greater clinical disease activity (mean SLEDAI 13.6 versus 7.6) (SLEDAI > 7 in 5/5 versus 1/5; Fisher: 0.023; OR: 33; 95% CI: 2.3-469.8) and ESR (mean 43.6 versus 9.8; P < 0.05). In Group B, the mean age of the 57 unselected women with SLE was 37 years (SD 6.3) and the mean duration of the disease was 9.7 years (SD 6.3). Cerebral SPECT revealed normal perfusion or mild hypoperfusion (normal SPECT) in 30 patients (52.6%), and moderate or severe hypoperfusion in 27 (47.4%). Hypoperfusion was unrelated to age, duration of SLE or concentrations of anti-DNA antibodies and C3 and C4 fractions. Patients with significant cerebral hypoperfusion had more active clinical disease (mean SLEDAI 13.92; SD 8.44 versus 4.56; SD 4.15) (Mann-Whitney, P < 0.005), more cumulative tissue damage (mean SLICC 2.66; SD 2.84 versus 1.03; SD 1.51) (Mann-Whitney, P = 0

  19. Expression of heat shock proteins 70 and 47 in tissues following short-pulse laser irradiation: assessment of thermal damage and healing.

    PubMed

    Sajjadi, Amir Yousef; Mitra, Kunal; Grace, Michael

    2013-10-01

    In order to develop effective laser-based therapeutics, the extent of laser-induced damage must be quantified for given laser parameters. Therefore, we want to determine the spatiotemporal expression patterns of heat shock proteins, both to understand the roles of heat shock proteins in laser-induced tissue damage and repair and to develop heat shock proteins as tools to illustrate the extent of laser-induced damage and wound healing following irradiation. We exposed anesthetized mice to the focused beam of a short-pulse Nd:YAG laser (1064 nm; 200 ns pulsewidth) for 15s, while measuring temperature distribution in the skin using an infrared thermal camera. Following irradiation, we examined expression of HSP47 and HSP70 over time (0-24h) as indicators of the heat shock response and recovery from damage in the laser-irradiated region. Expression patterns of HSP70 and HSP47 as detected by immunohistochemistry and confocal microscopy delineate the extent of damage and the process of healing in tissue. Both HSP70 and HSP47 were expressed in dermis and epidermis following laser irradiation, and the spatial and temporal changes in HSP expression patterns define the laser-induced thermal damage zone and the process of healing in tissues. HSP70 may define biochemically the thermal damage zone in which cells are targeted for destruction, and HSP47 may illustrate the process of recovery from thermally induced damage. Studying the effects of different laser parameters on the expression of HSPs will allow development of effective laser therapies that provide accurate and precise tissue ablation and may promote rapid wound healing following laser-based surgery.

  20. Acute and chronic effects of oestrogen on endothelial tissue-type plasminogen activator release in postmenopausal women

    PubMed Central

    Hoetzer, Greta L; Stauffer, Brian L; Irmiger, Heather M; Ng, Marilyn; Smith, Derek T; DeSouza, Christopher A

    2003-01-01

    The capacity of vascular endothelium to locally release tissue-type plasminogen activator (t-PA) represents an important endogenous defence mechanism against intravascular fibrin deposition and thrombosis. We determined the influence of chronic and acute oestrogen administration on endothelial t-PA release in postmenopausal women. Sixty-three healthy postmenopausal women were studied: 31 non-users (age 58 ± 1 years) and 32 users of hormone replacement therapy, including oestrogen alone (ORT: 62 ± 2 years; n = 15) and in combination with progesterone (HRT: 57 ± 1 years; n = 17). Net endothelial t-PA release was determined in vivo, in response to intrabrachial infusions of bradykinin and sodium nitroprusside. To examine the acute effects of oestrogen on endothelial t-PA release, bradykinin and sodium nitroprusside dose-response curves were repeated in the presence of 17 β-oestradiol in 20 of the 31 non-users. Net endothelial release of t-PA was ≈30 % higher (P < 0.01) in women taking ORT (from 2.0 ± 1.0 to 83.6 ± 9.2 ng (100 ml tissue)−1 min−1) compared with those taking HRT (from 1.4 ± 0.4 to 63.5 ± 5.6 ng (100 ml tissue)−1 min−1) and those not taking supplementation (1.0 ± 0.7 to 63.0 ± 4.7 ng (100 ml tissue)−1 min−1). Intra-arterial infusion of 17 β-oestradiol significantly potentiated bradykinin-induced t-PA release. Net endothelial release of t-PA was ≈45 % higher (P < 0.01) after (from 1.0 ± 0.8 to 87.4 ± 9.9 ng (100 ml tissue)−1 min−1) versus before (1.2 ± 0.6 to 60.8 ± 5.6 ng (100 ml tissue)−1 min−1) acute 17 β-oestradiol administration. Our results suggest that oestrogen has a direct modulatory effect on the capacity of the endothelium to release t-PA in healthy postmenopausal women. However, progesterone appears to oppose the favourable influence of oestrogen on endothelial fibrinolytic capacity. PMID:12815179

  1. Systemic thrombolysis with recombinant tissue plasminogen activator for acute life-threatening Blalock-Taussig shunt obstruction.

    PubMed

    Diaz, Franco; Sasser, William C; Law, Mark A; Alten, Jeffrey A

    2016-07-01

    Modified Blalock-Taussig shunt (mBTS) obstruction can be life-threatening, especially when it represents the only source of pulmonary blood flow. Current therapeutic options to reverse obstruction include surgical shunt revision/replacement, interventional endovascular procedures including balloon angioplasty and/or stent placement, and a combination of local and systemic thrombolytic therapy. We report two cases of acute mBTS thrombosis successfully treated with systemic recombinant tissue plasminogen activator in infants convalescing after cardiac surgery when the clinical status and resources precluded traditionally described rescue therapies. PMID:27555699

  2. Systemic thrombolysis with recombinant tissue plasminogen activator for acute life-threatening Blalock-Taussig shunt obstruction

    PubMed Central

    Diaz, Franco; Sasser, William C.; Law, Mark A.; Alten, Jeffrey A.

    2016-01-01

    Modified Blalock-Taussig shunt (mBTS) obstruction can be life-threatening, especially when it represents the only source of pulmonary blood flow. Current therapeutic options to reverse obstruction include surgical shunt revision/replacement, interventional endovascular procedures including balloon angioplasty and/or stent placement, and a combination of local and systemic thrombolytic therapy. We report two cases of acute mBTS thrombosis successfully treated with systemic recombinant tissue plasminogen activator in infants convalescing after cardiac surgery when the clinical status and resources precluded traditionally described rescue therapies. PMID:27555699

  3. Gastroprotective Effect of Cochinchina momordica Seed Extract in Nonsteroidal Anti-Inflammatory Drug-Induced Acute Gastric Damage in a Rat Model

    PubMed Central

    Lim, Ji Hwan; Kim, Joo-Hyun; Lee, Byoung Hwan; Seo, Pyoung Ju; Kang, Jung Mook; Jo, So Young; Park, Ji Hyun; Nam, Ryoung Hee; Chang, Hyun; Kwon, Jin-Won; Lee, Dong Ho

    2014-01-01

    Background/Aims The major compounds of Cochinchina momordica seed extract (SK-MS10) include momordica saponins. We report that the gastroprotective effect of SK-MS10 in an ethanol-induced gastric damage rat model is mediated by suppressing proinflammatory cytokines and downregulating cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase (5-LOX), and the activation of calcitonin gene-related peptide. In this study, we evaluated the gastroprotective effects of SK-MS10 in the nonsteroidal anti-inflammatory drug (NSAID)-induced gastric damage rat model. Methods The pretreatment effect of SK-MS10 was evaluated in the NSAID-induced gastric damage rat model using aspirin, indomethacin, and diclofenac in 7-week-old rats. Gastric damage was evaluated based on the gross ulcer index by gastroenterologists, and the damage area (%) was measured using the MetaMorph 7.0 video image analysis system. Myeloperoxidase (MPO) was measured by enzyme-linked immunosorbent assay, and Western blotting was used to analyze the levels of cyclooxygenase (COX)-1, COX-2, cPLA2, and 5-LOX. Results All NSAIDs induced gastric damage based on the gross ulcer index and damage area (p<0.05). Gastric damage was significantly attenuated by SK-MS10 pretreatment compared with NSAID treatment alone (p<0.05). The SK-MS10 pretreatment group exhibited lower MPO levels than the diclofenac group. The expression of cPLA2 and 5-LOX was decreased by SK-MS10 pretreatment in each of the three NSAID treatment groups. Conclusions SK-MS10 exhibited a gastroprotective effect against NSAID-induced acute gastric damage in rats. However, its protective mechanism may be different across the three types of NSAID-induced gastric damage models in rats. PMID:24516701

  4. Modifying Radiation Damage

    PubMed Central

    Kim, Kwanghee; McBride, William H.

    2011-01-01

    Radiation leaves a fairly characteristic footprint in biological materials, but this is rapidly all but obliterated by the canonical biological responses to the radiation damage. The innate immune recognition systems that sense “danger” through direct radiation damage and through associated collateral damage set in motion a chain of events that, in a tissue compromised by radiation, often unwittingly result in oscillating waves of molecular and cellular responses as tissues attempt to heal. Understanding “nature’s whispers” that inform on these processes will lead to novel forms of intervention targeted more precisely towards modifying them in an appropriate and timely fashion so as to improve the healing process and prevent or mitigate the development of acute and late effects of normal tissue radiation damage, whether it be accidental, as a result of a terrorist incident, or of therapeutic treatment of cancer. Here we attempt to discuss some of the non-free radical scavenging mechanisms that modify radiation responses and comment on where we see them within a conceptual framework of an evolving radiation-induced lesion. PMID:20583981

  5. Acute ischemic stroke treated with intravenous tissue plasminogen activator in a patient taking dabigatran with radiographic evidence of recanalization.

    PubMed

    Sangha, Navdeep; El Khoury, Ramy; Misra, Vivek; Lopez, George

    2012-11-01

    Dabigatran etexelate is a new oral direct thrombin inhibitor that has been approved by the US Food and Drug Administration to prevent stroke in patients with nonvalvular atrial fibrillation. A 51-year-old man with a history of atrial fibrillation who was taking dabigatran presented with an acute ischemic stroke. The patient had a normal international normalized ratio, activated partial thromboplastin time, and an elevated thrombin time of 26.4 seconds. Recanalization of the middle cerebral artery with intravenous tissue plasminogen activator was apparent on digital subtraction angiography, and there was no evidence of intracerebral hemorrhage on the repeat computed tomographic scan. This is the first report of a patient who was taking dabigatran etexilate and who had an ischemic stroke caused by a middle cerebral artery occlusion, with an elevated thrombin time and radiographic recanalization with intravenous tissue plasminogen activator without evidence of hemorrhagic transformation. PMID:22683118

  6. The isolated perfused kidney: an in vitro test system for evaluation of renal tissue damage induced by high-energy shockwaves sources.

    PubMed

    Bergsdorf, Th; Thüroff, S; Chaussy, Ch

    2005-09-01

    Most of our knowledge of shockwave-induced renal damage is based on animal experiments and clinical observation. We developed a tissue model using isolated porcine kidneys perfused with Berliner Blau dye in physiologic saline using a Ureteromat Perez-Castro peristaltic pump connected to the renal artery. Reproducible results were obtained under a variety of experimental conditions. Further refinements of the model might consist of interposition of tissue layers in the shockwave path or simulation of ventilatory movements.

  7. Nociceptive Sensitizers Are Regulated in Damaged Joint Tissues, Including Articular Cartilage, When Osteoarthritic Mice Display Pain Behavior

    PubMed Central

    Driscoll, Clare; Chanalaris, Anastasios; Knights, Chancie; Ismail, Heba; Sacitharan, Pradeep K.; Gentry, Clive; Bevan, Stuart

    2016-01-01

    also largely regulated in the articular cartilage, although there were some differences between the 2 models. NGF and tachykinin were strongly regulated by simple mechanical injury of cartilage in vitro in a transforming growth factor β–activated kinase 1–, fibroblast growth factor 2–, and Src kinase–dependent manner. Conclusion Damaged joint tissues produce proalgesic molecules, including NGF, in murine OA. PMID:26605536

  8. The Effects of Acute Neutrophil Depletion on Resolution of Acute Influenza Infection, Establishment of Tissue Resident Memory (TRM), and Heterosubtypic Immunity

    PubMed Central

    Reilly, Emma C.; Lambert-Emo, Kris; Topham, David J.

    2016-01-01

    After disease resolution, a small subset of influenza specific CD8+ T cells can remain in the airways of the lung as a tissue resident memory population (TRM). These cells are critical for protection from subsequent infections with heterosubtypic influenza viruses. Although it is well established that expression of the collagen IV binding integrin alpha 1 is necessary for the retention and maintenance of TRM cells, other requirements allowing them to localize to the airways and persist are less well understood. We recently demonstrated that inhibition of neutrophils or neutrophil derived chemokine CXCL12 during acute influenza virus infection reduces the effector T cell response and affects the ability of these cells to localize to the airways. We therefore sought to determine whether the defects that occur in the absence of neutrophils would persist throughout resolution of the disease and impact the development of the TRM population. Interestingly, the early alterations in the CD8+ T cell response recover by two weeks post-infection, and mice form a protective population of TRM cells. Overall, these observations show that acute neutrophil depletion results in a delay in the effector CD8+ T cell response, but does not adversely impact the development of TRM. PMID:27741316

  9. Downstream signaling pathways in mouse adipose tissues following acute in vivo administration of fibroblast growth factor 21.

    PubMed

    Muise, Eric S; Souza, Sandra; Chi, An; Tan, Yejun; Zhao, Xuemei; Liu, Franklin; Dallas-Yang, Qing; Wu, Margaret; Sarr, Tim; Zhu, Lan; Guo, Hongbo; Li, Zhihua; Li, Wenyu; Hu, Weiwen; Jiang, Guoqiang; Paweletz, Cloud P; Hendrickson, Ronald C; Thompson, John R; Mu, James; Berger, Joel P; Mehmet, Huseyin

    2013-01-01

    FGF21 is a novel secreted protein with robust anti-diabetic, anti-obesity, and anti-atherogenic activities in preclinical species. In the current study, we investigated the signal transduction pathways downstream of FGF21 following acute administration of the growth factor to mice. Focusing on adipose tissues, we identified FGF21-mediated downstream signaling events and target engagement biomarkers. Specifically, RNA profiling of adipose tissues and phosphoproteomic profiling of adipocytes, following FGF21 treatment revealed several specific changes in gene expression and post-translational modifications, specifically phosphorylation, in several relevant proteins. Affymetrix microarray analysis of white adipose tissues isolated from both C57BL/6 (fed either regular chow or HFD) and db/db mice identified over 150 robust potential RNA transcripts and over 50 potential secreted proteins that were changed greater than 1.5 fold by FGF21 acutely. Phosphoprofiling analysis identified over 130 phosphoproteins that were modulated greater than 1.5 fold by FGF21 in 3T3-L1 adipocytes. Bioinformatic analysis of the combined gene and phosphoprotein profiling data identified a number of known metabolic pathways such as glucose uptake, insulin receptor signaling, Erk/Mapk signaling cascades, and lipid metabolism. Moreover, a number of novel events with hitherto unknown links to FGF21 signaling were observed at both the transcription and protein phosphorylation levels following treatment. We conclude that such a combined "omics" approach can be used not only to identify robust biomarkers for novel therapeutics but can also enhance our understanding of downstream signaling pathways; in the example presented here, novel FGF21-mediated signaling events in adipose tissue have been revealed that warrant further investigation.

  10. Downstream Signaling Pathways in Mouse Adipose Tissues Following Acute In Vivo Administration of Fibroblast Growth Factor 21

    PubMed Central

    Chi, An; Tan, Yejun; Zhao, Xuemei; Liu, Franklin; Dallas-yang, Qing; Wu, Margaret; Sarr, Tim; Zhu, Lan; Guo, Hongbo; Li, Zhihua; Li, Wenyu; Hu, Weiwen; Jiang, Guoqiang; Paweletz, Cloud P.; Hendrickson, Ronald C.; Thompson, John R.; Mu, James; Berger, Joel P.; Mehmet, Huseyin

    2013-01-01

    FGF21 is a novel secreted protein with robust anti-diabetic, anti-obesity, and anti-atherogenic activities in preclinical species. In the current study, we investigated the signal transduction pathways downstream of FGF21 following acute administration of the growth factor to mice. Focusing on adipose tissues, we identified FGF21-mediated downstream signaling events and target engagement biomarkers. Specifically, RNA profiling of adipose tissues and phosphoproteomic profiling of adipocytes, following FGF21 treatment revealed several specific changes in gene expression and post-translational modifications, specifically phosphorylation, in several relevant proteins. Affymetrix microarray analysis of white adipose tissues isolated from both C57BL/6 (fed either regular chow or HFD) and db/db mice identified over 150 robust potential RNA transcripts and over 50 potential secreted proteins that were changed greater than 1.5 fold by FGF21 acutely. Phosphoprofiling analysis identified over 130 phosphoproteins that were modulated greater than 1.5 fold by FGF21 in 3T3-L1 adipocytes. Bioinformatic analysis of the combined gene and phosphoprotein profiling data identified a number of known metabolic pathways such as glucose uptake, insulin receptor signaling, Erk/Mapk signaling cascades, and lipid metabolism. Moreover, a number of novel events with hitherto unknown links to FGF21 signaling were observed at both the transcription and protein phosphorylation levels following treatment. We conclude that such a combined "omics" approach can be used not only to identify robust biomarkers for novel therapeutics but can also enhance our understanding of downstream signaling pathways; in the example presented here, novel FGF21-mediated signaling events in adipose tissue have been revealed that warrant further investigation. PMID:24039848

  11. Acute and long-term effects of tissue culture on contractile reactivity in renal arteries of the rat.

    PubMed

    De Mey, J G; Uitendaal, M P; Boonen, H C; Vrijdag, M J; Daemen, M J; Struyker-Boudier, H A

    1989-10-01

    To evaluate long-term effects of contractile and mitogenic stimuli on the contractile reactivity of arterial smooth muscle, we measured the incorporation of the thymidine analogue 5-bromo-2'-deoxyuridine (BrdUrd) and mechanical responses in arterial segments that had been maintained in tissue culture. The experiments were performed on renal arteries that had been isolated from adult rats, chemically sympathectomized, mechanically denuded from endothelium and mounted under distension. Exposure of arterial segments for up to 3 weeks to culture medium supplemented with fetal calf serum resulted in the following consecutive changes: a strong acute contraction, selective pharmacological changes that included decreased contractile responses to phenylephrine and vasopressin and increased relaxing responses to isoproterenol, increased incorporation of BrdUrd, a progressive fall in contractile responses to all vasoconstrictor stimuli, and an increase in excitability. Serum-free medium resulted in a much smaller acute arterial contraction, induced less incorporation of BrdUrd, accelerated the occurrence of hyperexcitability, but did not affect early pharmacological changes or the subsequent fall in overall arterial contractility with tissue culture. Dialysis of the serum or addition of ketanserin abolished the contractile effect of serum but did not affect the incorporation of BrdUrd or the loss of contractility with tissue culture. Addition of serotonin to serum-free culture medium mimicked the contractile response to serum but not the stimulation of BrdUrd incorporation. These data indicate that tissue culture alters the properties of the arterial wall, that contraction does not underlie the proliferative response of arterial smooth muscle to serum-derived mitogens in vitro, and that stimulation of DNA synthesis does in itself not lead to selective changes in arterial contractility.

  12. TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-alpha blockade.

    PubMed

    Kroll-Palhares, Karina; Silvério, Jaline Coutinho; Silva, Andrea Alice da; Michailowsky, Vladimir; Marino, Ana Paula; Silva, Neide Maria; Carvalho, Cristiano Marcelo Espinola; Pinto, Luzia Maria de Oliveira; Gazzinelli, Ricardo Tostes; Lannes-Vieira, Joseli

    2008-06-01

    In Chagas disease, understanding how the immune response controls parasite growth but also leads to heart damage may provide insight into the design of new therapeutic strategies. Tumor necrosis factor-alpha (TNF-alpha) is important for resistance to acute Trypanosoma cruzi infection; however, in patients suffering from chronic T. cruzi infection, plasma TNF-alpha levels correlate with cardiomyopathy. Recent data suggest that CD8-enriched chagasic myocarditis formation involves CCR1/CCR5-mediated cell migration. Herein, the contribution of TNF-alpha, especially signaling through the receptor TNFR1/p55, to the pathophysiology of T. cruzi infection was evaluated with a focus on the development of myocarditis and heart dysfunction. Colombian strain-infected C57BL/6 mice had increased frequencies of TNFR1/p55+ and TNF-alpha+ splenocytes. Although TNFR1-/- mice exhibited reduced myocarditis in the absence of parasite burden, they succumbed to acute infection. Similar to C57BL/6 mice, Benznidazole-treated TNFR1-/- mice survived acute infection. In TNFR1-/- mice, reduced CD8-enriched myocarditis was associated with defective activation of CD44+CD62Llow/- and CCR5+ CD8+ lymphocytes. Also, anti-TNF-alpha treatment reduced the frequency of CD8+CCR5+ circulating cells and myocarditis, though parasite load was unaltered in infected C3H/HeJ mice. TNFR1-/- and anti-TNF-alpha-treated infected mice showed regular expression of connexin-43 and reduced fibronectin deposition, respectively. Furthermore, anti-TNF-alpha treatment resulted in lower levels of CK-MB, a cardiomyocyte lesion marker. Our results suggest that TNF/TNFR1 signaling promotes CD8-enriched myocarditis formation and heart tissue damage, implicating the TNF/TNFR1 signaling pathway as a potential therapeutic target for control of T. cruzi-elicited cardiomyopathy.

  13. Endothelial microparticles carrying hedgehog-interacting protein induce continuous endothelial damage in the pathogenesis of acute graft-versus-host disease.

    PubMed

    Nie, Di-Min; Wu, Qiu-Ling; Zheng, Peng; Chen, Ping; Zhang, Ran; Li, Bei-Bei; Fang, Jun; Xia, Ling-Hui; Hong, Mei

    2016-05-15

    Accumulating evidence suggests that endothelial microparticles (EMPs), a marker of endothelial damage, are elevated in acute graft-versus-host disease (aGVHD), and that endothelial damage is implicated in the pathogenesis of aGVHD, but the mechanisms remain elusive. In this study, we detected the plasma EMP levels and endothelial damage in patients and mice with aGVHD in vivo and then examined the effects of EMPs derived from injured endothelial cells (ECs) on endothelial damage and the role of hedgehog-interacting protein (HHIP) carried by EMPs in these effects in vitro. Our results showed that EMPs were persistently increased in the early posttransplantation phase in patients and mice with aGVHD. Meanwhile, endothelial damage was continuous in aGVHD mice, but was temporary in non-aGVHD mice after transplantation. In vitro, EMPs induced endothelial damage, including increased EC apoptosis, enhanced reactive oxygen species, decreased nitric oxide production and impaired angiogenic activity. Enhanced expression of HHIP, an antagonist for the Sonic hedgehog (SHH) signaling pathway, was observed in patients and mice with aGVHD and EMPs from injured ECs. The endothelial damage induced by EMPs was reversed when the HHIP incorporated into EMPs was silenced with an HHIP small interfering RNA or inhibited with the SHH pathway agonist, Smoothened agonist. This work supports a feasible vicious cycle in which EMPs generated during endothelial injury, in turn, aggravate endothelial damage by carrying HHIP into target ECs, contributing to the continuously deteriorating endothelial damage in the development of aGVHD. EMPs harboring HHIP would represent a potential therapeutic target for aGVHD. PMID:27009877

  14. Metabonomic analysis of liver tissue from BALB/c mice with d-galactosamine/lipopolysaccharide-induced acute hepatic failure

    PubMed Central

    2013-01-01

    Background Compared with biofluids, target tissues and organs more directly reflect the pathophysiological state of a disease process. In this study, a D-galactosamine (GalN) / lipopolysaccharide (LPS)-induced mouse model was constructed to investigate metabonomics of liver tissue and directly characterize metabolic changes in acute liver failure (ALF). Methods After pretreatment of liver tissue, gas chromatography coupled to time-of-flight mass spectrometry (GC/TOFMS) was used to separate and identify the liver metabolites. Partial least squares – discriminant analysis models were constructed to separate the ALF and control groups and to find those compounds whose liver levels differed significantly between the two groups. Results Distinct clustering was observed between the ALF and control mice. Fifty-eight endogenous metabolites were identified. Compared with the control mice, many metabolites, including sugars, amino acids, fatty acids, and organic acids, underwent significant changes in the ALF group, some of which differed from changes observed in plasma. Significant reduction of some important intermediate metabolites indicates that production of ketone bodies, the tricarboxylic acid and urea cycles, gluconeogenesis, glycolysis and pentose phosphate pathways are inhibited after GalN/LPS administration. Conclusions GC/TOFMS can be a powerful technique to perform metabonomic studies of liver tissue. GalN/LPS treatment can severely disturb substance metabolism in the liver, with different effects on metabolites compared with those observed in the plasma. PMID:23627910

  15. Israeli acute paralysis virus associated paralysis symptoms, viral tissue distribution and Dicer-2 induction in bumblebee workers (Bombus terrestris).

    PubMed

    Wang, Haidong; Meeus, Ivan; Smagghe, Guy

    2016-08-01

    Although it is known that Israeli acute paralysis virus (IAPV) can cause bee mortality, the symptoms of paralysis and the distribution of the virus in different body tissues and their potential to respond with an increase of the siRNA antiviral immune system have not been studied. In this project we worked with Bombus terrestris, which is one of the most numerous bumblebee species in Europe and an important pollinator for wild flowers and many crops in agriculture. Besides the classic symptoms of paralysis and trembling prior to death, we report a new IAPV-related symptom, crippled/immobilized forelegs. Reverse-transcriptase quantitative PCR showed that IAPV accumulates in different body tissues (midgut, fat body, brain and ovary). The highest levels of IAPV were observed in the fat body. With fluorescence in situ hybridization (FISH) we detected IAPV in the Kenyon cells of mushroom bodies and neuropils from both antennal and optic lobes of the brain in IAPV-infected workers. Finally, we observed an induction of Dicer-2, a core gene of the RNAi antiviral immune response, in the IAPV-infected tissues of B. terrestris workers. According to our results, tissue tropism and the induction strength of Dicer-2 could not be correlated with virus-related paralysis symptoms.

  16. Israeli acute paralysis virus associated paralysis symptoms, viral tissue distribution and Dicer-2 induction in bumblebee workers (Bombus terrestris).

    PubMed

    Wang, Haidong; Meeus, Ivan; Smagghe, Guy

    2016-08-01

    Although it is known that Israeli acute paralysis virus (IAPV) can cause bee mortality, the symptoms of paralysis and the distribution of the virus in different body tissues and their potential to respond with an increase of the siRNA antiviral immune system have not been studied. In this project we worked with Bombus terrestris, which is one of the most numerous bumblebee species in Europe and an important pollinator for wild flowers and many crops in agriculture. Besides the classic symptoms of paralysis and trembling prior to death, we report a new IAPV-related symptom, crippled/immobilized forelegs. Reverse-transcriptase quantitative PCR showed that IAPV accumulates in different body tissues (midgut, fat body, brain and ovary). The highest levels of IAPV were observed in the fat body. With fluorescence in situ hybridization (FISH) we detected IAPV in the Kenyon cells of mushroom bodies and neuropils from both antennal and optic lobes of the brain in IAPV-infected workers. Finally, we observed an induction of Dicer-2, a core gene of the RNAi antiviral immune response, in the IAPV-infected tissues of B. terrestris workers. According to our results, tissue tropism and the induction strength of Dicer-2 could not be correlated with virus-related paralysis symptoms. PMID:27230225

  17. The expression of ob gene is not acutely regulated by insulin and fasting in human abdominal subcutaneous adipose tissue.

    PubMed

    Vidal, H; Auboeuf, D; De Vos, P; Staels, B; Riou, J P; Auwerx, J; Laville, M

    1996-07-15

    The regulation of ob gene expression in abdominal subcutaneous adipose tissue was investigated using a reverse transcription-competitive PCR method to quantify the mRNA level of leptin. Leptin mRNA level was highly correlated with the body mass index of 26 subjects (12 lean, 7 non-insulin-dependent diabetic, and 7 obese patients). The effect of fasting on ob gene expression was investigated in 10 subjects maintained on a hypocaloric diet (1045 KJ/d) for 5 d. While their metabolic parameters significantly changed (decrease in insulinemia, glycemia, and resting metabolic rate and increase in plasma ketone bodies), the caloric restriction did not modify the leptin mRNA level in the adipose tissue. To verify whether insulin regulates ob gene expression, six lean subjects underwent a 3-h euglycemic hyperinsulinemic (846 +/- 138 pmol/liter) clamp. Leptin and Glut 4 mRNA levels were quantified in adipose tissue biopsies taken before and at the end of the clamp. Insulin infusion produced a significant threefold increase in Glut 4 mRNA while leptin mRNA was not affected. It is concluded that ob gene expression is not acutely regulated by insulin or by metabolic factors related to fasting in human abdominal subcutaneous adipose tissue. PMID:8755631

  18. Skimmed, sterilized, and concentrated bovine late colostrum promotes both prevention and recovery from intestinal tissue damage in mice.

    PubMed

    Cairangzhuoma; Yamamoto, M; Muranishi, H; Inagaki, M; Uchida, K; Yamashita, K; Saito, S; Yabe, T; Kanamaru, Y

    2013-03-01

    Bovine colostrum is a rich source of tissue repair and growth factors, and inhibits gastrointestinal injury induced by the side effects of nonsteroidal antiinflammatory drugs (NSAID), such as indomethacin. Nonsteroidal antiinflammatory drugs are drugs with analgesic and antipyretic effects, but in higher doses they have inflammatory effects. The pathogenesis of small intestinal damage caused by NSAID is unclear. The present study was performed to investigate the antiinflammatory effects of skimmed, sterilized, and concentrated bovine late colostrum on intestinal injury induced by side effects of NSAID, and then to identify the active ingredient in the colostrum for intestinal tissue. In Japan, the sale of bovine colostrum within 5 d after parturition is prohibited by law. Therefore, we focused on bovine late colostrum obtained from healthy lactating cows 6 to 7 d after parturition. Proliferation of small intestine epithelial cells was stimulated in mice fed the colostrum for 1 wk. With regard to indomethacin-induced enteropathy, both prefeeding and postfeeding with colostrum facilitated growth of the intestinal villi, indicating preventive and healing effects. Furthermore, to identify the active ingredient in the colostrum responsible for this effect, the casein and whey fractions were prepared from the colostrum and fed to normal mice. Only the colostrum casein fraction stimulated intestinal villus elongation, whereas the whey fraction and mature milk casein showed no such effect. Taken together, these observations indicate that the skimmed, sterilized, and concentrated bovine late colostrum, especially the casein fraction, could be used to treat the injurious effects of NSAID in the intestine and could be effective for treatment of other ulcerative conditions in the bowel, suggesting that the colostrum has therapeutic potential for intestinal inflammation. PMID:23295115

  19. Time dependent alterations of serum matrix metalloproteinase-1 and metalloproteinase-1 tissue inhibitor after successful reperfusion of acute myocardial infarction.

    PubMed Central

    Hirohata, S.; Kusachi, S.; Murakami, M.; Murakami, T.; Sano, I.; Watanabe, T.; Komatsubara, I.; Kondo, J.; Tsuji, T.

    1997-01-01

    OBJECTIVE: To test the hypothesis that changes in serum matrix metalloproteinase-1 (MMP-1) and tissue inhibitors of metalloproteinase-1 (TIMP-1) after acute myocardial infarction reflect extracellular matrix remodelling and the infarct healing process. PATIENTS: 13 consecutive patients with their first acute myocardial infarction who underwent successful reperfusion. METHODS: Blood was sampled on the day of admission, and on days 2, 3, 4, 5, 7, 14, and 28. Serum MMP-1 and TIMP-1 were measured by one step sandwich enzyme immunoassay. Left ventricular volume indices were determined by left ventriculography performed four weeks after the infarct. RESULTS: Serum concentrations of both MMP-1 and TIMP-1 changed over time. The average serum MMP-1 was more than 1 SD below the mean control values during the initial four days, increased thereafter, reaching a peak concentration around day 14, and then returned to the middle control range. Negative correlations with left ventricular end systolic volume index and positive correlations with left ventricular ejection fraction were obtained for serum MMP-1 on day 5, when it began to rise, and for the magnitude of rise in MMP-1 on day 5 compared to admission. Serum TIMP-1 at admission was more than 1 SD below the mean control value, and increased gradually thereafter, reaching a peak on around day 14. Negative correlations with left ventricular end systolic volume index and positive correlations with left ventricular ejection fraction were obtained for serum TIMP-1 on days 5 and 7, and for the magnitude of rise in TIMP-1 on days 5 and 7 compared to admission. CONCLUSIONS: Both MMP-1 and TIMP-1 showed significant time dependent alteration after acute myocardial infarction. Thus MMP-1 and TIMP-1 may provide useful information in evaluating the healing process as it affects left ventricular remodelling after acute myocardial infarction. PMID:9391291

  20. Acute delta 9-tetrahydrocannabinol exposure alters Ca2+ ATPase activity in neuroendocrine and gonadal tissues in mice.

    PubMed

    Dalterio, S L; Bernard, S A; Esquivel, C R

    1987-05-01

    Acute administration of delta 9-tetrahydrocannabinol (THC) (50 mg/kg) at puberty (35-40 days) significantly (P less than 0.05) reduced Ca2+ ATPase activity in hypothalamic plasma membranes but increased, although not significantly, enzyme activity in hypothalamic tissue obtained from adult mice. In contrast, testicular Ca2+ ATPase activity was increased in pubertal THC-treated males, and significantly reduced in adults. Pituitary Ca2+ ATPase activity exhibited a dose-related decrease after acute THC administration at 0.5, 5 or 50 mg/kg, but there were no differential effects of age. Pituitary plasma membranes obtained from THC-treated males did not respond to in vitro exposure to luteinizing hormone releasing hormone (LHRH, 10(-7) M) with the marked reduction (approximately 40%) in Ca2+ ATPase activity observed in pituitaries from oil-treated controls. In addition, effects of THC appear specific for Ca2+ ATPase activity, since Mg2+ ATPase and Na+/K+ ATPase activities were not affected. These findings indicate that acute in vivo administration of THC influences Ca2+ membrane transport, in particular Ca2+ ATPase activity. These effects occur at each level of the hypothalamic-pituitary-gonadal (HPG) axis, are related to dose and developmental age at exposure, and also appear specific for Ca2+-dependent ATPase activity. Furthermore, THC exposure modulates pituitary sensitivity to LHRH receptor-mediated effects on Ca2+ ATPase activity. Therefore, effects on Ca2+ membrane transport may be involved in acute THC actions on hormonal activity at these HPG sites.

  1. Radioprotective effects of hesperidin on oxidative damages and histopathological changes induced by X-irradiation in rats heart tissue

    PubMed Central

    Rezaeyan, Abolhasan; Haddadi, Gholam Hassan; Hosseinzadeh, Massood; Moradi, Maryam; Najafi, Masoud

    2016-01-01

    This study was carried out to evaluate radioprotective effects of hesperidin (HES) administration before the irradiation on the cardiac oxidative stress and histopathological changes in an experimental rat model. The cardiovascular complications of radiation exposure cause morbidity and mortality in patients who received radiotherapy. HES, an antioxidant flavonoid found in citrus fruits, suggests the protection against the tissue damage. Fifty-eight rats were divided into four groups: Group 1 received phosphate buffered saline (PBS) and sham radiation; Group 2, HES and sham radiation; Group 3, PBS and radiation; and Group 4, HES and radiation. The rats were exposed to single dose of 18 Gy of 6 MV X-ray. One hundred milligrams per kilogram doses of HES was administered for 7 days before irradiation. The estimation of superoxide dismutase (SOD), malondialdehyde (MDA), and histopathological analyses was performed at 24 h and 8 weeks after radiation exposure. The irradiation of chest area resulted in an elevated MDA level and decreased SOD activity. Moreover, long-term pathological lesions of radiation were inflammation, fibrosis, the increased number of mast cells and macrophages, and development of plaque, vascular leakage, myocardial degeneration, and myocyte necrosis. Although the administration of HES decreases inflammation, fibrosis, mast cell and macrophage numbers, and myocyte necrosis, it did not result in reduced thrombus, myocardium degeneration, and vascular leakage. In conclusion, these results suggest that HES can perform a radioprotection action. The protective effect of HES may be attributable to its immunomodulatory effects and free radical-scavenging properties. PMID:27651565

  2. Radioprotective effects of hesperidin on oxidative damages and histopathological changes induced by X-irradiation in rats heart tissue.

    PubMed

    Rezaeyan, Abolhasan; Haddadi, Gholam Hassan; Hosseinzadeh, Massood; Moradi, Maryam; Najafi, Masoud

    2016-01-01

    This study was carried out to evaluate radioprotective effects of hesperidin (HES) administration before the irradiation on the cardiac oxidative stress and histopathological changes in an experimental rat model. The cardiovascular complications of radiation exposure cause morbidity and mortality in patients who received radiotherapy. HES, an antioxidant flavonoid found in citrus fruits, suggests the protection against the tissue damage. Fifty-eight rats were divided into four groups: Group 1 received phosphate buffered saline (PBS) and sham radiation; Group 2, HES and sham radiation; Group 3, PBS and radiation; and Group 4, HES and radiation. The rats were exposed to single dose of 18 Gy of 6 MV X-ray. One hundred milligrams per kilogram doses of HES was administered for 7 days before irradiation. The estimation of superoxide dismutase (SOD), malondialdehyde (MDA), and histopathological analyses was performed at 24 h and 8 weeks after radiation exposure. The irradiation of chest area resulted in an elevated MDA level and decreased SOD activity. Moreover, long-term pathological lesions of radiation were inflammation, fibrosis, the increased number of mast cells and macrophages, and development of plaque, vascular leakage, myocardial degeneration, and myocyte necrosis. Although the administration of HES decreases inflammation, fibrosis, mast cell and macrophage numbers, and myocyte necrosis, it did not result in reduced thrombus, myocardium degeneration, and vascular leakage. In conclusion, these results suggest that HES can perform a radioprotection action. The protective effect of HES may be attributable to its immunomodulatory effects and free radical-scavenging properties. PMID:27651565

  3. Radioprotective effects of hesperidin on oxidative damages and histopathological changes induced by X-irradiation in rats heart tissue

    PubMed Central

    Rezaeyan, Abolhasan; Haddadi, Gholam Hassan; Hosseinzadeh, Massood; Moradi, Maryam; Najafi, Masoud

    2016-01-01

    This study was carried out to evaluate radioprotective effects of hesperidin (HES) administration before the irradiation on the cardiac oxidative stress and histopathological changes in an experimental rat model. The cardiovascular complications of radiation exposure cause morbidity and mortality in patients who received radiotherapy. HES, an antioxidant flavonoid found in citrus fruits, suggests the protection against the tissue damage. Fifty-eight rats were divided into four groups: Group 1 received phosphate buffered saline (PBS) and sham radiation; Group 2, HES and sham radiation; Group 3, PBS and radiation; and Group 4, HES and radiation. The rats were exposed to single dose of 18 Gy of 6 MV X-ray. One hundred milligrams per kilogram doses of HES was administered for 7 days before irradiation. The estimation of superoxide dismutase (SOD), malondialdehyde (MDA), and histopathological analyses was performed at 24 h and 8 weeks after radiation exposure. The irradiation of chest area resulted in an elevated MDA level and decreased SOD activity. Moreover, long-term pathological lesions of radiation were inflammation, fibrosis, the increased number of mast cells and macrophages, and development of plaque, vascular leakage, myocardial degeneration, and myocyte necrosis. Although the administration of HES decreases inflammation, fibrosis, mast cell and macrophage numbers, and myocyte necrosis, it did not result in reduced thrombus, myocardium degeneration, and vascular leakage. In conclusion, these results suggest that HES can perform a radioprotection action. The protective effect of HES may be attributable to its immunomodulatory effects and free radical-scavenging properties.

  4. Tissue-Specific Expression Patterns of MicroRNA during Acute Graft-versus-Host Disease in the Rat

    PubMed Central

    Jalapothu, Dasaradha; Boieri, Margherita; Crossland, Rachel E.; Shah, Pranali; Butt, Isha A.; Norden, Jean; Dressel, Ralf; Dickinson, Anne M.; Inngjerdingen, Marit

    2016-01-01

    MicroRNAs (miRNA) have emerged as central regulators of diverse biological processes and contribute to driving pathology in several diseases. Acute graft-versus-host disease (aGvHD) represents a major complication after allogeneic hematopoietic stem cell transplantation, caused by alloreactive donor T cells attacking host tissues leading to inflammation and tissue destruction. Changes in miRNA expression patterns occur during aGvHD, and we hypothesized that we could identify miRNA signatures in target tissues of aGvHD that may potentially help understand the underlying molecular pathology of the disease. We utilized a rat model of aGvHD with transplantation of fully MHC-mismatched T cell depleted bone marrow, followed by infusion of donor T cells. The expression pattern of 423 rat miRNAs was investigated in skin, gut, and lung tissues and intestinal T cells with the NanoString hybridization platform, in combination with validation by quantitative PCR. MHC-matched transplanted rats were included as controls. In the skin, upregulation of miR-34b and downregulation of miR-326 was observed, while in the intestines, we detected downregulation of miR-743b and a trend toward downregulation of miR-345-5p. Thus, tissue-specific expression patterns of miRNAs were observed. Neither miR-326 nor miR-743b has previously been associated with aGvHD. Moreover, we identified upregulation of miR-146a and miR-155 in skin tissue of rats suffering from aGvHD. Analysis of intestinal T cells indicated 23 miRNAs differentially regulated between aGvHD and controls. Two of these miRNAs were differentially expressed either in skin (miR-326) or in intestinal (miR-345-5p) tissue. Comparison of intestinal and peripheral blood T cells indicated common dysregulated expression of miR-99a, miR-223, miR-326, and miR-345-5p. Analysis of predicted gene targets for these miRNAs indicated potential targeting of an inflammatory network both in skin and in the intestines that may further regulate

  5. Tissue-Specific Expression Patterns of MicroRNA during Acute Graft-versus-Host Disease in the Rat

    PubMed Central

    Jalapothu, Dasaradha; Boieri, Margherita; Crossland, Rachel E.; Shah, Pranali; Butt, Isha A.; Norden, Jean; Dressel, Ralf; Dickinson, Anne M.; Inngjerdingen, Marit

    2016-01-01

    MicroRNAs (miRNA) have emerged as central regulators of diverse biological processes and contribute to driving pathology in several diseases. Acute graft-versus-host disease (aGvHD) represents a major complication after allogeneic hematopoietic stem cell transplantation, caused by alloreactive donor T cells attacking host tissues leading to inflammation and tissue destruction. Changes in miRNA expression patterns occur during aGvHD, and we hypothesized that we could identify miRNA signatures in target tissues of aGvHD that may potentially help understand the underlying molecular pathology of the disease. We utilized a rat model of aGvHD with transplantation of fully MHC-mismatched T cell depleted bone marrow, followed by infusion of donor T cells. The expression pattern of 423 rat miRNAs was investigated in skin, gut, and lung tissues and intestinal T cells with the NanoString hybridization platform, in combination with validation by quantitative PCR. MHC-matched transplanted rats were included as controls. In the skin, upregulation of miR-34b and downregulation of miR-326 was observed, while in the intestines, we detected downregulation of miR-743b and a trend toward downregulation of miR-345-5p. Thus, tissue-specific expression patterns of miRNAs were observed. Neither miR-326 nor miR-743b has previously been associated with aGvHD. Moreover, we identified upregulation of miR-146a and miR-155 in skin tissue of rats suffering from aGvHD. Analysis of intestinal T cells indicated 23 miRNAs differentially regulated between aGvHD and controls. Two of these miRNAs were differentially expressed either in skin (miR-326) or in intestinal (miR-345-5p) tissue. Comparison of intestinal and peripheral blood T cells indicated common dysregulated expression of miR-99a, miR-223, miR-326, and miR-345-5p. Analysis of predicted gene targets for these miRNAs indicated potential targeting of an inflammatory network both in skin and in the intestines that may further regulate

  6. Effects of DHA-rich fish oil supplementation on the lipid profile, markers of muscle damage, and neutrophil function in wheelchair basketball athletes before and after acute exercise.

    PubMed

    Marques, Camila Garcia; Santos, Vinicius Coneglian; Levada-Pires, Adriana Cristina; Jacintho, Thiago Manzoni; Gorjão, Renata; Pithon-Curi, Tânia Cristina; Cury-Boaventura, Maria Fernanda

    2015-06-01

    We investigated the effects of docosahexaenoic acid (DHA)-rich fish oil (FO) supplementation on the lipid profile, levels of plasma inflammatory mediators, markers of muscle damage, and neutrophil function in wheelchair basketball players before and after acute exercise. We evaluated 8 male basketball wheelchair athletes before and after acute exercise both prior to (S0) and following (S1) FO supplementation. The subjects were supplemented with 3 g of FO daily for 30 days. The following components were measured: the plasma lipid profile (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides), plasma inflammatory mediators (C-reactive protein, interleukin (IL)-1β, IL-1ra, IL-4, IL-6, IL-8, and tumor necrosis factor-α), markers of muscle damage (creatine kinase and lactate dehydrogenase (LDH)), and neutrophil function (cytokine production, phagocytic capacity, loss of membrane integrity, mitochondrial membrane potential, neutral lipid accumulation, phosphatidylserine externalization, DNA fragmentation, and production of reactive oxygen species (ROS)). Acute exercise increased the plasma levels of total cholesterol, LDH, IL1ra, and IL-6, led to the loss of membrane integrity, ROS production, and a high mitochondrial membrane potential in neutrophils, and reduced the phagocytic capacity and IL-6 production by the neutrophils (S0). However, supplementation prevented the increases in the plasma levels of LDH and IL-6, the loss of membrane integrity, and the alterations in ROS production and mitochondrial membrane potential in the neutrophils that were induced by exercise (S1). In conclusion, DHA-rich FO supplementation reduces the markers of muscle damage, inflammatory disturbances, and neutrophil death induced by acute exercise in wheelchair athletes.

  7. Green tea (Camellia sinensis) alleviates arsenic-induced damages to DNA and intestinal tissues in rat and in situ intestinal loop by reinforcing antioxidant system.

    PubMed

    Acharyya, Nirmallya; Sajed Ali, Sk; Deb, Bimal; Chattopadhyay, Sandip; Maiti, Smarajit

    2015-09-01

    This study elucidates the protective role of Green tea (Camellia sinensis or CS) against arsenic-induced mutagenic DNA-breakage/intestinal (small) damages in female rats. Intestinal epithelial cells receive ingested arsenic initially. Though, the possibility of damages in this tissue is immense and the therapeutic strategies against this damage are of great concern, reports on either issue are scanty. Our earlier study on arsenic-exposed human unveils a link between carcinogenesis and mutagenic DNA damage. Here, we demonstrate that supplementation of CS-extract (10 mg/mL water) with NaAsO2 (0.6 ppm)/100 g b.w. for 28 days to rats offered a significant protection against arsenic-induced oxidative damages to DNA and intestinal (small) tissues by buttressing antioxidant systems. Necrotic and apoptotic damages and their CS-protection are shown in DNA-fragmentation, comet-assay, and histoarchitecture (hematoxylin and eosin and periodic acid-schiff staining) results. Only arsenic exposure significantly decreased intestinal superoxide dismutase, catalase activities, and level of soluble thiol with a concomitant increase in malondialdehyde/conjugated dienes. Alteration of serum necrotic marker lactate dehydrogenase and the metabolic inflammatory marker c-reactive protein also indicate the impairment may be occurring at transcription and/or cellular signal transduction level. In addition, in situ incubation in rat intestinal loop filled for 24 h with NaAsO2 alone (250 µM) or with aqueous CS-extract (250 mg/mL) suggests that small intestinal epithelial cells are significantly protected by CS against arsenic-associated necrotic/mutagenic damages, which is observed in DNA-breakage studies. In conclusion, besides intensifying endogenous antioxidant system, CS polyphenols also offer a direct role on free radical scavenging activity that is associated to the protection from mutagenic DNA-breakages and prevention of tissue necrosis/carcinogenesis generated by arsenic.

  8. Tissue damage drives co-localization of NF-κB, Smad3, and Nrf2 to direct Rev-erb sensitive wound repair in mouse macrophages

    PubMed Central

    Eichenfield, Dawn Z; Troutman, Ty Dale; Link, Verena M; Lam, Michael T; Cho, Han; Gosselin, David; Spann, Nathanael J; Lesch, Hanna P; Tao, Jenhan; Muto, Jun; Gallo, Richard L; Evans, Ronald M; Glass, Christopher K

    2016-01-01

    Although macrophages can be polarized to distinct phenotypes in vitro with individual ligands, in vivo they encounter multiple signals that control their varied functions in homeostasis, immunity, and disease. Here, we identify roles of Rev-erb nuclear receptors in regulating responses of mouse macrophages to complex tissue damage signals and wound repair. Rather than reinforcing a specific program of macrophage polarization, Rev-erbs repress subsets of genes that are activated by TLR ligands, IL4, TGFβ, and damage-associated molecular patterns (DAMPS). Unexpectedly, a complex damage signal promotes co-localization of NF-κB, Smad3, and Nrf2 at Rev-erb-sensitive enhancers and drives expression of genes characteristic of multiple polarization states in the same cells. Rev-erb-sensitive enhancers thereby integrate multiple damage-activated signaling pathways to promote a wound repair phenotype. DOI: http://dx.doi.org/10.7554/eLife.13024.001 PMID:27462873

  9. Venlafaxine treatment after endothelin-1-induced cortical stroke modulates growth factor expression and reduces tissue damage in rats.

    PubMed

    Zepeda, Rodrigo; Contreras, Valentina; Pissani, Claudia; Stack, Katherine; Vargas, Macarena; Owen, Gareth I; Lazo, Oscar M; Bronfman, Francisca C

    2016-08-01

    Neuromodulators, such as antidepressants, may contribute to neuroprotection by modulating growth factor expression to exert anti-inflammatory effects and to support neuronal plasticity after stroke. Our objective was to study whether early treatment with venlafaxine, a serotonin-norepinephrine reuptake inhibitor, modulates growth factor expression and positively contributes to reducing the volume of infarcted brain tissue resulting in increased functional recovery. We studied the expression of BDNF, FGF2 and TGF-β1 by examining their mRNA and protein levels and cellular distribution using quantitative confocal microscopy at 5 days after venlafaxine treatment in control and infarcted brains. Venlafaxine treatment did not change the expression of these growth factors in sham rats. In infarcted rats, BDNF mRNA and protein levels were reduced, while the mRNA and protein levels of FGF2 and TGF-β1 were increased. Venlafaxine treatment potentiated all of the changes that were induced by cortical stroke alone. In particular, increased levels of FGF2 and TGF-β1 were observed in astrocytes at 5 days after stroke induction, and these increases were correlated with decreased astrogliosis (measured by GFAP) and increased synaptophysin immunostaining at twenty-one days after stroke in venlafaxine-treated rats. Finally, we show that venlafaxine reduced infarct volume after stroke resulting in increased functional recovery, which was measured using ladder rung motor tests, at 21 days after stroke. Our results indicate that the early oral administration of venlafaxine positively contributes to neuroprotection during the acute and late events that follow stroke. PMID:26965219

  10. Arsenic-Induced Antioxidant Depletion, Oxidative DNA Breakage, and Tissue Damages are Prevented by the Combined Action of Folate and Vitamin B12.

    PubMed

    Acharyya, Nirmallya; Deb, Bimal; Chattopadhyay, Sandip; Maiti, Smarajit

    2015-11-01

    Arsenic is a grade I human carcinogen. It acts by disrupting one-carbon (1C) metabolism and cellular methyl (-CH3) pool. The -CH3 group helps in arsenic disposition and detoxification of the biological systems. Vitamin B12 and folate, the key promoters of 1C metabolism were tested recently (daily 0.07 and 4.0 μg, respectively/100 g b.w. of rat for 28 days) to evaluate their combined efficacy in the protection from mutagenic DNA-breakage and tissue damages. The selected tissues like intestine (first-pass site), liver (major xenobiotic metabolizer) and lung (major arsenic accumulator) were collected from arsenic-ingested (0.6 ppm/same schedule) female rats. The hemo-toxicity and liver and kidney functions were monitored. Our earlier studies on arsenic-exposed humans can correlate carcinogenesis with DNA damage. Here, we demonstrate that the supplementation of physiological/therapeutic dose of vitamin B12 and folate protected the rodents significantly from arsenic-induced DNA damage (DNA fragmentation and comet assay) and hepatic and renal tissue degeneration (histo-architecture, HE staining). The level of arsenic-induced free-radical products (TBARS and conjugated diene) was significantly declined by the restored actions of several antioxidants viz. urate, thiol, catalase, xanthine oxidase, lactoperoxidase, and superoxide dismutase in the tissues of vitamin-supplemented group. The alkaline phosphatase, transaminases, urea and creatinine (hepatic and kidney toxicity marker), and lactate dehydrogenase (tissue degeneration marker) were significantly impaired in the arsenic-fed group. But a significant protection was evident in the vitamin-supplemented group. In conclusion, the combined action of folate and B12 results in the restitution in the 1C metabolic pathway and cellular methyl pool. The cumulative outcome from the enhanced arsenic methylation and antioxidative capacity was protective against arsenic induced mutagenic DNA breakages and tissue damages.

  11. Arsenic-Induced Antioxidant Depletion, Oxidative DNA Breakage, and Tissue Damages are Prevented by the Combined Action of Folate and Vitamin B12.

    PubMed

    Acharyya, Nirmallya; Deb, Bimal; Chattopadhyay, Sandip; Maiti, Smarajit

    2015-11-01

    Arsenic is a grade I human carcinogen. It acts by disrupting one-carbon (1C) metabolism and cellular methyl (-CH3) pool. The -CH3 group helps in arsenic disposition and detoxification of the biological systems. Vitamin B12 and folate, the key promoters of 1C metabolism were tested recently (daily 0.07 and 4.0 μg, respectively/100 g b.w. of rat for 28 days) to evaluate their combined efficacy in the protection from mutagenic DNA-breakage and tissue damages. The selected tissues like intestine (first-pass site), liver (major xenobiotic metabolizer) and lung (major arsenic accumulator) were collected from arsenic-ingested (0.6 ppm/same schedule) female rats. The hemo-toxicity and liver and kidney functions were monitored. Our earlier studies on arsenic-exposed humans can correlate carcinogenesis with DNA damage. Here, we demonstrate that the supplementation of physiological/therapeutic dose of vitamin B12 and folate protected the rodents significantly from arsenic-induced DNA damage (DNA fragmentation and comet assay) and hepatic and renal tissue degeneration (histo-architecture, HE staining). The level of arsenic-induced free-radical products (TBARS and conjugated diene) was significantly declined by the restored actions of several antioxidants viz. urate, thiol, catalase, xanthine oxidase, lactoperoxidase, and superoxide dismutase in the tissues of vitamin-supplemented group. The alkaline phosphatase, transaminases, urea and creatinine (hepatic and kidney toxicity marker), and lactate dehydrogenase (tissue degeneration marker) were significantly impaired in the arsenic-fed group. But a significant protection was evident in the vitamin-supplemented group. In conclusion, the combined action of folate and B12 results in the restitution in the 1C metabolic pathway and cellular methyl pool. The cumulative outcome from the enhanced arsenic methylation and antioxidative capacity was protective against arsenic induced mutagenic DNA breakages and tissue damages. PMID

  12. Effects of zinc supplementation on the element distribution in kidney tissue of diabetic rats subjected to acute swimming.

    PubMed

    Sivrikaya, Abdullah; Bicer, Mursel; Akil, Mustafa; Baltaci, Abdulkerim Kasim; Mogulkoc, Rasim

    2012-06-01

    In this study, we report the effect of zinc supplementation on the distribution of elements in kidney tissue of diabetic rats subjected to acute swimming exercise. Diabetes was induced by two subcutaneous injections of 40 mg/kg of streptozotocin within a 24-h period. Zinc was given intraperitoneally at a dose of 6 mg/kg per day for a period of 4 weeks. The rats (n = 80) were equally divided into eight study groups: controls, zinc-supplemented, swimming, diabetic, zinc-supplemented diabetic, zinc-supplemented swimming, diabetic swimming, and zinc-supplemented diabetic swimming. The levels of lead, cobalt, molybdenum, chromium, boron, magnesium, iron, copper, calcium, zinc, and selenium were determined in the kidney tissue samples by ICP-AES. Higher molybdenum, calcium, zinc, and selenium values were found in both swimming and nonswimming diabetic rats. Significantly higher iron values were found in swimming, diabetic, diabetic swimming, and zinc-supplemented diabetic swimming rats (p < 0.001). Diabetic, zinc-supplemented diabetic, diabetic swimming, and zinc-supplemented diabetic swimming rats had the highest copper values. These results show that zinc supplementation normalized the higher levels of molybdenum, calcium, selenium, and iron levels seen in diabetic rats, indicating that zinc may have a regulatory effect on element metabolism in kidney tissue. PMID:22161314

  13. Distribution of bovine virus diarrhoea virus in tissues and white blood cells of cattle during acute infection.

    PubMed

    Bruschke, C J; Weerdmeester, K; Van Oirschot, J T; Van Rijn, P A

    1998-11-01

    This study is performed to gain knowledge about the quantitative distribution of bovine virus diarrhoea virus (BVDV) in tissues and white blood cells (WBC) at different intervals after acute infection. Ten specific pathogen-free calves were intranasally inoculated with 10(5) 50% tissue culture infective dose of the non-cytopathic BVDV strain 4800. Twelve hours after inoculation tonsil biopsies were taken and WBC were collected daily for virus isolation and titration. Each day one calf was killed and virus isolations and titrations were performed from a range of tissues. The results indicate that BVDV first replicates in nasal mucosa and to high titers in the tonsil. The virus then appeared to spread to the regional lymph nodes and then disseminates throughout the body. The virus titers were highest in tonsil, thymus and ileum and were low in the WBC. Also after in vitro infection virus titers in WBC were very low, whereas, they were high in epithelial cells. Although the WBC might not be as important as other cells for replication of BVDV, they may play a role in the spread of the virus throughout the body.

  14. Epicardial Adipose Tissue (EAT) Thickness Is Associated with Cardiovascular and Liver Damage in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Pisano, Giuseppina; Consonni, Dario; Tiraboschi, Silvia; Baragetti, Andrea; Bertelli, Cristina; Norata, Giuseppe Danilo; Dongiovanni, Paola; Valenti, Luca; Grigore, Liliana; Tonella, Tatiana; Catapano, Alberico; Fargion, Silvia

    2016-01-01

    Background and Aims Epicardial adipose tissue (EAT) has been proposed as a cardiometabolic and hepatic fibrosis risk factor in patients with non alcoholic fatty liver disease (NAFLD). Aim of this study was to evaluate the role of EAT in NAFLD by analyzing 1) the association between EAT, the other metabolic parameters and the severity of steatosis 2) the relationship between cardiovascular (cIMT, cplaques, E/A), liver (presence of NASH and significant fibrosis) damage and metabolic risk factors including EAT 3) the relationship between EAT and genetic factors strongly influencing liver steatosis. Methods In a cross-sectional study, we considered 512 consecutive patients with NAFLD (confirmed by biopsy in 100). EAT, severity of steatosis, carotid intima-media thickness (cIMT) and plaques were evaluated by ultrasonography and results analysed by multiple linear and logistic regression models. Variables independently associated with EAT (mm) were female gender (p = 0.003), age (p = 0.001), BMI (p = 0.01), diastolic blood pressure (p = 0.009), steatosis grade 2 (p = 0.01) and 3 (p = 0.04), fatty liver index (p = 0.001) and statin use (p = 0.03). Variables independently associated with carotid IMT were age (p = 0.0001), hypertension (p = 0.009), diabetes (p = 0.04), smoking habits (p = 0.04) and fatty liver index (p = 0.02), with carotid plaques age (p = 0.0001), BMI (p = 0.03), EAT (p = 0.02),) and hypertension (p = 0.02), and with E/A age (p = 0.0001), diabetes (p = 0.005), hypertension (p = 0.04) and fatty liver index (p = 0.004). In the 100 patients with available liver histology non alcoholic steatohepatitis (NASH) was independently associated with EAT (p = 0.04) and diabetes (p = 0.054) while significant fibrosis with EAT (p = 0.02), diabetes (p = 0.01) and waist circumference (p = 0.05). No association between EAT and PNPLA3 and TM6SF2 polymorphisms was found. Conclusion In patients with NAFLD, EAT is associated with the severity of liver and vascular damage

  15. High-strain-rate brain injury model using submerged acute rat brain tissue slices.

    PubMed

    Sarntinoranont, Malisa; Lee, Sung J; Hong, Yu; King, Michael A; Subhash, Ghatu; Kwon, Jiwoon; Moore, David F

    2012-01-20

    Blast-induced traumatic brain injury (bTBI) has received increasing attention in recent years due to ongoing military operations in Iraq and Afghanistan. Sudden impacts or explosive blasts generate stress and pressure waves that propagate at high velocities and affect sensitive neurological tissues. The immediate soft tissue response to these stress waves is difficult to assess using current in vivo imaging technologies. However, these stress waves and resultant stretching and shearing of tissue within the nano- to microsecond time scale of blast and impact are likely to cause initial injury. To visualize the effects of stress wave loading, we have developed a new ex vivo model in which living tissue slices from rat brain, attached to a ballistic gelatin substrate, were subjected to high-strain-rate loads using a polymer split Hopkinson pressure bar (PSHPB) with real-time high-speed imaging. In this study, average peak fluid pressure within the test chamber reached a value of 1584±63.3 psi. Cavitation due to a trailing underpressure wave was also observed. Time-resolved images of tissue deformation were collected and large maximum eigenstrains (0.03-0.42), minimum eigenstrains (-0.33 to -0.03), maximum shear strains (0.09-0.45), and strain rates (8.4×10³/sec) were estimated using digital image correlation (DIC). Injury at 4 and 6 h was quantified using Fluoro-Jade C. Neuronal injury due to PSHPB testing was found to be significantly greater than injury associated with the tissue slice paradigm alone. While large pressures and strains were encountered for these tests, this system provides a controllable test environment to study injury to submerged brain slices over a range of strain rate, pressure, and strain loads. PMID:21970544

  16. Testing chemotherapeutic agents in the feather follicle identifies a selective blockade of cell proliferation and a key role for sonic hedgehog signaling in chemotherapy-induced tissue damage.

    PubMed

    Xie, Guojiang; Wang, Hangwei; Yan, Zhipeng; Cai, Linyan; Zhou, Guixuan; He, Wanzhong; Paus, Ralf; Yue, Zhicao

    2015-03-01

    Chemotherapeutic agents induce complex tissue responses in vivo and damage normal organ functions. Here we use the feather follicle to investigate details of this damage response. We show that cyclophosphamide treatment, which causes chemotherapy-induced alopecia in mice and man, induces distinct defects in feather formation: feather branching is transiently and reversibly disrupted, thus leaving a morphological record of the impact of chemotherapeutic agents, whereas the rachis (feather axis) remains unperturbed. Similar defects are observed in feathers treated with 5-fluorouracil or taxol but not with doxorubicin or arabinofuranosyl cytidine (Ara-C). Selective blockade of cell proliferation was seen in the feather branching area, along with a downregulation of sonic hedgehog (Shh) transcription, but not in the equally proliferative rachis. Local delivery of the Shh inhibitor, cyclopamine, or Shh silencing both recapitulated this effect. In mouse hair follicles, those chemotherapeutic agents that disrupted feather formation also downregulated Shh gene expression and induced hair loss, whereas doxorubicin or Ara-C did not. Our results reveal a mechanism through which chemotherapeutic agents damage rapidly proliferating epithelial tissue, namely via the cell population-specific, Shh-dependent inhibition of proliferation. This mechanism may be targeted by future strategies to manage chemotherapy-induced tissue damage.

  17. Inhibition of Notch signaling by Dll4-Fc promotes reperfusion of acutely ischemic tissues

    SciTech Connect

    Liu, Ren; Trindade, Alexandre; Sun, Zhanfeng; Kumar, Ram; Weaver, Fred A.; Krasnoperov, Valery; Naga, Kranthi; Duarte, Antonio; Gill, Parkash S.

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer Low dose Dll4-Fc increases vascular proliferation and overall perfusion. Black-Right-Pointing-Pointer Low dose Dll4-Fc helps vascular injury recovery in hindlimb ischemia model. Black-Right-Pointing-Pointer Low dose Dll4-Fc helps vascular injury recovery in skin flap model. Black-Right-Pointing-Pointer Dll4 heterozygous deletion promotes vascular injury recovery. Black-Right-Pointing-Pointer Dll4 overexpression delays vascular injury recovery. -- Abstract: Notch pathway regulates vessel development and maturation. Dll4, a high-affinity ligand for Notch, is expressed predominantly in the arterial endothelium and is induced by hypoxia among other factors. Inhibition of Dll4 has paradoxical effects of reducing the maturation and perfusion in newly forming vessels while increasing the density of vessels. We hypothesized that partial and/or intermittent inhibition of Dll4 may lead to increased vascular response and still allow vascular maturation to occur. Thus tissue perfusion can be restored rapidly, allowing quicker recovery from ischemia or tissue injury. Our studies in two different models (hindlimb ischemia and skin flap) show that inhibition of Dll4 at low dose allows faster recovery from vascular and tissue injury. This opens a new possibility for Dll4 blockade's therapeutic application in promoting recovery from vascular injury and restoring blood supply to ischemic tissues.

  18. Postmortem tissue contents of {sup 241}Am in a person with a massive acute exposure

    SciTech Connect

    McInroy, J.F.; Kathren, R.L.; Toohey, R.E. |

    1995-09-01

    {sup 241}Am was determined radiochemically in the tissues of USTUR Case 246, a 76-y-old man who died of cardiovascular disease 11 y after massive percutaneous exposure following a chemical explosion in a glove box. This worker was treated extensively with a chelation drug, DTPA, for over 4 y after exposure. The estimate {sup 241}Am deposition at the time of death was 540 kBq, of which 90% was in the skeleton, 5.1% in the liver, and 3.5% in muscle and fat. Among the soft tissues, the highest concentrations were observed in liver (22 Bq g{sup -1}), certain cartilaginous structures such as the larynx (15 Bq g{sup -1}) and the red marrow (9.7 Bq g{sup -1}), as compared with the mean soft tissue concentration of approximately 1 Bq g{sup -1}. Concentration in muscle was approximately that of the soft tissue average, while concentrations in the pancreas, a hilar lymph node and fat were less than the average. Concentrations in bone ash were inversely related to the ratio of ash weight to wet weight a surrogate for bone volume-to-surface ratio. the distribution of activity in this case is reasonable consistent with that observed in another human case, when allowance is made for chelation therapy, and also tends to support more recent models of {sup 241}Am metabolism. 26 refs., 2 figs., 4 tabs.

  19. Can pulsed ultrasound increase tissue damage during ischemia? A study of the effects of ultrasound on infarcted and non-infarcted myocardium in anesthetized pigs

    PubMed Central

    Olivecrona, Göran K; Härdig, Bjarne Madsen; Roijer, Anders; Block, Mattias; Grins, Edgars; Persson, Hans W; Johansson, Leif; Olsson, Bertil

    2005-01-01

    Background The same mechanisms by which ultrasound enhances thrombolysis are described in connection with non-beneficial effects of ultrasound. The present safety study was therefore designed to explore effects of beneficial ultrasound characteristics on the infarcted and non-infarcted myocardium. Methods In an open chest porcine model (n = 17), myocardial infarction was induced by ligating a coronary diagonal branch. Pulsed ultrasound of frequency 1 MHz and intensity 0.1 W/cm2 (ISATA) was applied during one hour to both infarcted and non-infarcted myocardial tissue. These ultrasound characteristics are similar to those used in studies of ultrasound enhanced thrombolysis. Using blinded assessment technique, myocardial damage was rated according to histopathological criteria. Results Infarcted myocardium exhibited a significant increase in damage score compared to non-infarcted myocardium: 6.2 ± 2.0 vs. 4.3 ± 1.5 (mean ± standard deviation), (p = 0.004). In the infarcted myocardium, ultrasound exposure yielded a further significant increase of damage scores: 8.1 ± 1.7 vs. 6.2 ± 2.0 (p = 0.027). Conclusion Our results suggest an instantaneous additive effect on the ischemic damage in myocardial tissue when exposed to ultrasound of stated characteristics. The ultimate damage degree remains to be clarified. PMID:15831106

  20. Chronic caloric restriction reduces tissue damage and improves spatial memory in a rat model of traumatic brain injury.

    PubMed

    Rich, Nicholas J; Van Landingham, Jacob W; Figueiroa, Silvia; Seth, Rohit; Corniola, Rikki S; Levenson, Cathy W

    2010-10-01

    Although it has been known for some time that chronic caloric or dietary restriction reduces the risk of neurodegenerative disorders and injury following ischemia, the possible role of chronic restriction in improving outcomes after traumatic brain injury (TBI) has not been previously studied. Therefore, 2-month-old male Sprague-Dawley rats were divided into two dietary groups, an ad libitum fed group (AL) and a caloric-restriction group (CR) that was provided with 70% of the food intake of AL rats (n = 10/group). After 4 months, a weight-drop device (300 g) was used to produce a 2-mm bilateral medial frontal cortex contusion following craniotomy. Additional animals in each dietary group (n = 10) were used as sham-operated controls. The CR diet resulted in body weights that were reduced by 30% compared with AL controls. Not only did CR decrease the size of the cortical lesion after injury, there were marked improvements in spatial memory as measured by Morris water maze that included an increase in the number of animals successfully finding the platform as well as significantly reduced time to finding the hidden platform. Western analysis, used to examine the expression of proteins that play a role in neuronal survival, revealed significant increases in brain-derived neurotrophic factor (BDNF) in the cortical region around the site of injury and in the hippocampus in CR rats after injury. These findings suggest that molecular mechanisms involved in cell survival may play a role in reducing tissue damage and improving cognition after TBI and that these mechanisms can be regulated by dietary interventions. PMID:20544832

  1. Repurposing an old drug to improve the safety and use of tissue plasminogen activator for acute ischemic stroke: Minocycline

    PubMed Central

    Hess, David C; Fagan, Susan

    2014-01-01

    There is only 1 US Food and Drug Administration-approved drug for acute ischemic stroke: tissue plasminogen activator (tPA). Due to a short time window and fear of intracerebral hemorrhage (ICH), tPA remains underutilized. There is great interest in developing combination drugs to use with tPA to improve the odds of a favorable recovery and to reduce the risk of ICH. Minocycline is a broad spectrum antibiotic that has been found to be a neuroprotective agent in preclinical ischemic stroke models. Minocycline inhibits matrix metalloproteinase-9, a biomarker for ICH associated with tPA use. Minocycline is also an anti-inflammatory agent and inhibits poly (ADP-ribose) polymerase- 1. Minocycline has been safe and well tolerated in the clinical trials conducted to date. PMID:20575623

  2. Analyzing the relationship between decorrelation time and tissue thickness in acute rat brain slices using multispeckle diffusing wave spectroscopy.

    PubMed

    Brake, Joshua; Jang, Mooseok; Yang, Changhuei

    2016-02-01

    Novel techniques in the field of wavefront shaping have enabled light to be focused deep inside or through scattering media such as biological tissue. However, most of these demonstrations have been limited to thin, static samples since these techniques are very sensitive to changes in the arrangement of the scatterers within. As the samples of interest get thicker, the influence of the dynamic nature of the sample becomes even more pronounced and the window of time in which the wavefront solutions remain valid shrinks further. In this paper, we examine the time scales upon which this decorrelation happens in acute rat brain slices via multispeckle diffusing wave spectroscopy and investigate the relationship between this decorrelation time and the thickness of the sample using diffusing wave spectroscopy theory and Monte Carlo photon transport simulation.

  3. Altered Lipid Composition of Surfactant and Lung Tissue in Murine Experimental Malaria-Associated Acute Respiratory Distress Syndrome.

    PubMed

    Scaccabarozzi, Diletta; Deroost, Katrien; Lays, Natacha; Omodeo Salè, Fausta; Van den Steen, Philippe E; Taramelli, Donatella

    2015-01-01

    Malaria-associated acute lung injury (MA-ALI) and its more severe form malaria-associated acute respiratory distress syndrome (MA-ARDS) are common, often fatal complications of severe malaria infections. However, little is known about their pathogenesis. In this study, biochemical alterations of the lipid composition of the lungs were investigated as possible contributing factors to the severity of murine MA-ALI/ARDS. C57BL/6J mice were infected with Plasmodium berghei NK65 to induce lethal MA-ARDS, or with Plasmodium chabaudi AS, a parasite strain that does not induce lung pathology. The lipid profile of the lung tissue from mice infected with Plasmodium berghei NK65 developing MA-ALI/ARDS, but not that from mice without lung pathology or controls, was characterized by high levels of phospholipids -mainly phosphatidylcholine- and esterified cholesterol. The high levels of polyunsaturated fatty acids and the linoleic/oleic fatty acid ratio of the latter reflect the fatty acid composition of plasma cholesterol esters. In spite of the increased total polyunsaturated fatty acid pool, which augments the relative oxidability of the lung membranes, and the presence of hemozoin, a known pro-oxidant, no excess oxidative stress was detected in the lungs of Plasmodium berghei NK65 infected mice. The bronchoalveolar lavage (BAL) fluid of Plasmodium berghei NK65 infected mice was characterized by high levels of plasma proteins. The phospholipid profile of BAL large and small aggregate fractions was also different from uninfected controls, with a significant increase in the amounts of sphingomyelin and lysophosphatidylcholine and the decrease in phosphatidylglycerol. Both the increase of proteins and lysophosphatidylcholine are known to decrease the intrinsic surface activity of surfactant. Together, these data indicate that an altered lipid composition of lung tissue and BAL fluid, partially ascribed to oedema and lipoprotein infiltration, is a characteristic feature of murine

  4. Altered Lipid Composition of Surfactant and Lung Tissue in Murine Experimental Malaria-Associated Acute Respiratory Distress Syndrome

    PubMed Central

    Scaccabarozzi, Diletta; Deroost, Katrien; Lays, Natacha; Taramelli, Donatella

    2015-01-01

    Malaria-associated acute lung injury (MA-ALI) and its more severe form malaria-associated acute respiratory distress syndrome (MA-ARDS) are common, often fatal complications of severe malaria infections. However, little is known about their pathogenesis. In this study, biochemical alterations of the lipid composition of the lungs were investigated as possible contributing factors to the severity of murine MA-ALI/ARDS. C57BL/6J mice were infected with Plasmodium berghei NK65 to induce lethal MA-ARDS, or with Plasmodium chabaudi AS, a parasite strain that does not induce lung pathology. The lipid profile of the lung tissue from mice infected with Plasmodium berghei NK65 developing MA-ALI/ARDS, but not that from mice without lung pathology or controls, was characterized by high levels of phospholipids -mainly phosphatidylcholine- and esterified cholesterol. The high levels of polyunsaturated fatty acids and the linoleic/oleic fatty acid ratio of the latter reflect the fatty acid composition of plasma cholesterol esters. In spite of the increased total polyunsaturated fatty acid pool, which augments the relative oxidability of the lung membranes, and the presence of hemozoin, a known pro-oxidant, no excess oxidative stress was detected in the lungs of Plasmodium berghei NK65 infected mice. The bronchoalveolar lavage (BAL) fluid of Plasmodium berghei NK65 infected mice was characterized by high levels of plasma proteins. The phospholipid profile of BAL large and small aggregate fractions was also different from uninfected controls, with a significant increase in the amounts of sphingomyelin and lysophosphatidylcholine and the decrease in phosphatidylglycerol. Both the increase of proteins and lysophosphatidylcholine are known to decrease the intrinsic surface activity of surfactant. Together, these data indicate that an altered lipid composition of lung tissue and BAL fluid, partially ascribed to oedema and lipoprotein infiltration, is a characteristic feature of murine

  5. Tissue responses to low protracted doses of high let radiations or photons: Early and late damage relevant to radio-protective countermeasures

    SciTech Connect

    Ainsworth, E.J.; Afzal, S.M.J.; Crouse, D.A.; Hanson, W.R.; Fry, R.J.M.

    1988-01-01

    Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Low dose rates per fraction were used in some neutron experiments. Split-dose lethality studies (LD 50/30) with fission neutrons indicated greater accumulation of injury during a 9 fraction course (over 17 days) than was the case for ..gamma..-radiation. When total doses of 96 or 247 cGy of neutrons or ..gamma.. rays were given as a single dose or in 9 fractions, a significant sparing effect on femur CFU-S depression was observed for both radiation qualities during the first 11 days, but there was not an earlier return to normal with dose fractionation. During the 9 fraction sequence, a significant sparing effect of low dose rate on CFU-S depression was observed in both neutron and ..gamma..-irradiated mice. CFU-S content at the end of the fractionation sequence did not correlate with measured LD 50/30. Sustained depression of femur and spleen CFU-S and a significant thrombocytopenia were observed when a total neutron dose of 240 cGy was given in 72 fractions over 24 weeks at low dose rates. The temporal aspects of CFU-S repopulation were different after a single versus fractionated neutron doses. The sustained reduction in the size of the CFU-S population was accompanied by an increase in the fraction in DNA synthesis. The proliferation characteristics and effects of age were different for radial CFU-S population closely associated with bone, compared with the axial population that can be readily aspirated from the femur. In aged irradiated animals, the CFU-S proliferation/redistribution response to typhoid vaccine showed both an age and radiation effect. 63 refs., 6 figs., 7 tabs.

  6. Tissue responses to low protracted doses of high LET radiations or photons: Early and late damage relevant to radio-protective countermeasures

    NASA Astrophysics Data System (ADS)

    Ainsworth, E. J.; Afzal, S. M. J.; Crouse, D. A.; Hanson, W. R.; Fry, R. J. M.

    Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Low dose rates per fraction were used in some neutron experiments. Split-dose lethality studies (LD 50/30) with fission neutrons indicated greater accumulation of injury during a 9 fraction course (over 17 days) than was the case for γ-radiation. When total doses of 96 or 247 cGy of neutrons or γ rays were given as a single dose or in 9 fractions, a significant sparing effect on femur CFU-S depression was observed for both radiation qualities during the first 11 days, but there was not an earlier return to normal with dose fractionation. During the 9 fraction sequence, a significant sparing effect of low dose rate on CFU-S depression was observed in both neutron and γ-irradiated mice. CFU-S content at the end of the fractionation sequence did not correlate with measured LD 50/30. Sustained depression of femur and spleen CFU-S and a significant thrombocytopenia were observed when a total neutron dose of 240 cGy was given in 72 fractions over 24 weeks at low dose rates. The temporal aspects of CFU-S repopulation were different after a single versus fractionated neutron doses. The sustained reduction in the size of the CFU-S population was accompanied by an increase in the fraction in DNA synthesis. The proliferation characteristics and effects of age were different for radial CFU-S population closely associated with bone, compared with the axial population that can be readily aspirated from the femur. In aged irradiated animals, the CFU-S proliferation/redistribution response to typhoid vaccine showed both an age and radiation effect. After high single doses of neutrons or γ rays, a significant age- and radiation-related deficiency

  7. Protective effect of white tea extract against acute oxidative injury caused by adriamycin in different tissues.

    PubMed

    Espinosa, Cristóbal; López-Jiménez, José Ángel; Cabrera, Lorena; Larqué, Elvira; Almajano, María Pilar; Arnao, Marino B; Zamora, Salvador; Pérez-Llamas, Francisca

    2012-10-15

    Adriamycin (ADR) is an anticancer agent that increases oxidative stress in cells. We evaluated the protective effect of the long term consumption of white tea at two different doses against this drug. For this purpose rats were given distilled water (controls), 0.15 mg (Dose 1) or 0.45 mg (Dose 2) of solid tea extract/kg body weight for 12 months. All the animals received an injection of ADR, except half of the control group, which were given an injection of saline solution. This gave four experimental groups: Control (C), C+ADR, Dose 1+ADR, and Dose 2+ADR. The antioxidant activity (in liver, heart and brain microsomes) was analysed. White tea consumption for 12 months, at a non-pharmacological dose, reversed the oxidative damage caused by ADR, on both protein and lipid levels in all three organs. The heart recovered its antioxidant activity only at the highest dose of tea.

  8. Ischemic tissue injury in the dorsal skinfold chamber of the mouse: a skin flap model to investigate acute persistent ischemia.

    PubMed

    Harder, Yves; Schmauss, Daniel; Wettstein, Reto; Egaña, José T; Weiss, Fabian; Weinzierl, Andrea; Schuldt, Anna; Machens, Hans-Günther; Menger, Michael D; Rezaeian, Farid

    2014-11-17

    Despite profound expertise and advanced surgical techniques, ischemia-induced complications ranging from wound breakdown to extensive tissue necrosis are still occurring, particularly in reconstructive flap surgery. Multiple experimental flap models have been developed to analyze underlying causes and mechanisms and to investigate treatment strategies to prevent ischemic complications. The limiting factor of most models is the lacking possibility to directly and repetitively visualize microvascular architecture and hemodynamics. The goal of the protocol was to present a well-established mouse model affiliating these before mentioned lacking elements. Harder et al. have developed a model of a musculocutaneous flap with a random perfusion pattern that undergoes acute persistent ischemia and results in ~50% necrosis after 10 days if kept untreated. With the aid of intravital epi-fluorescence microscopy, this chamber model allows repetitive visualization of morphology and hemodynamics in different regions of interest over time. Associated processes such as apoptosis, inflammation, microvascular leakage and angiogenesis can be investigated and correlated to immunohistochemical and molecular protein assays. To date, the model has proven feasibility and reproducibility in several published experimental studies investigating the effect of pre-, peri- and postconditioning of ischemically challenged tissue.

  9. Diode laser (808 nm) applied to oral soft tissue lesions: a retrospective study to assess histopathological diagnosis and evaluate physical damage.

    PubMed

    Angiero, Francesca; Parma, Luisa; Crippa, Rolando; Benedicenti, Stefano

    2012-03-01

    The diode laser is today widely used in oral pathology to excise lesions; however, some controversy surrounds laser surgery, specifically the accuracy of pathological diagnosis and the control over thermal tissue damage. This study aimed to establish if physical damage induced by the diode laser could affect the histopathological diagnosis and to evaluate the damage caused to the resection margins. Between 2005 and 2010, at S. Gerardo Hospital, Milan, 608 cases of soft tissue lesions localized in the oral cavity (cheek, gingiva, buccal mucosa, tongue, and lips) were examined. Specimens were excised with an 808-nm diode laser, output 1.6-2.7 W, in continuous-wave mode with fibers of 320 μm. Specimens were fixed in 10% buffered formalin solution and examined separately under an optical microscope by two pathologists. In all of the specimens, changes to the epithelium, connective tissue and blood vessels, shape of incision damage, and overall width of modified tissues were evaluated. The data for specimens larger than 3 mm excised with the diode laser were not significant in terms of stromal changes or vascular stasis, while epithelial and stromal changes were significantly more frequent in specimens with a mean size below 3 mm; the diagnosis was not achievable in 46.15%. Our data show that the diode laser is a valid therapeutic instrument for excising oral lesions larger than 3 mm in diameter, but induces serious thermal effects in small lesions (mean size below 3 mm). However, from a clinical standpoint, it is suggested necessary that the specimens taken have in vivo a diameter of at least 5 mm in order to have a reliable reading of the histological sample. PMID:21387158

  10. Intravenous tissue plasminogen activator and size of infarct, left ventricular function, and survival in acute myocardial infarction.

    PubMed Central

    Van de Werf, F.; Arnold, A. E.

    1988-01-01

    STUDY OBJECTIVE--To assess effect of intravenous recombinant tissue type plasminogen activator on size of infarct, left ventricular function, and survival in acute myocardial infarction. DESIGN--Double blind, randomised, placebo controlled prospective trial of patients with acute myocardial infarction within five hours after onset of symptoms. SETTING--Twenty six referral centres participating in European cooperative study for recombinant tissue type plasminogen activator. PATIENTS--Treatment group of 355 patients with acute myocardial infarction allocated to receive intravenous recombinant plasminogen activator. Controls comprised 366 similar patients allocated to receive placebo. INTERVENTION--All patients were given aspirin 250 mg and bolus injection of 5000 IU heparin immediately before start of trial. Patients in treatment group were given 100 mg recombinant tissue plasminogen activator over three hours (10 mg intravenous bolus, 50 mg during one hour, and 40 mg during next two hours) by infusion. Controls were given placebo by same method. Full anticoagulation treatment and aspirin were given to both groups until angiography (10-22 days after admission). beta Blockers were given at discharge. END POINT--Left ventricular function at 10-22 days, enzymatic infarct size, clinical course, and survival to three month follow up. MEASUREMENTS AND MAIN RESULTS--Mortality was reduced by 51% (95% confidence interval -76 to 1) in treated patients at 14 days after start of treatment and by 36% (-63 to 13) at three months. For treatment within three hours after myocardial infarction mortality was reduced by 82% (-95 to -31) at 14 days and by 59% (-83 to -2) at three months. During 14 days in hospital incidence of cardiac complications was lower in treated patients than controls (cardiogenic shock, 2.5% v 6.0%; ventricular fibrillation, 3.4% v 6.3%; and pericarditis, 6.2% v 11.0% respectively), but that of angioplasty or artery bypass, or both was higher (15.8% v 9

  11. Delivery of human mesenchymal adipose-derived stem cells restores multiple urological dysfunctions in a rat model mimicking radical prostatectomy damages through tissue-specific paracrine mechanisms.

    PubMed

    Yiou, René; Mahrouf-Yorgov, Meriem; Trébeau, Céline; Zanaty, Marc; Lecointe, Cécile; Souktani, Richard; Zadigue, Patricia; Figeac, Florence; Rodriguez, Anne-Marie

    2016-02-01

    Urinary incontinence (UI) and erectile dysfunction (ED) are the most common functional urological disorders and the main sequels of radical prostatectomy (RP) for prostate cancer. Mesenchymal stem cell (MSC) therapy holds promise for repairing tissue damage due to RP. Because animal studies accurately replicating post-RP clinical UI and ED are lacking, little is known about the mechanisms underlying the urological benefits of MSC in this setting. To determine whether and by which mechanisms MSC can repair damages to both striated urethral sphincter (SUS) and penis in the same animal, we delivered human multipotent adipose stem cells, used as MSC model, in an immunocompetent rat model replicating post-RP UI and ED. In this model, we demonstrated by using noninvasive methods in the same animal from day 7 to day 90 post-RP injury that MSC administration into both the SUS and the penis significantly improved urinary continence and erectile function. The regenerative effects of MSC therapy were not due to transdifferentiation and robust engraftment at injection sites. Rather, our results suggest that MSC benefits in both target organs may involve a paracrine process with not only soluble factor release by the MSC but also activation of the recipient's secretome. These two effects of MSC varied across target tissues and damaged-cell types. In conclusion, our work provides new insights into the regenerative properties of MSC and supports the ability of MSC from a single source to repair multiple types of damage, such as those seen after RP, in the same individual.

  12. Acute sleep fragmentation induces tissue-specific changes in cytokine gene expression and increases serum corticosterone concentration.

    PubMed

    Dumaine, Jennifer E; Ashley, Noah T

    2015-06-15

    Sleep deprivation induces acute inflammation and increased glucocorticosteroids in vertebrates, but effects from fragmented, or intermittent, sleep are poorly understood. Considering the latter is more representative of sleep apnea in humans, we investigated changes in proinflammatory (IL-1β, TNF-α) and anti-inflammatory (TGF-β1) cytokine gene expression in the periphery (liver, spleen, fat, and heart) and brain (hypothalamus, prefrontal cortex, and hippocampus) of a murine model exposed to varying intensities of sleep fragmentation (SF). Additionally, serum corticosterone was assessed. Sleep was disrupted in male C57BL/6J mice using an automated sleep fragmentation chamber that moves a sweeping bar at specified intervals (Lafayette Industries). Mice were exposed to bar sweeps every 20 s (high sleep fragmentation, HSF), 120 s (low sleep fragmentation, LSF), or the bar remained stationary (control). Trunk blood and tissue samples were collected after 24 h of SF. We predicted that HSF mice would exhibit increased proinflammatory expression, decreased anti-inflammatory expression, and elevated stress hormones in relation to LSF and controls. SF significantly elevated IL-1β gene expression in adipose tissue, heart (HSF only), and hypothalamus (LSF only) relative to controls. SF did not increase TNF-α expression in any of the tissues measured. HSF increased TGF-β1 expression in the hypothalamus and hippocampus relative to other groups. Serum corticosterone concentration was significantly different among groups, with HSF mice exhibiting the highest, LSF intermediate, and controls with the lowest concentration. This indicates that 24 h of SF is a potent inducer of inflammation and stress hormones in the periphery, but leads to upregulation of anti-inflammatory cytokines in the brain.

  13. Role of P-450 activity and glutathione levels in 1,2-dibromo-3-chloropropane tissue distribution, renal necrosis and in vivo DNA damage.

    PubMed

    Låg, M; Omichinski, J G; Søderlund, E J; Brunborg, G; Holme, J A; Dahl, J E; Nelson, S D; Dybing, E

    1989-06-16

    Treatments known to alter P-450 activity and glutathione levels were used to elucidate the involvement of P-450 and glutathione S-transferase metabolism in 1,2-dibromo-3-chloropropane (DBCP) organ toxicity in the rat. Phenobarbital pretreatment abolished DBCP-induced renal necrosis, whereas it had only a small effect on initial renal DNA damage. The DBCP levels in plasma and tissues were markedly reduced by phenobarbital pretreatment. Perdeuterated DBCP had much higher plasma and tissue levels than protio-DBCP in phenobarbital-pretreated animals, but perdeuteration was without effect in uninduced animals. This indicates that P-450 metabolism of DBCP is of major importance only in phenobarbital-pretreated animals. In order to study the effects of decreased glutathione levels on renal distribution and toxicity, rats were pretreated with either diethyl maleate or buthionine sulfoximine. The DBCP levels in plasma and tissues showed transitory elevations after diethyl maleate and buthionine sulfoximine pretreatment compared to the control situation. Despite the fact that diethyl maleate and buthionine sulfoximine pretreatments are known to block DBCP-induced DNA damage in vitro, these pretreatments did not significantly alter DBCP-induced renal necrosis nor DNA damage. Thus, a role for glutathione conjugation in DBCP-induced in vivo renal toxicity could not be established in the present study. PMID:2734806

  14. Normal Tissue Complication Probability Modeling of Acute Hematologic Toxicity in Cervical Cancer Patients Treated With Chemoradiotherapy

    SciTech Connect

    Rose, Brent S.; Aydogan, Bulent; Liang, Yun; Yeginer, Mete; Hasselle, Michael D.; Dandekar, Virag; Bafana, Rounak; Yashar, Catheryn M.; Mundt, Arno J.; Roeske, John C.; Mell, Loren K.

    2011-03-01

    Purpose: To test the hypothesis that increased pelvic bone marrow (BM) irradiation is associated with increased hematologic toxicity (HT) in cervical cancer patients undergoing chemoradiotherapy and to develop a normal tissue complication probability (NTCP) model for HT. Methods and Materials: We tested associations between hematologic nadirs during chemoradiotherapy and the volume of BM receiving {>=}10 and 20 Gy (V{sub 10} and V{sub 20}) using a previously developed linear regression model. The validation cohort consisted of 44 cervical cancer patients treated with concurrent cisplatin and pelvic radiotherapy. Subsequently, these data were pooled with data from 37 identically treated patients from a previous study, forming a cohort of 81 patients for normal tissue complication probability analysis. Generalized linear modeling was used to test associations between hematologic nadirs and dosimetric parameters, adjusting for body mass index. Receiver operating characteristic curves were used to derive optimal dosimetric planning constraints. Results: In the validation cohort, significant negative correlations were observed between white blood cell count nadir and V{sub 10} (regression coefficient ({beta}) = -0.060, p = 0.009) and V{sub 20} ({beta} = -0.044, p = 0.010). In the combined cohort, the (adjusted) {beta} estimates for log (white blood cell) vs. V{sub 10} and V{sub 20} were as follows: -0.022 (p = 0.025) and -0.021 (p = 0.002), respectively. Patients with V{sub 10} {>=} 95% were more likely to experience Grade {>=}3 leukopenia (68.8% vs. 24.6%, p < 0.001) than were patients with V{sub 20} > 76% (57.7% vs. 21.8%, p = 0.001). Conclusions: These findings support the hypothesis that HT increases with increasing pelvic BM volume irradiated. Efforts to maintain V{sub 10} < 95% and V{sub 20} < 76% may reduce HT.

  15. Light damage in the rat retina: effect of a radioprotective agent (WR-77913) on acute rod outer segment disk disruptions.

    PubMed

    Remé, C E; Braschler, U F; Roberts, J; Dillon, J

    1991-07-01

    Primary events in the course of light induced retinal lesions are still not fully elucidated. Under chronic conditions, lipid peroxidation in the retina and death of photoreceptor cells are observed. The radioprotective agent WR-77913 scavenges singlet oxygen, hydrated electrons and free radicals. WR-77913 was used to protect against acute light induced photoreceptor outer segment membrane disruptions in the rat retina. There was a partial but not complete protection at higher illuminance levels (800 lx for 30 min), whereas threshold lesions (400 lx for 30 min) were almost completely prevented. These observations indicate an involvement of photodynamic reactions in causing acute photoreceptor lesions. PMID:1658823

  16. Therapeutic benefit of bortezomib on acute GVHD is tissue specific and is associated with IL-6 levels

    PubMed Central

    Pai, Chien-Chun Steven; Hsiao, Hui-Hua; Sun, Kai; Chen, Mingyi; Hagino, Takeshi; Tellez, Joseph; Mall, Christine; Blazar, Bruce R.; Monjazeb, Arta; Abedi, Mehrdad; Murphy, William J.

    2014-01-01

    Bortezomib, a proteasome inhibitor capable of direct anti-tumor effects, has been shown to prevent acute graft-versus-host disease (aGVHD) when administered in a short course immediately after bone marrow transplantation (BMT) in mice. However, when given continuously, CD4+ T cell mediated gastrointestinal tract damages increase GVHD mortality. To investigate the protective effects of bortezomib on other organs, we have used a CD8 dependent aGVHD model of C3H.SW donor T cells engrafted into irradiated C57BL/6 recipients (minor MHC mismatch), which lack significant gut GVHD. Our data in this model show that bortezomib can be given continuously to prevent and treat aGVHD mediated by CD8+ T cells, but this effect is organ-specific such that only skin, but not liver, protection was observed. Despite the lack of hepatic protection, bortezomib still significantly improved survival primarily due to its skin protection. Reduced skin GVHD by bortezomib was correlated with reduced serum and skin IL-6 levels. Administration of a blocking IL-6 antibody in this model also resulted in similar cutaneous GVHD protection. These results indicate that bortezomib or blockade of IL-6 may prevent CD8+ T cell mediated cutaneous aGVHD. PMID:25064746

  17. Through metal binding, curcumin protects against lead- and cadmium-induced lipid peroxidation in rat brain homogenates and against lead-induced tissue damage in rat brain.

    PubMed

    Daniel, Sheril; Limson, Janice L; Dairam, Amichand; Watkins, Gareth M; Daya, Santy

    2004-02-01

    Curcumin, the major constituent of turmeric is a known, naturally occurring antioxidant. The present study examined the ability of this compound to protect against lead-induced damage to hippocampal cells of male Wistar rats, as well as lipid peroxidation induced by lead and cadmium in rat brain homogenate. The thiobarbituric assay (TBA) was used to measure the extent of lipid peroxidation induced by lead and cadmium in rat brain homogenate. The results show that curcumin significantly protects against lipid peroxidation induced by both these toxic metals. Coronal brain sections of rats injected intraperitoneally with lead acetate (20 mg/kg) in the presence and absence of curcumin (30 mg/kg) were compared microscopically to determine the extent of lead-induced damage to the cells in the hippocampal CA1 and CA3 regions, and to establish the capacity of curcumin to prevent such damage. Lead-induced damage to the neurons was significantly curtailed in the rats injected with curcumin. Possible chelation of lead and cadmium by curcumin as its mechanism of neuroprotection against such heavy metal insult to the brain was investigated using electrochemical, ultraviolet spectrophotometric and infrared spectroscopic analyses. The results of the study show that there is an interaction between curcumin and both cadmium and lead, with the possible formation of a complex between the metal and this ligand. These results imply that curcumin could be used therapeutically to chelate these toxic metals, thus potentially reducing their neurotoxicity and tissue damage.

  18. ACUTE EFFECTS OF INSTRUMENT ASSISTED SOFT TISSUE MOBILIZATION FOR IMPROVING POSTERIOR SHOULDER RANGE OF MOTION IN COLLEGIATE BASEBALL PLAYERS

    PubMed Central

    Compton, Bryce D.; McLoda, Todd A.; Walters, Chris M.

    2014-01-01

    Background: Due to the repetitive rotational and distractive forces exerted onto the posterior shoulder during the deceleration phase of the overhead throwing motion, limited glenohumeral (GH) range of motion (ROM) is a common trait found among baseball players, making them prone to a wide variety of shoulder injuries. Although utilization of instrument‐assisted soft tissue mobilization (IASTM), such as the Graston® Technique, has proven effective for various injuries and disorders, there is currently no empirical data regarding the effectiveness of this treatment on posterior shoulder tightness. Purpose: To determine the effectiveness of IASTM in improving acute passive GH horizontal adduction and internal rotation ROM in collegiate baseball players. Methods: Thirty‐five asymptomatic collegiate baseball players were randomly assigned to one of two groups. Seventeen participants received one application of IASTM to the posterior shoulder in between pretest and posttest measurements of passive GH horizontal adduction and internal rotation ROM. The remaining 18 participants did not receive a treatment intervention between tests, serving as the controls. Data were analyzed using separate 2× 2 mixed‐model analysis of variance, with treatment group as the between‐subjects variable and time as the within‐subjects variable. Results: A significant group‐by‐time interaction was present for GH horizontal adduction ROM with the IASTM group showing greater improvements in ROM (11.1°) compared to the control group (‐0.12°) (p <0.001). A significant group‐by‐time interaction was also present for GH internal rotation ROM with the IASTM group having greater improvements (4.8°) compared to the control group (‐0.14°) (p < 0.001). Conclusions: The results of this study indicate that an application of IASTM to the posterior shoulder provides acute improvements in both GH horizontal adduction ROM and internal rotation ROM among baseball players. Level of

  19. Neuroendocrinal, Neurodevelopmental, and Embryotoxic Effects of Recombinant Tissue Plasminogen Activator Treatment for Pregnant Women with Acute Ischemic Stroke

    PubMed Central

    Steinberg, Anna; Moreira, Tiago P.

    2016-01-01

    Thrombolysis with recombinant tissue plasminogen activator (rTPA) was the first evidence-based treatment approved for acute stroke. Ischemic stroke is relatively uncommon in fertile women but treatment is often delayed or not given. In randomized trials, pregnancy has been an exclusion criterion for thrombolysis. Physiologic TPA has been shown to have neuroendocrine effects namely in vasopressin secretion. Important TPA effects in brain function and development include neurite outgrowth, migration of cerebellar granular neurons and promotion of long-term potentiation, among others. Until now, no neuroendocrine side-effects have been reported in pregnant women treated with rTPA. The effects of rTPA exposure in the fetus following intravenous thrombolysis in pregnant women are still poorly understood. This depends on low case frequency, short-duration of exposure and the fact that rTPA molecule is too large to pass the placenta. rTPA has a short half-life of 4–5 min, with only 10% of its concentration remaining in circulation after 20 min, which may explain its safety at therapeutically doses. Ischemic stroke during pregnancy occurs most often in the third trimester. Complication rates of rTPA in pregnant women treated for thromboembolic conditions and ischemic stroke were found to be similar when compared to non-pregnant women (7–9% mortality). In embryos of animal models so far, no indications of a teratogenic or mutagenic potential were found. Pregnancy is still considered a relative contraindication when treating acute ischemic stroke with rTPA, however, treatment risk must be balanced against the potential of maternal disability and/or death. PMID:26941596

  20. No increases in biomarkers of genetic damage or pathological changes in heart and brain tissues in male rats administered methylphenidate hydrochloride (Ritalin) for 28 days.

    PubMed

    Witt, Kristine L; Malarkey, David E; Hobbs, Cheryl A; Davis, Jeffrey P; Kissling, Grace E; Caspary, William; Travlos, Gregory; Recio, Leslie

    2010-01-01

    Following a 2005 report of chromosomal damage in children with attention deficit/hyperactivity disorder (ADHD) who were treated with the commonly prescribed medication methylphenidate (MPH), numerous studies have been conducted to clarify the risk for MPH-induced genetic damage. Although most of these studies reported no changes in genetic damage endpoints associated with exposure to MPH, one recent study (Andreazza et al. [2007]: Prog Neuropsychopharmacol Biol Psychiatry 31:1282-1288) reported an increase in DNA damage detected by the Comet assay in blood and brain cells of Wistar rats treated by intraperitoneal injection with 1, 2, or 10 mg/kg MPH; no increases in micronucleated lymphocyte frequencies were observed in these rats. To clarify these findings, we treated adult male Wistar Han rats with 0, 2, 10, or 25 mg/kg MPH by gavage once daily for 28 consecutive days and measured micronucleated reticulocyte (MN-RET) frequencies in blood, and DNA damage in blood, brain, and liver cells 4 hr after final dosing. Flow cytometric evaluation of blood revealed no significant increases in MN-RET. Comet assay evaluations of blood leukocytes and cells of the liver, as well as of the striatum, hippocampus, and frontal cortex of the brain showed no increases in DNA damage in MPH-treated rats in any of the three treatment groups. Thus, the previously reported observations of DNA damage in blood and brain tissue of rats exposed to MPH for 28 days were not confirmed in this study. Additionally, no histopathological changes in brain or heart, or elevated serum biomarkers of cardiac injury were observed in these MPH-exposed rats.

  1. The impact of acute temperature stress on hemocytes of invasive and native mussels (Mytilus galloprovincialis and Mytilus californianus): DNA damage, membrane integrity, apoptosis and signaling pathways.

    PubMed

    Yao, Cui-Luan; Somero, George N

    2012-12-15

    We investigated the effects of acute heat stress and cold stress on cell viability, lysosome membrane stability, double- and single-stranded DNA breakage, and signaling mechanisms involved in cellular homeostasis and apoptosis in hemocytes of native and invasive mussels, Mytilus californianus and Mytilus galloprovincialis, respectively. Both heat stress (28, 32°C) and cold stress (2, 6°C) led to significant double- and single-stranded breaks in DNA. The type and extent of DNA damage were temperature and time dependent, as was caspase-3 activation, an indicator of apoptosis, which may occur in response to DNA damage. Hemocyte viability and lysosomal membrane stability decreased significantly under heat stress. Western blot analyses of hemocyte extracts with antibodies for proteins associated with cell signaling and stress responses [including members of the phospho-specific mitogen-activated protein kinase (MAPK) family c-JUN NH(2)-terminal kinase (JNK) and p38-MAPK, and apoptosis executor caspase-3] revealed that heat and cold stress induced a time-dependent activation of JNK, p38-MAPK and caspase-3 and that these signaling and stress responses differed between species. The thermal limits for activation of cell signaling processes linked to the repair of stress-induced damage may help determine cellular thermal tolerance limits. Our results show similarities in responses to cold and heat stress and suggest causal linkages between levels of DNA damage at both extremes of temperature and downstream regulatory responses, including induction of apoptosis. Compared with M. californianus, M. galloprovincialis might have a wider temperature tolerance due to a lower amount of single- and double-stranded DNA damage, faster signaling activation and transduction, and stronger repair ability against temperature stress.

  2. Airway Tissue Plasminogen Activator Prevents Acute Mortality Due to Lethal Sulfur Mustard Inhalation

    PubMed Central

    Veress, Livia A.; Anderson, Dana R.; Hendry-Hofer, Tara B.; Houin, Paul R.; Rioux, Jacqueline S.; Garlick, Rhonda B.; Loader, Joan E.; Paradiso, Danielle C.; Smith, Russell W.; Rancourt, Raymond C.; Holmes, Wesley W.; White, Carl W.

    2015-01-01

    Rationale: Sulfur mustard (SM) is a chemical weapon stockpiled today in volatile regions of the world. SM inhalation causes a life-threatening airway injury characterized by airway obstruction from fibrin casts, which can lead to respiratory failure and death. Mortality in those requiring intubation is more than 80%. No therapy exists to prevent mortality after SM exposure. Our previous work using the less toxic analog of SM, 2-chloroethyl ethyl sulfide, identified tissue plasminogen activator (tPA) an effective rescue therapy for airway cast obstruction (Veress, L. A., Hendry-Hofer, T. B., Loader, J. E., Rioux, J. S., Garlick, R. B., and White, C. W. (2013). Tissue plasminogen activator prevents mortality from sulfur mustard analog-induced airway obstruction. Am. J. Respir. Cell Mol. Biol. 48, 439–447). It is not known if exposure to neat SM vapor, the primary agent used in chemical warfare, will also cause death due to airway casts, and if tPA could be used to improve outcome. Methods: Adult rats were exposed to SM, and when oxygen saturation reached less than 85% (median: 6.5 h), intratracheal tPA or placebo was given under isoflurane anesthesia every 4 h for 48 h. Oxygen saturation, clinical distress, and arterial blood gases were assessed. Microdissection was done to assess airway obstruction by casts. Results: Intratracheal tPA treatment eliminated mortality (0% at 48 h) and greatly improved morbidity after lethal SM inhalation (100% death in controls). tPA normalized SM-associated hypoxemia, hypercarbia, and lactic acidosis, and improved respiratory distress. Moreover, tPA treatment resulted in greatly diminished airway casts, preventing respiratory failure from airway obstruction. Conclusions: tPA given via airway more than 6 h after exposure prevented death from lethal SM inhalation, and normalized oxygenation and ventilation defects, thereby rescuing from respiratory distress and failure. Intra-airway tPA should be considered as a life

  3. The effect of acute microgravity on mechanically-induced membrane damage and membrane-membrane fusion events

    NASA Technical Reports Server (NTRS)

    Clarke, M. S.; Vanderburg, C. R.; Feeback, D. L.; McIntire, L. V. (Principal Investigator)

    2001-01-01

    Although it is unclear how a living cell senses gravitational forces there is no doubt that perturbation of the gravitational environment results in profound alterations in cellular function. In the present study, we have focused our attention on how acute microgravity exposure during parabolic flight affects the skeletal muscle cell plasma membrane (i.e. sarcolemma), with specific reference to a mechanically-reactive signaling mechanism known as mechanically-induced membrane disruption or "wounding". Both membrane rupture and membrane resealing events mediated by membrane-membrane fusion characterize this response. We here present experimental evidence that acute microgravity exposure can inhibit membrane-membrane fusion events essential for the resealing of sarcolemmal wounds in individual human myoblasts. Additional evidence to support this contention comes from experimental studies that demonstrate acute microgravity exposure also inhibits secretagogue-stimulated intracellular vesicle fusion with the plasma membrane in HL-60 cells. Based on our own observations and those of other investigators in a variety of ground-based models of membrane wounding and membrane-membrane fusion, we suggest that the disruption in the membrane resealing process observed during acute microgravity is consistent with a microgravity-induced decrease in membrane order.

  4. The Effect of Acute Microgravity on Mechanically-Induced Membrane Damage and Membrane-Membrane Fusion Events

    NASA Technical Reports Server (NTRS)

    Clarke, Mark, S. F.; Vanderburg, Charles R.; Feedback, Daniel L.

    2001-01-01

    Although it is unclear how a living cell senses gravitational forces there is no doubt that perturbation of the gravitational environment results in profound alterations in cellular function. In the present study, we have focused our attention on how acute microgravity exposure during parabolic flight affects the skeletal muscle cell plasma membrane (i.e. sarcolemma), with specific reference to a mechanically-reactive signaling mechanism known as mechanically-induced membrane disruption or "wounding". This response is characterized by both membrane rupture and membrane resealing events mediated by membrane-membrane fusion. We here present experimental evidence that acute microgravity exposure can inhibit membrane-membrane fusion events essential for the resealing of sarcolemmal wounds in individual human myoblasts. Additional evidence to support this contention comes from experimental studies that demonstrate acute microgravity exposure also inhibits secretagogue-stimulated intracellular vesicle fusion with the plasma membrane in HL-60 cells. Based on our own observations and those of other investigators in a variety of ground-based models of membrane wounding and membrane-membrane fusion, we suggest that the disruption in the membrane resealing process observed during acute microgravity is consistent with a microgravity-induced decrease in membrane order.

  5. MicroRNA Stability in Postmortem FFPE Tissues: Quantitative Analysis Using Autoptic Samples from Acute Myocardial Infarction Patients.

    PubMed

    Kakimoto, Yu; Kamiguchi, Hiroshi; Ochiai, Eriko; Satoh, Fumiko; Osawa, Motoki

    2015-01-01

    MicroRNAs (miRNAs) are very short (18-24 nucleotides) nucleic acids that are expressed in a number of biological tissues and have been shown to be more resistant to extreme temperatures and pH compared to longer RNA molecules, like mRNAs. As miRNAs contribute to diverse biological process and respond to various kinds of cellular stress, their utility as diagnostic biomarkers and/or therapeutic targets has recently been explored. Here, we have evaluated the usefulness of miRNA quantification during postmortem examination of cardiac tissue from acute myocardial infarction (AMI) patients. Cardiac tissue was collected within one week of the patient's death and either frozen (19 samples) or fixed in formalin for up to three years (36 samples). RNA integrity was evaluated with an electropherogram, and it appears that longer RNAs are fragmented after death in the long-term fixed samples. Quantitative PCR was also performed for seven miRNAs and three other small RNAs in order to determine the appropriate controls for our postmortem analysis. Our data indicate that miR-191 and miR-26b are more suitable than the other types of small RNA molecules as they are stably detected after death and long-term fixation. Further, we also applied our quantitation method, using these endogenous controls, to evaluate the expression of three previously identified miRNA biomarkers, miR-1, miR-208b, and miR-499a, in formalin-fixed tissues from AMI patients. Although miR-1 and miR-208b decreased (1.4-fold) and increased (1.2-fold), respectively, in the AMI samples compared to the controls, the significance of these changes was limited by our sample size. In contrast, the relative level of miR-499a was significantly decreased in the AMI samples (2.1-fold). This study highlights the stability of miRNAs after death and long-term fixation, validating their use as reliable biomarkers for AMI during postmortem examination. PMID:26046358

  6. Freezing without Ice Crystal Damage: Semithin and Ultrathin Frozen Sections of Ethanol-Infiltrated Tissue for Microscopy, with Applications to Immunocytochemistry

    NASA Astrophysics Data System (ADS)

    Christensen, A. Kent; Lowry, Terry B.

    1995-10-01

    Ethanol (ethyl alcohol) has long been a standard reagent used in preparing tissues for light and electron microscopy. After fixation, tissues are usually dehydrated with ethanol before being embedded in paraffin or plastic. In this study we show that the ethanol-infiltrated tissue can be frozen and sectioned directly without embedding. When tissue impregnated with ethanol is cooled below about [minus sign]117°C with liquid nitrogen, the ethanol solidifies without appreciable crystallization. The frozen tissue can then be sectioned in a commercial cryoultramicrotome that is set at [minus sign]155 to [minus sign]170°C to produce semithin frozen sections (0.5 to 3 [mu]m thick) for light microscopy or ultrathin frozen sections (50 to 100 nm thick) for electron microscopy. Sections are picked up and mounted on glass slides or EM grids by means that are in current use for ice ultrathin frozen sectioning. Because there is no apparent freezing damage, the morphology in these ethanol frozen sections of unembedded tissue appears generally quite good, often resembling that obtained by conventional EM techniques. Examples are provided that illustrate the use of this material for immunocytochemistry at the light and electron microscope levels.

  7. Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/ref-1) and DNA damage in the caudal region of acute and chronic spinal cord injured rats treated by embryonic neural stem cells.

    PubMed

    DAGCI, T; ARMAGAN, G; KONYALIOGLU, S; YALCIN, A

    2009-01-01

    The oxidative mechanisms of injury-induced damage of neurons within the spinal cord are not very well understood. We used a model of T8-T9 spinal cord injury (SCI) in the rat to induce neuronal degeneration. In this spinal cord injury model, unilateral avulsion of the spinal cord causes oxidative stress of neurons. We tested the hypothesis that apurinic/apyrimidinic endonuclease (or redox effector factor-1, APE/Ref-1) regulates this neuronal oxidation mechanism in the spinal cord region caudal to the lesion, and that DNA damage is an early upstream signal. The embryonic neural stem cell therapy significantly decreased DNA-damage levels in both study groups - acutely (followed up to 7 days after SCI), and chronically (followed up to 28 days after SCI) injured animals. Meanwhile, mRNA levels of APE/Ref-1 significantly increased after embryonic neural stem cell therapy in acutely and chronically injured animals when compared to acute and chronic sham groups. Our data has demonstrated that an increase of APE/Ref-1 mRNA levels in the caudal region of spinal cord strongly correlated with DNA damage after traumatic spinal cord injury. We suggest that DNA damage can be observed both in lesional and caudal regions of the acutely and chronically injured groups, but DNA damage is reduced with embryonic neural stem cell therapy.

  8. Regulation of Lipolysis and Adipose Tissue Signaling during Acute Endotoxin-Induced Inflammation: A Human Randomized Crossover Trial

    PubMed Central

    Rittig, Nikolaj; Bach, Ermina; Thomsen, Henrik Holm; Pedersen, Steen Bønlykke; Nielsen, Thomas Sava; Jørgensen, Jens O.; Jessen, Niels; Møller, Niels

    2016-01-01

    Background Lipolysis is accelerated during the acute phase of inflammation, a process being regulated by pro-inflammatory cytokines (e.g. TNF-α), stress-hormones, and insulin. The intracellular mechanisms remain elusive and we therefore measured pro- and anti-lipolytic signaling pathways in adipocytes after in vivo endotoxin exposure. Methods Eight healthy, lean, male subjects were investigated using a randomized cross over trial with two interventions: i) bolus injection of saline (Placebo) and ii) bolus injection of lipopolysaccharide endotoxin (LPS). A 3H-palmitate tracer was used to measure palmitate rate of appearance (Rapalmitate) and indirect calorimetry was performed to measure energy expenditures and lipid oxidation rates. A subcutaneous abdominal fat biopsy was obtained during both interventions and subjected to western blotting and qPCR quantifications. Results LPS caused a mean increase in serum free fatty acids (FFA) concentrations of 90% (CI-95%: 37–142, p = 0.005), a median increase in Rapalmitate of 117% (CI-95%: 77–166, p<0.001), a mean increase in lipid oxidation of 49% (CI-95%: 1–96, p = 0.047), and a median increase in energy expenditure of 28% (CI-95%: 16–42, p = 0.001) compared with Placebo. These effects were associated with increased phosphorylation of hormone sensitive lipase (pHSL) at ser650 in adipose tissue (p = 0.03), a trend towards elevated pHSL at ser552 (p = 0.09) and cAMP-dependent protein kinase A (PKA) phosphorylation of perilipin 1 (PLIN1) (p = 0.09). Phosphatase and tensin homolog (PTEN) also tended to increase (p = 0.08) while phosphorylation of Akt at Thr308 tended to decrease (p = 0.09) during LPS compared with Placebo. There was no difference between protein or mRNA expression of ATGL, G0S2, and CGI-58. Conclusion LPS stimulated lipolysis in adipose tissue and is associated with increased pHSL and signs of increased PLIN1 phosphorylation combined with a trend toward decreased insulin signaling. The combination of

  9. The cyanogenic syndrome in rubber tree Hevea brasiliensis: tissue-damage-dependent activation of linamarase and hydroxynitrile lyase accelerates hydrogen cyanide release

    PubMed Central

    Kadow, Daniel; Voß, Karsten; Selmar, Dirk; Lieberei, Reinhard

    2012-01-01

    Background and Aims The release of hydrogen cyanide (HCN) from injured plant tissue affects multiple ecological interactions. Plant-derived HCN can act as a defence against herbivores and also plays an important role in plant–pathogen interactions. Crucial for activity as a feeding deterrent is the amount of HCN generated per unit time, referred to as cyanogenic capacity (HCNc). Strong intraspecific variation in HCNc has been observed among cyanogenic plants. This variation, in addition to genotypic variability (e.g. in Trifolium repens), can result from modifications in the expression level of the enzymes involved in either cyanogenic precursor formation or HCN release (as seen in Sorghum bicolor and Phaseolus lunatus). Thus, a modification or modulation of HCNc in reaction to the environment can only be achieved from one to the next generation when under genetic control and within days or hours when transcriptional regulations are involved. In the present study, it is shown that in rubber tree (Hevea brasiliensis) HCNc is modulated by post-translational activity regulation of the key enzymes for cyanide release. Methods Linamarase (LIN) and hydroxynitrile lyase (HNL) activity was determined by colorimetric assays utilizing dissociation of the substrates p-nitrophenyl-β-d-glucopyranoside and acetone cyanohydrin, respectively. Key Results In rubber tree leaves, LIN and HNL show up to ten-fold increased activity in response to tissue damage. This enzyme activation occurs within seconds and results in accelerated HCN formation. It is restricted to the damaged leaf area and depends on the severity of tissue damage. Conclusions LIN and HNL activation (in contrast to genetic and transcriptional regulations) allows an immediate, local and damage type-dependent modulation of the cyanogenic response. Accordingly, this post-translational activation plays a decisive role in the defence of H. brasiliensis against herbivores as well as pathogens and may allow more flexible

  10. Increased Reliance on Muscle-based Thermogenesis upon Acute Minimization of Brown Adipose Tissue Function.

    PubMed

    Bal, Naresh C; Maurya, Santosh K; Singh, Sushant; Wehrens, Xander H T; Periasamy, Muthu

    2016-08-12

    Skeletal muscle has been suggested as a site of nonshivering thermogenesis (NST) besides brown adipose tissue (BAT). Studies in birds, which do not contain BAT, have demonstrated the importance of skeletal muscle-based NST. However, muscle-based NST in mammals remains poorly characterized. We recently reported that sarco/endoplasmic reticulum Ca(2+) cycling and that its regulation by SLN can be the basis for muscle NST. Because of the dominant role of BAT-mediated thermogenesis in rodents, the role of muscle-based NST is less obvious. In this study, we investigated whether muscle will become an important site of NST when BAT function is conditionally minimized in mice. We surgically removed interscapular BAT (iBAT, which constitutes ∼70% of total BAT) and exposed the mice to prolonged cold (4 °C) for 9 days. The iBAT-ablated mice were able to maintain optimal body temperature (∼35-37 °C) during the entire period of cold exposure. After 4 days in the cold, both sham controls and iBAT-ablated mice stopped shivering and resumed routine physical activity, indicating that they are cold-adapted. The iBAT-ablated mice showed higher oxygen consumption and decreased body weight and fat mass, suggesting an increased energy cost of cold adaptation. The skeletal muscles in these mice underwent extensive remodeling of both the sarcoplasmic reticulum and mitochondria, including alteration in the expression of key components of Ca(2+) handling and mitochondrial metabolism. These changes, along with increased sarcolipin expression, provide evidence for the recruitment of NST in skeletal muscle. These studies collectively suggest that skeletal muscle becomes the major site of NST when BAT activity is minimized.

  11. Increased Reliance on Muscle-based Thermogenesis upon Acute Minimization of Brown Adipose Tissue Function.

    PubMed

    Bal, Naresh C; Maurya, Santosh K; Singh, Sushant; Wehrens, Xander H T; Periasamy, Muthu

    2016-08-12

    Skeletal muscle has been suggested as a site of nonshivering thermogenesis (NST) besides brown adipose tissue (BAT). Studies in birds, which do not contain BAT, have demonstrated the importance of skeletal muscle-based NST. However, muscle-based NST in mammals remains poorly characterized. We recently reported that sarco/endoplasmic reticulum Ca(2+) cycling and that its regulation by SLN can be the basis for muscle NST. Because of the dominant role of BAT-mediated thermogenesis in rodents, the role of muscle-based NST is less obvious. In this study, we investigated whether muscle will become an important site of NST when BAT function is conditionally minimized in mice. We surgically removed interscapular BAT (iBAT, which constitutes ∼70% of total BAT) and exposed the mice to prolonged cold (4 °C) for 9 days. The iBAT-ablated mice were able to maintain optimal body temperature (∼35-37 °C) during the entire period of cold exposure. After 4 days in the cold, both sham controls and iBAT-ablated mice stopped shivering and resumed routine physical activity, indicating that they are cold-adapted. The iBAT-ablated mice showed higher oxygen consumption and decreased body weight and fat mass, suggesting an increased energy cost of cold adaptation. The skeletal muscles in these mice underwent extensive remodeling of both the sarcoplasmic reticulum and mitochondria, including alteration in the expression of key components of Ca(2+) handling and mitochondrial metabolism. These changes, along with increased sarcolipin expression, provide evidence for the recruitment of NST in skeletal muscle. These studies collectively suggest that skeletal muscle becomes the major site of NST when BAT activity is minimized. PMID:27298322

  12. Acute and chronic structural effects of pilocarpine on monkey outflow tissues.

    PubMed Central

    Lütjen-Drecoll, E; Wiendl, H; Kaufman, P L

    1998-01-01

    PURPOSE: Determine the effects of supraclinical topical doses of pilocarpine on the structure of the trabecular meshwork (TM), ciliary muscle (CM), and ciliary processes in monkeys. METHODS: Cynomolgus monkeys received topical pilocarpine hydrochloride doses of 1 to 2 mg unilaterally once or twice daily for 1 to 211 days. Both eyes were examined by light and electron microscopy. RESULTS: After 1 dose, the TM was expanded and the flow pathways open. Some elastic anterior CM tendons were disconnected from the muscle tips and/or the tips themselves were disrupted; macrophage-like cells accumulated in these regions. In eyes that had long-term treatment, scar tissue at the muscle tips and disruption of myofibrils within muscle cells indicated regions of previous disconnection. Most collagen tendons inserting into the peripheral cornea were unaffected. With increasing treatment duration in younger monkeys, there was anteroposterior shortening of Schlemm's canal, TM densification due to collapse, and increased cellularity in the subendothelial region of Schlemm's canal. TM densification and Schlemm's canal shortening were not found in older monkeys, implicating posterior movement of the elastic young limbal region induced by strong CM contraction, rather than pilocarpine toxicity. In the ciliary body we found vasodilation, Greeff's vesicles, and blood-aqueous barrier breakdown in the anterior ciliary processes and vasodilation, edema, and round-cell infiltration in the posterior pars plana. CONCLUSIONS: Large pilocarpine doses induce morphologic changes in the monkey anterior segment, likely consequent to intense CM contraction. Changes in the TM and Schlemm's canal are seen only in young monkeys, apparently owing to mechanical deformation of the elastic limbal region. Images FIGURE 2A FIGURE 2B FIGURE 2C FIGURE 2D FIGURE 3 A FIGURE 3 B FIGURE 4 A FIGURE 4 B FIGURE 4 C FIGURE 5 PMID:10360289

  13. The Different Effects of BMI and WC on Organ Damage in Patients from a Cardiac Rehabilitation Program after Acute Coronary Syndrome.

    PubMed

    Xu, Lin; Zhao, Hui; Qiu, Jian; Zhu, Wei; Lei, Hongqiang; Cai, Zekun; Lin, Wan-Hua; Huang, Wenhua; Zhang, Heye; Zhang, Yuan-Ting

    2015-01-01

    One of the purposes of cardiac rehabilitation (CR) after acute coronary syndrome (ACS) is to monitor and control weight of the patient. Our study is to compare the different obesity indexes, body mass index (BMI), and waist circumference (WC), through one well-designed CR program (CRP) with ACS in Guangzhou city of Guangdong Province, China, in order to identify different effects of BMI and WC on organ damage. In our work, sixty-one patients between October 2013 and January 2014 fulfilled our study. We collected the vital signs by medical records, the clinical variables of body-metabolic status by fasting blood test, and the organ damage variables by submaximal exercise treadmill test (ETT) and ultrasonic cardiogram (UCG) both on our inpatient and four-to-five weeks of outpatient part of CRP after ACS. We mainly used two-tailed Pearson's test and liner regression to evaluate the relationship of BMI/WC and organ damage. Our results confirmed that WC could be more accurate than BMI to evaluate the cardiac function through the changes of left ventricular structure on the CRP after ACS cases. It makes sense of early diagnosis, valid evaluation, and proper adjustment to ACS in CRP of the obesity individuals in the future. PMID:26247035

  14. The Different Effects of BMI and WC on Organ Damage in Patients from a Cardiac Rehabilitation Program after Acute Coronary Syndrome.

    PubMed

    Xu, Lin; Zhao, Hui; Qiu, Jian; Zhu, Wei; Lei, Hongqiang; Cai, Zekun; Lin, Wan-Hua; Huang, Wenhua; Zhang, Heye; Zhang, Yuan-Ting

    2015-01-01

    One of the purposes of cardiac rehabilitation (CR) after acute coronary syndrome (ACS) is to monitor and control weight of the patient. Our study is to compare the different obesity indexes, body mass index (BMI), and waist circumference (WC), through one well-designed CR program (CRP) with ACS in Guangzhou city of Guangdong Province, China, in order to identify different effects of BMI and WC on organ damage. In our work, sixty-one patients between October 2013 and January 2014 fulfilled our study. We collected the vital signs by medical records, the clinical variables of body-metabolic status by fasting blood test, and the organ damage variables by submaximal exercise treadmill test (ETT) and ultrasonic cardiogram (UCG) both on our inpatient and four-to-five weeks of outpatient part of CRP after ACS. We mainly used two-tailed Pearson's test and liner regression to evaluate the relationship of BMI/WC and organ damage. Our results confirmed that WC could be more accurate than BMI to evaluate the cardiac function through the changes of left ventricular structure on the CRP after ACS cases. It makes sense of early diagnosis, valid evaluation, and proper adjustment to ACS in CRP of the obesity individuals in the future.

  15. Real-time optical coherence tomography observation of retinal tissue damage during laser photocoagulation therapy on ex-vivo porcine samples

    NASA Astrophysics Data System (ADS)

    Steiner, P.; Považay, B.; Stoller, M.; Morgenthaler, P.; Inniger, D.; Arnold, P.; Sznitman, R.; Meier, Ch.

    2015-07-01

    Retinal laser photocoagulation represents a widely used treatment for retinal pathologies such as diabetic chorioretinopathy or diabetic edema. For effective treatment, an appropriate choice of the treatment energy dose is crucial to prevent excessive tissue damage caused by over-irradiation of the retina. In this manuscript we investigate simultaneous and time-resolved optical coherence tomography for its applicability to provide feedback to the ophthalmologist about the introduced retinal damage during laser photocoagulation. Time-resolved and volumetric optical coherence tomography data of 96 lesions on ex-vivo porcine samples, set with a 577 nm laser prototype and irradiance of between 300 and 8800 W=cm2 were analyzed. Time-resolved scans were compared to volumetric scans of the lesion and correlated with ophthalmoscopic visibility. Lastly, image parameters extracted from optical coherence tomography Mscans, suitable for lesion classification were identified. Results presented in this work support the hypothesis that simultaneous optical coherence tomography provides valuable information about the extent of retinal tissue damage and may be used to guide retinal laser photocoagulation in the future.

  16. Hair cell counts in a rat model of sound damage: Effects of tissue preparation & identification of regions of hair cell loss.

    PubMed

    Neal, Christopher; Kennon-McGill, Stefanie; Freemyer, Andrea; Shum, Axel; Staecker, Hinrich; Durham, Dianne

    2015-10-01

    Exposure to intense sound can damage or kill cochlear hair cells (HC). This loss of input typically manifests as noise induced hearing loss, but it can also be involved in the initiation of other auditory disorders such as tinnitus or hyperacusis. In this study we quantify changes in HC number following exposure to one of four sound damage paradigms. We exposed adult, anesthetized Long-Evans rats to a unilateral 16 kHz pure tone that varied in intensity (114 dB or 118 dB) and duration (1, 2, or 4 h) and sacrificed animals 2-4 weeks later. We compared two different methods of tissue preparation, plastic embedding/sectioning and whole mount dissection, for quantifying hair cell loss as a function of frequency. We found that the two methods of tissue preparation produced largely comparable cochleograms, with whole mount dissections allowing a more rapid evaluation of hair cell number. Both inner and outer hair cell loss was observed throughout the length of the cochlea irrespective of sound damage paradigm. Inner HC loss was either equal to or greater than outer HC loss. Increasing the duration of sound exposures resulted in more severe HC loss, which included all HC lesions observed in an analogous shorter duration exposure.

  17. Glucocorticoids Acutely Increase Brown Adipose Tissue Activity in Humans, Revealing Species-Specific Differences in UCP-1 Regulation.

    PubMed

    Ramage, Lynne E; Akyol, Murat; Fletcher, Alison M; Forsythe, John; Nixon, Mark; Carter, Roderick N; van Beek, Edwin J R; Morton, Nicholas M; Walker, Brian R; Stimson, Roland H

    2016-07-12

    The discovery of brown adipose tissue (BAT) in adult humans presents a new therapeutic target for metabolic disease; however, little is known about the regulation of human BAT. Chronic glucocorticoid excess causes obesity in humans, and glucocorticoids suppress BAT activation in rodents. We tested whether glucocorticoids regulate BAT activity in humans. In vivo, the glucocorticoid prednisolone acutely increased (18)fluorodeoxyglucose uptake by BAT (measured using PET/CT) in lean healthy men during mild cold exposure (16°C-17°C). In addition, prednisolone increased supraclavicular skin temperature (measured using infrared thermography) and energy expenditure during cold, but not warm, exposure in lean subjects. In vitro, glucocorticoids increased isoprenaline-stimulated respiration and UCP-1 in human primary brown adipocytes, but substantially decreased isoprenaline-stimulated respiration and UCP-1 in primary murine brown and beige adipocytes. The highly species-specific regulation of BAT function by glucocorticoids may have important implications for the translation of novel treatments to activate BAT to improve metabolic health. PMID:27411014

  18. Effects of acute exercise on the levels of iron, magnesium, and uric acid in liver and spleen tissues.

    PubMed

    Kaptanoğlu, B; Turgut, G; Genç, O; Enli, Y; Karabulut, I; Zencir, M; Turgut, S

    2003-02-01

    In this study, we investigated the effects of acute exercise on tissue levels of iron, magnesium, and uric acid of rats. Twenty adult Wistar albino rats were used for the study. They were divided into two groups: controls (n=10) and the study group (n=10). The study group was left into a small water pool and allowed to do swimming exercise for 30 min while controls rested. All of the animals were sacrificed, and their livers and spleens removed and homogenized immediately. The iron, magnesium, and uric acid levels of the homogenates were measured by an autoanalyzer (ILAB 900, Italy) with commercial kits from the same company. Results were evaluated by the Mann-Whitney U-test. According to our results, the liver iron levels increased significantly with exercise, whereas spleen iron levels decreased significantly (p<0.05) compared to controls. We found no significant differences in the levels of the other two parameters with exercise. These results show that the iron distribution in organs changes with exercise. PMID:12719612

  19. Cost-Effectiveness of Intraarterial Treatment as an Adjunct to Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke

    PubMed Central

    Leppert, Michelle H; Campbell, Jonathan D; Simpson, Jennifer R; Burke, James F

    2015-01-01

    Background and Purpose The objective of this study was to determine the cost-effectiveness of intraarterial treatment within the 0- to 6- hour window after intravenous (IV) tissue plasminogen activator (tPA) within 0- to 4.5-hours compared to IV tPA alone, in the US setting and from a social perspective. Methods A decision analytic model estimated the lifetime costs and outcomes associated with the additional benefit of intraarterial therapy compared to standard treatment with IV tPA alone. Model inputs were obtained from published literature, the MR CLEAN study, and claims databases in the United States. Health outcomes were measured in quality adjusted life years (QALYs). Treatment benefit was assessed by calculating the cost per QALY gained. One-way and probabilistic sensitivity analyses were performed to estimate the overall uncertainty of model results. Results The addition of intraarterial therapy compared with standard treatment alone yielded a lifetime gain of 0.7 QALY for an additional cost of $9,911, which resulted in a cost of $14,137 per QALY. Multivariable sensitivity analysis predicted cost-effectiveness (≤$50,000 per QALY) in 97.6% of simulation runs. Conclusion Intraarterial treatment after IV tPA for patients with anterior circulation strokes within the 6 hour window is likely cost effective. From a societal perspective, increased investment in access to intraarterial treatment for acute stroke may be justified. PMID:26012639

  20. Current perspectives on the use of intravenous recombinant tissue plasminogen activator (tPA) for treatment of acute ischemic stroke

    PubMed Central

    Chapman, Sherita N; Mehndiratta, Prachi; Johansen, Michelle C; McMurry, Timothy L; Johnston, Karen C; Southerland, Andrew M

    2014-01-01

    In 1995, the NINDS (National Institute of Neurological Disorders and Stroke) tPA (tissue plasminogen activator) Stroke Study Group published the results of a large multicenter clinical trial demonstrating efficacy of intravenous tPA by revealing a 30% relative risk reduction (absolute risk reduction 11%–15%) compared with placebo at 90 days in the likelihood of having minimal or no disability. Since approval in 1996, tPA remains the only drug treatment for acute ischemic stroke approved by the US Food and Drug Administration. Over the years, an abundance of research and clinical data has supported the safe and efficacious use of intravenous tPA in all eligible patients. Despite such supporting data, it remains substantially underutilized. Challenges to the utilization of tPA include narrow eligibility and treatment windows, risk of symptomatic intracerebral hemorrhage, perceived lack of efficacy in certain high-risk subgroups, and a limited pool of neurological and stroke expertise in the community. With recent US census data suggesting annual stroke incidence will more than double by 2050, better education and consensus among both the medical and lay public are necessary to optimize the use of tPA for all eligible stroke patients. Ongoing and future research should continue to improve upon the efficacy of tPA through more rapid stroke diagnosis and treatment, refinement of advanced neuroimaging and stroke biomarkers, and successful demonstration of alternative means of reperfusion. PMID:24591838

  1. Not just the brain: methamphetamine disrupts blood-spinal cord barrier and induces acute glial activation and structural damage of spinal cord cells.

    PubMed

    Kiyatkin, Eugene A; Sharma, Hari S

    2015-01-01

    Acute methamphetamine (METH) intoxication induces metabolic brain activation as well as multiple physiological and behavioral responses that could result in life-threatening health complications. Previously, we showed that METH (9 mg/kg) used in freely moving rats induces robust leakage of blood-brain barrier, acute glial activation, vasogenic edema, and structural abnormalities of brain cells. These changes were tightly correlated with drug-induced brain hyperthermia and were greatly potentiated when METH was used at warm ambient temperatures (29°C), inducing more robust and prolonged hyperthermia. Extending this line of research, here we show that METH also strongly increases the permeability of the blood-spinal cord barrier as evidenced by entry of Evans blue and albumin immunoreactivity in T9-12 segments of the spinal cord. Similar to the blood-brain barrier, leakage of bloodspinal cord barrier was associated with acute glial activation, alterations of ionic homeostasis, water tissue accumulation (edema), and structural abnormalities of spinal cord cells. Similar to that in the brain, all neurochemical alterations correlated tightly with drug-induced elevations in brain temperature and they were enhanced when the drug was used at 29°C and brain hyperthermia reached pathological levels (>40°C). We discuss common features and differences in neural responses between the brain and spinal cord, two inseparable parts of the central nervous system affected by METH exposure. PMID:25687701

  2. Not just the brain: methamphetamine disrupts blood-spinal cord barrier and induces acute glial activation and structural damage of spinal cord cells.

    PubMed

    Kiyatkin, Eugene A; Sharma, Hari S

    2015-01-01

    Acute methamphetamine (METH) intoxication induces metabolic brain activation as well as multiple physiological and behavioral responses that could result in life-threatening health complications. Previously, we showed that METH (9 mg/kg) used in freely moving rats induces robust leakage of blood-brain barrier, acute glial activation, vasogenic edema, and structural abnormalities of brain cells. These changes were tightly correlated with drug-induced brain hyperthermia and were greatly potentiated when METH was used at warm ambient temperatures (29°C), inducing more robust and prolonged hyperthermia. Extending this line of research, here we show that METH also strongly increases the permeability of the blood-spinal cord barrier as evidenced by entry of Evans blue and albumin immunoreactivity in T9-12 segments of the spinal cord. Similar to the blood-brain barrier, leakage of bloodspinal cord barrier was associated with acute glial activation, alterations of ionic homeostasis, water tissue accumulation (edema), and structural abnormalities of spinal cord cells. Similar to that in the brain, all neurochemical alterations correlated tightly with drug-induced elevations in brain temperature and they were enhanced when the drug was used at 29°C and brain hyperthermia reached pathological levels (>40°C). We discuss common features and differences in neural responses between the brain and spinal cord, two inseparable parts of the central nervous system affected by METH exposure.

  3. The involvement of oxidative stress in the mechanisms of damaging cadmium action in bone tissue: A study in a rat model of moderate and relatively high human exposure

    SciTech Connect

    Brzoska, Malgorzata M. Rogalska, Joanna; Kupraszewicz, Elzbieta

    2011-02-01

    It was investigated whether cadmium (Cd) may induce oxidative stress in the bone tissue in vivo and in this way contribute to skeleton damage. Total antioxidative status (TAS), antioxidative enzymes (glutathione peroxidase, superoxide dismutase, catalase), total oxidative status (TOS), hydrogen peroxide (H{sub 2}O{sub 2}), lipid peroxides (LPO), total thiol groups (TSH) and protein carbonyl groups (PC) as well as Cd in the bone tissue at the distal femoral epiphysis and femoral diaphysis of the male rats that received drinking water containing 0, 5, or 50 mg Cd/l for 6 months were measured. Cd, depending on the level of exposure and bone location, decreased the bone antioxidative capacity and enhanced its oxidative status resulting in oxidative stress and oxidative protein and/or lipid modification. The treatment with 5 and 50 mg Cd/l decreased TAS and activities of antioxidative enzymes as well as increased TOS and concentrations of H{sub 2}O{sub 2} and PC at the distal femur. Moreover, at the higher exposure, the concentration of LPO increased and that of TSH decreased. The Cd-induced changes in the oxidative/antioxidative balance of the femoral diaphysis, abundant in cortical bone, were less advanced than at the distal femur, where trabecular bone predominates. The results provide evidence that, even moderate, exposure to Cd induces oxidative stress and oxidative modifications in the bone tissue. Numerous correlations noted between the indices of oxidative/antioxidative bone status, and Cd accumulation in the bone tissue as well as indices of bone turnover and bone mineral status, recently reported by us (Toxicology 2007, 237, 89-103) in these rats, allow for the hypothesis that oxidative stress is involved in the mechanisms of damaging Cd action in the skeleton. The paper is the first report from an in vivo study indicating that Cd may affect bone tissue through disorders in its oxidative/antioxidative balance resulting in oxidative stress.

  4. Effect of L-arginine and L-NAME on Kidney Tissue Damage in Rats after 24 h of Bilateral Ureteral Obstruction

    PubMed Central

    Tirani, Shahnaz Amani; Pezeshki, Zahra; Nematbakhsh, Mehdi; Nasri, Hamid; Talebi, Ardeshir

    2015-01-01

    Background: Bilateral ureteral obstruction (BUO) affects renal function adversely. Previous investigations have implied that nitric oxide (NO) improves renal function in obstructive nephropathy. The aim of the current study was to investigate the role of NO precursor, L-arginine, and NO blocker agent, L-NAME on kidney tissue damage in rats after 24 h of BUO. Methods: Forty Wistar rats (18 male, 22 female) were divided into four groups as follows; group 1: Sham or negative control group that received saline 3 days prior to the sham operation, group 2: Vehicle or positive control group that received saline 3 days prior to BUO, and groups 3 and 4: L-arginine and L-NAME groups that were treated same as group 2 except L-arginine (300 mg/kg) and L-NAME (4 mg/kg) instead of saline, respectively. Twenty-four hours after obstruction, the serum levels of blood urea nitrogen (BUN), creatinine (Cr), nitrite, and malondialdehyde (MDA) as well as kidney tissue levels of nitrite and MDA were measured and histopathological studies were done on left kidney. Results: The serum levels of BUN and Cr and kidney and body weights increased and the tissue levels of MDA and nitrite decreased significantly in all BUO groups (P < 0.05). However, the tissue damage score was significantly lower in the L-arginine treated group in comparison to the vehicle and L-NAME groups (P < 0.05). As expected, the serum level of nitrite significantly increased in the L-arginine group (P < 0.05). Conclusions: Endogenous NO donor; L-arginine, may protect the kidney tissue against BUO. However, this renoprotective role of L-arginine did not attenuate the increased kidney function markers (BUN and Cr) induced by obstruction. PMID:26288704

  5. Chilling-related cell damage of apple (Malus × domestica Borkh.) fruit cortical tissue impacts antioxidant, lipid and phenolic metabolism.

    PubMed

    Leisso, Rachel S; Buchanan, David A; Lee, Jinwook; Mattheis, James P; Sater, Chris; Hanrahan, Ines; Watkins, Christopher B; Gapper, Nigel; Johnston, Jason W; Schaffer, Robert J; Hertog, Maarten L A T M; Nicolaï, Bart M; Rudell, David R

    2015-02-01

    'Soggy breakdown' (SB) is an internal flesh disorder of 'Honeycrisp' apple (Malus × domestica Borkh.) fruit that occurs during low temperature storage. The disorder is a chilling injury (CI) in which visible symptoms typically appear after several weeks of storage, but information about the underlying metabolism associated with its induction and development is lacking. The metabolic profile of flesh tissue from wholly healthy fruit and brown and healthy tissues from fruit with SB was characterized using gas chromatography-mass spectrometry (GC-MS) and liquid chromatograph-mass spectrometry (LC-MS). Partial least squares discriminant analysis (PLS-DA) and correlation networks revealed correlation among ester volatile compounds by composition and differences in phytosterol, phenolic and putative triacylglycerides (TAGs) metabolism among the tissues. anova-simultaneous component analysis (ASCA) was used to test the significance of metabolic changes linked with tissue health status. ASCA-significant components included antioxidant compounds, TAGs, and phytosterol conjugates. Relative to entirely healthy tissues, elevated metabolite levels in symptomatic tissue included γ-amino butyric acid, glycerol, sitosteryl (6'-O-palmitoyl) β-d-glucoside and sitosteryl (6'-O-stearate) β-d-glucoside, and TAGs containing combinations of 16:0, 18:3, 18:2 and 18:1 fatty acids. Reduced metabolite levels in SB tissue included 5-caffeoyl quinate, β-carotene, catechin, epicatechin, α-tocopherol, violaxanthin and sitosteryl β-d glucoside. Pathway analysis indicated aspects of primary metabolism differed according to tissue condition, although differences in metabolites involved were more subtle than those of some secondary metabolites. The results implicate oxidative stress and membrane disruption processes in SB development and constitute a diagnostic metabolic profile for the disorder.

  6. Chilling-related cell damage of apple (Malus × domestica Borkh.) fruit cortical tissue impacts antioxidant, lipid and phenolic metabolism.

    PubMed

    Leisso, Rachel S; Buchanan, David A; Lee, Jinwook; Mattheis, James P; Sater, Chris; Hanrahan, Ines; Watkins, Christopher B; Gapper, Nigel; Johnston, Jason W; Schaffer, Robert J; Hertog, Maarten L A T M; Nicolaï, Bart M; Rudell, David R

    2015-02-01

    'Soggy breakdown' (SB) is an internal flesh disorder of 'Honeycrisp' apple (Malus × domestica Borkh.) fruit that occurs during low temperature storage. The disorder is a chilling injury (CI) in which visible symptoms typically appear after several weeks of storage, but information about the underlying metabolism associated with its induction and development is lacking. The metabolic profile of flesh tissue from wholly healthy fruit and brown and healthy tissues from fruit with SB was characterized using gas chromatography-mass spectrometry (GC-MS) and liquid chromatograph-mass spectrometry (LC-MS). Partial least squares discriminant analysis (PLS-DA) and correlation networks revealed correlation among ester volatile compounds by composition and differences in phytosterol, phenolic and putative triacylglycerides (TAGs) metabolism among the tissues. anova-simultaneous component analysis (ASCA) was used to test the significance of metabolic changes linked with tissue health status. ASCA-significant components included antioxidant compounds, TAGs, and phytosterol conjugates. Relative to entirely healthy tissues, elevated metabolite levels in symptomatic tissue included γ-amino butyric acid, glycerol, sitosteryl (6'-O-palmitoyl) β-d-glucoside and sitosteryl (6'-O-stearate) β-d-glucoside, and TAGs containing combinations of 16:0, 18:3, 18:2 and 18:1 fatty acids. Reduced metabolite levels in SB tissue included 5-caffeoyl quinate, β-carotene, catechin, epicatechin, α-tocopherol, violaxanthin and sitosteryl β-d glucoside. Pathway analysis indicated aspects of primary metabolism differed according to tissue condition, although differences in metabolites involved were more subtle than those of some secondary metabolites. The results implicate oxidative stress and membrane disruption processes in SB development and constitute a diagnostic metabolic profile for the disorder. PMID:24944043

  7. Accumulation of DNA damage-induced chromatin alterations in tissue-specific stem cells: the driving force of aging?

    PubMed

    Schuler, Nadine; Rübe, Claudia E

    2013-01-01

    Accumulation of DNA damage leading to stem cell exhaustion has been proposed to be a principal mechanism of aging. Using 53BP1-foci as a marker for DNA double-strand breaks (DSBs), hair follicle stem cells (HFSCs) in mouse epidermis were analyzed for age-related DNA damage response (DDR). We observed increasing amounts of 53BP1-foci during the natural aging process independent of telomere shortening and after protracted low-dose radiation, suggesting substantial accumulation of DSBs in HFSCs. Electron microscopy combined with immunogold-labeling showed multiple small 53BP1 clusters diffusely distributed throughout the highly compacted heterochromatin of aged HFSCs, but single large 53BP1 clusters in irradiated HFSCs. These remaining 53BP1 clusters did not colocalize with core components of non-homologous end-joining, but with heterochromatic histone modifications. Based on these results we hypothesize that these lesions were not persistently unrepaired DSBs, but may reflect chromatin rearrangements caused by the repair or misrepair of DSBs. Flow cytometry showed increased activation of repair proteins and damage-induced chromatin modifications, triggering apoptosis and cellular senescence in irradiated, but not in aged HFSCs. These results suggest that accumulation of DNA damage-induced chromatin alterations, whose structural dimensions reflect the complexity of the initial genotoxic insult, may lead to different DDR events, ultimately determining the biological outcome of HFSCs. Collectively, our findings support the hypothesis that aging might be largely the remit of structural changes to chromatin potentially leading to epigenetically induced transcriptional deregulation.

  8. Bacteriological studies of blood, tissue fluid, lymph and lymph nodes in patients with acute dermatolymphangioadenitis (DLA) in course of 'filarial' lymphedema.

    PubMed

    Olszewski, W L; Jamal, S; Manokaran, G; Pani, S; Kumaraswami, V; Kubicka, U; Lukomska, B; Tripathi, F M; Swoboda, E; Meisel-Mikolajczyk, F; Stelmach, E; Zaleska, M

    1999-10-15

    Filarial lymphedema is complicated by frequent episodes of dermatolymphangioadenitis (DLA). Severe systemic symptoms during attacks of DLA resemble those of septicemia. The question we asked was whether bacterial isolates can be found in the peripheral blood of patients during the episodes of DLA. Out of 100 patients referred to us with 'filarial' lymphedema 14 displayed acute and five subacute symptoms of DLA. All were on admission blood microfilariae negative but had a positive test in the past. Blood bacterial isolates were found in nine cases, four acute (21%) and five subacute (26%). In 10 acute cases blood cultures were found negative. Six blood isolates belonged to Bacilli, four to Cocci and one was Sarcina. To identify the sites of origin of bacterial dissemination, swabs taken from the calf skin biopsy wounds and tissue fluid, lymph and lymph node specimens were cultured. Swabs from the calf skin biopsy wound contained isolates in nine (47%) cases. They were Bacilli in nine, Cocci in three, Acinetobacter and Erwinia in two cases. Tissue fluid was collected from 10 patients and contained Bacilli in four (40%) and Staphylococci in three (30%). Lymph was drained in four patients and contained isolates in all samples (100%). They were Staphylococcus epidermis, xylosus and aureus, Acinetobacter, Bacillus subtilis and Sarcina. Three lymph nodes were biopsied and contained Staphylococcus chromogenes, xylosus, Enterococcus and Bacillus cereus. In six cases the same phenotypically defined species of bacteria were found in blood and limb tissues or fluids. In the 'control' group of patients with lymphedema without acute or subacute changes all blood cultures were negative. Interestingly, swabs from biopsy wound of these patients contained isolates in 80%, tissue fluid in 68%, lymph in 70% and lymph nodes in 58% of cases. In healthy controls, tissue fluid did not contain bacteria, and lymph isolates were found only in 12% of cases. This study demonstrates that

  9. Iron-sulfur cluster damage by the superoxide radical in neural tissues of the SOD1(G93A) ALS rat model.

    PubMed

    Popović-Bijelić, Ana; Mojović, Miloš; Stamenković, Stefan; Jovanović, Miloš; Selaković, Vesna; Andjus, Pavle; Bačić, Goran

    2016-07-01

    Extensive clinical investigations, in hand with biochemical and biophysical research, have associated brain iron accumulation with the pathogenesis of the amyotrophic lateral sclerosis (ALS) disease. The origin of iron is still not identified, but it is proposed that it forms redox active complexes that can participate in the Fenton reaction generating the toxic hydroxyl radical. In this paper, the state of iron in the neural tissues isolated from SOD1(G93A) transgenic rats was investigated using low temperature EPR spectroscopy and is compared with that of nontransgenic (NTg) littermates. The results showed that iron in neural tissues is present as high- and low-spin, heme and non-heme iron. It appears that the SOD1(G93A) rat neural tissues were most likely exposed in vivo to higher amounts of reactive oxygen species when compared to the corresponding NTg tissues, as they showed increased oxidized [3Fe-4S](1+) cluster content relative to [4Fe-4S](1+). Also, the activity of cytochrome c oxidase (CcO) was found to be reduced in these tissues, which may be associated with the observed uncoupling of heme a3 Fe and CuB in the O2-reduction site of the enzyme. Furthermore, the SOD1(G93A) rat spinal cords and brainstems contained more manganese, presumably from MnSOD, than those of NTg rats. The addition of potassium superoxide to all neural tissues ex vivo, led to the [4Fe-4S]→[3Fe-4S] cluster conversion and concurrent release of Fe. These results suggest that the superoxide anion may be the cause of the observed oxidative damage to SOD1(G93A) rat neural tissues and that the iron-sulfur clusters may be the source of poorly liganded redox active iron implicated in ALS pathogenesis. Low temperature EPR spectroscopy appears to be a valuable tool in assessing the role of metals in neurodegenerative diseases.

  10. Protective Effect of Proteinase-Activated Receptor 2 Activation on Motility Impairment and Tissue Damage Induced by Intestinal Ischemia/Reperfusion in Rodents

    PubMed Central

    Cattaruzza, Fiore; Cenac, Nicolas; Barocelli, Elisabetta; Impicciatore, Mariannina; Hyun, Eric; Vergnolle, Nathalie; Sternini, Catia

    2006-01-01

    We hypothesized that proteinase-activated receptor-2 (PAR2) modulates intestinal injuries induced by ischemia/reperfusion. Ischemia (1 hour) plus reperfusion (6 hours) significantly delayed gastrointestinal transit (GIT) compared with sham operation. Intraduodenal injection of PAR2-activating peptide SLIGRL-NH2 significantly accelerated transit in ischemia/reperfusion but not in sham-operated rats. GIT was significantly delayed in ischemia/reperfusion and sham-operated PAR2−/− mice compared with PAR2+/+. SLIGRL-NH2 significantly accelerated transit in ischemia/reperfusion in PAR2+/+ but not in PAR2−/− mice. Prevention of mast cell degranulation with cromolyn, ablation of visceral afferents with capsaicin, and antagonism of calcitonin gene-related peptide (CGRP) and neurokinin-1 receptors with CGRP8–37 and RP67580, respectively, abolished the SLIGRL-NH2-induced stimulatory effect on transit in ischemia/reperfusion. Tissue damage was significantly reduced by SLIGRL-NH2; this effect was not observed in cromolyn-, capsaicin-, or RP67580-treated rats but was detected following CGRP8–37. Intestinal PAR2 mRNA levels were not affected by SLIGRL-NH2 in ischemia/reperfusion. We propose that PAR2 modulates GIT and tissue damage in intestinal ischemia/reperfusion by a mechanism dependent on mast cells and visceral afferents. PAR2 effect on transit might be mediated by CGRP and substance P, whereas the effect on tissue damage appears to involve substance P but not CGRP. PAR2 might be a signaling system in the neuroimmune communication in intestinal ischemia/reperfusion. PMID:16816371

  11. In-vivo optical imaging of hsp70 expression to assess collateral tissue damage associated with infrared laser ablation of skin

    PubMed Central

    Wilmink, Gerald J.; Opalenik, Susan R.; Beckham, Joshua T.; Mackanos, Mark A.; Nanney, Lillian B.; Contag, Christopher H.; Davidson, Jeffrey M.; Jansen, E. Duco

    2013-01-01

    Laser surgical ablation is achieved by selecting laser parameters that remove confined volumes of target tissue and cause minimal collateral damage. Previous studies have measured the effects of wavelength on ablation, but neglected to measure the cellular impact of ablation on cells outside the lethal zone. In this study, we use optical imaging in addition to conventional assessment techniques to evaluate lethal and sublethal collateral damage after ablative surgery with a free-electron laser (FEL). Heat shock protein (HSP) expression is used as a sensitive quantitative marker of sublethal damage in a transgenic mouse strain, with the hsp70 promoter driving luciferase and green fluorescent protein (GFP) expression (hsp70A1-L2G). To examine the wavelength dependence in the mid-IR, laser surgery is conducted on the hsp70A1-L2G mouse using wavelengths targeting water (OH stretch mode, 2.94 μm), protein (amide-II band, 6.45 μm), and both water and protein (amide-I band, 6.10 μm). For all wavelengths tested, the magnitude of hsp70 expression is dose-dependent and maximal 5 to 12 h after surgery. Tissues treated at 6.45 μm have approximately 4× higher hsp70 expression than 6.10 μm. Histology shows that under comparable fluences, tissue injury at the 2.94-μm wavelength was 2× and 3× deeper than 6.45 and 6.10 μm, respectively. The 6.10-μm wavelength generates the least amount of epidermal hyperplasia. Taken together, this data suggests that the 6.10-μm wavelength is a superior wavelength for laser ablation of skin. PMID:19021444

  12. Acute exacerbations of fibrotic interstitial lung disease.

    PubMed

    Churg, Andrew; Wright, Joanne L; Tazelaar, Henry D

    2011-03-01

    An acute exacerbation is the development of acute lung injury, usually resulting in acute respiratory distress syndrome, in a patient with a pre-existing fibrosing interstitial pneumonia. By definition, acute exacerbations are not caused by infection, heart failure, aspiration or drug reaction. Most patients with acute exacerbations have underlying usual interstitial pneumonia, either idiopathic or in association with a connective tissue disease, but the same process has been reported in patients with fibrotic non-specific interstitial pneumonia, fibrotic hypersensitivity pneumonitis, desquamative interstitial pneumonia and asbestosis. Occasionally an acute exacerbation is the initial manifestation of underlying interstitial lung disease. On biopsy, acute exacerbations appear as diffuse alveolar damage or bronchiolitis obliterans organizing pneumonia (BOOP) superimposed upon the fibrosing interstitial pneumonia. Biopsies may be extremely confusing, because the acute injury pattern can completely obscure the underlying disease; a useful clue is that diffuse alveolar damage and organizing pneumonia should not be associated with old dense fibrosis and peripheral honeycomb change. Consultation with radiology can also be extremely helpful, because the fibrosing disease may be evident on old or concurrent computed tomography scans. The aetiology of acute exacerbations is unknown, and the prognosis is poor; however, some patients survive with high-dose steroid therapy.

  13. Protective effect of green tea on lead-induced oxidative damage in rat's blood and brain tissue homogenates.

    PubMed

    Hamed, Enas A; Meki, Abdel-Raheim M A; Abd El-Mottaleb, Nashwa A

    2010-06-01

    Recent studies have shown that lead (Pb) could disrupt tissue prooxidant/antioxidant balance which lead to physiological dysfunction. Natural antioxidants are particularly useful in such situation. Current study was designed to investigate efficacy of green tea extract (GTE), on oxidative status in brain tissue and blood caused by chronic oral Pb administration in rats. Four groups of adult male rats (each 15 rats) were utilized: control group; GTE-group (oral 1.5% w/v GTE for 6 weeks); Pb-group (oral 0.4% lead acetate for 6 weeks), and Pb+GTE-group (1.5% GTE and 0.4% lead acetate for 6 weeks). Levels of prooxidant/antioxidant parameters [lipid peroxides (LPO), nitric oxides (NO), total antioxidant capacity (TAC), glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD)] in plasma, erythrocytes, and brain tissue homogenate were measured using colorimetric methods. Pb concentrations in whole blood and brain tissue homogenate were measured by atomic absorption. In Pb-group, levels of LPO were higher while NO and GSH were lower in plasma, erythrocytes, and brain tissue than controls. TAC in plasma, SOD in erythrocytes, and GST in brain tissue homogenate were lower in Pb-group versus control. GTE co-administrated with Pb-reduced Pb contents, increased antioxidant status than Pb-group. In erythrocytes, Pb correlated positively with LPO and negatively with NO, GSH, SOD, and Hb. In brain tissue homogenate, Pb correlated positively with LPO and negatively with GSH. This study suggests that lead induce toxicity by interfering balance between prooxidant/antioxidant. Treatment of rats with GTE combined with Pb enhances antioxidant/ detoxification system which reduced oxidative stress. These observations suggest that GTE is a potential complementary agent in treatment of chronic lead intoxication.

  14. Compensated overexpression of procollagens alpha 1(I) and alpha 1(III) following perilla mint ketone-induced acute pulmonary damage in horses.

    PubMed

    Schmidbauer, S-M; Venner, M; von Samson-Himmelstjerna, G; Drommer, W; Gruber, A D

    2004-01-01

    Interstitial lung disease with chronic fibrosis is a frequent cause of reduced performance in horses. The aim of this study was to establish a model of acute alveolar damage and interstitial lung disease in horses that could be used to monitor the histopathological lesions and changes in expression levels of genes relevant to pulmonary fibrosis. Six adult horses were given a single intravenous injection (6 mg per kg body weight) of perilla mint ketone (PMK). Transthoracic lung biopsy samples (1 x 0.2 x 0.2 cm) were collected before and after (days 1, 4, 8, 11, 15, 18, 22, 25 and 29) the administration of PMK. Light and electron microscopy revealed severe acute alveolar damage (days 1 to 4), proliferation of type II pneumocytes (days 4 to 11) and finally complete healing at about day 18. However, unexpectedly severe clinical signs necessitated euthanasia in two horses on days 9 and 11. The expression levels of the collagen genes COL1AI and COL3AI as well as transforming growth factor (TGF)-beta were examined in the biopsy samples by reverse transcription-real time quantitative polymerase chain reaction. COL1AI and COL3AI gene expressions were upregulated (3- and 17-fold, respectively) between days 1 and 29 in all six horses, whereas TGF-beta was upregulated in two horses (2- and 4-fold, respectively), between days 4 and 18. Although the gene expression analyses indicated a strong activation of the pro-fibrotic pathway, no interstitial fibrosis was seen in any horse. A complete necropsy performed on day 60 revealed complete recovery of the lungs of the four surviving horses, with no evidence of fibrosis. Unidentified compensatory mechanisms may have prevented pulmonary fibrosis, despite strong upregulation of pro-fibrotic genes.

  15. Organ Damage and Quality of Life in Antiphospholipid Syndrome.

    PubMed

    Alba, P; Gómez-Puerta, J A; Goycochea-Robles, M V; Amigo, M C

    2016-02-01

    Antiphospholipid syndrome (APS) affects young patients in the most productive years of their life, and the consequences of organic or tissue damage involve a decrease in health-related quality of life (HRQoL). While acute disease manifestations of APS are well known, information on the long-term prognosis and damage in affected patients is still very limited. Systemic lupus erythematosus (SLE) patients would be expected to experience long-term complications and even die as a consequence of APS. Organ damage in APS has been evaluated using different methods and definitions, including the SLICC/ACR Damage Index (SDI), which tend to underestimate aPL-related damage. A new damage index in APS has been proposed (DIAPS), and it seems to be more accurate than SDI. Given the implications for morbidity and mortality, it is imperative to assess accurately aPL-related damage and HRQoL in patients with APS.

  16. The Effects of Xiangqing Anodyne Spray on Treating Acute Soft-Tissue Injury Mainly Depend on Suppressing Activations of AKT and p38 Pathways

    PubMed Central

    Wang, Shudong; Li, Tao; Qu, Wei; Li, Xin; Ma, Shaoxin; Wang, Zheng; Liu, Wenya; Hou, Shanshan; Fu, Jihua

    2016-01-01

    Objectives. In the present study we try to elucidate the mechanism of Xiangqing anodyne spray (XQAS) effects on acute soft-tissue injury (STI). Methods. Acute STI model was established by hammer blow in the rat hind leg muscle. Within 8 hours, instantly after modeling and per 2-hour interval repeated topical applications with or without XQAS, CP or IH ethanol extracts spray (CPS and IHS) were performed, respectively; muscle swelling rate and inflammation-related biochemical parameters, muscle histological observation, and mRNA and protein expression were then examined. Results. XQAS dose-dependently suppressed STI-caused muscle swelling, proinflammatory mediator productions, and oxidative stress as well as severe pathological changes in the injured muscle tissue. Moreover, CPS mainly by blocking p38 activation while IHS majorly by blocking AKT activation led to cytoplastic IκBα degradation with NF-κB p65 translocated into the nucleus. There are synergistic effects between CP and IH components in the XQAS on preventing from acute STI with suppressing IκBα degradation, NF-κB p65 translocation, and subsequent inflammation and oxidative stress-related abnormality. Conclusion. Marked effects of XQAS on treating acute STI are ascribed to strong anti-inflammatory and antioxidative actions with a reasonable combination of CP active components, blocking p38-NF-κB pathway activated, and IH active components, blocking AKT-NF-κB pathway activated. PMID:27190541

  17. Chronic Neuropsychological Sequelae of Cholinesterase Inhibitors in the Absence of Structural Brain Damage: Two Cases of Acute Poisoning

    PubMed Central

    Roldán-Tapia, Lola; Leyva, Antonia; Laynez, Francisco; Santed, Fernando Sánchez

    2005-01-01

    Here we describe two cases of carbamate poisoning. Patients AMF and PVM were accidentally poisoned by cholinesterase inhibitors. The medical diagnosis in both cases was overcholinergic syndrome, as demonstrated by exposure to cholinesterase inhibitors. The widespread use of cholinesterase inhibitors, especially as pesticides, produces a great number of human poisoning events annually. The main known neurotoxic effect of these substances is cholinesterase inhibition, which causes cholinergic overstimulation. Once AMF and PVM had recovered from acute intoxication, they were subjected to extensive neuropsychological evaluation 3 and 12 months after the poisoning event. These assessments point to a cognitive deficit in attention, memory, perceptual, and motor domains 3 months after intoxication. One year later these sequelae remained, even though the brain magnetic resonance imaging (MRI) and computed tomography (CT) scans were interpreted as being within normal limits. We present these cases as examples of neuropsychological profiles of long-term sequelae related to acute poisoning by cholinesterase inhibitor pesticides and show the usefulness of neuropsychological assessment in detecting central nervous system dysfunction in the absence of biochemical or structural markers. PMID:15929901

  18. The Role of Inspiratory Muscle Training in Sickle Cell Anemia Related Pulmonary Damage due to Recurrent Acute Chest Syndrome Attacks

    PubMed Central

    Camcıoğlu, Burcu; Boşnak-Güçlü, Meral; Karadallı, Müşerrefe Nur; Akı, Şahika Zeynep; Türköz-Sucak, Gülsan

    2015-01-01

    Background. The sickling of red blood cells causes a constellation of musculoskeletal, cardiovascular, and pulmonary manifestations. A 32-year-old gentleman with sickle cell anemia (SCA) had been suffering from recurrent acute chest syndrome (ACS). Aim. To examine the effects of inspiratory muscle training (IMT) on pulmonary functions, respiratory and peripheral muscle strength, functional exercise capacity, and quality of life in this patient with SCA. Methods. Functional exercise capacity was evaluated using six-minute walk test, respiratory muscle strength using mouth pressure device, hand grip strength using hand-held dynamometer, pain using Visual Analogue Scale, fatigue using Fatigue Severity Scale, dyspnea using Modified Medical Research Council Scale, and health related quality of life using European Organization for Research and Treatment of Cancer QOL measurement. Results. A significant improvement has been demonstrated in respiratory muscle strength, functional exercise capacity, pain, fatigue, dyspnea, and quality of life. There was no admission to emergency department due to acute chest syndrome in the following 12 months after commencing regular erythrocytapheresis. Conclusion. This is the first report demonstrating the beneficial effects of inspiratory muscle training on functional exercise capacity, respiratory muscle strength, pain, fatigue, dyspnea, and quality of life in a patient with recurrent ACS. PMID:26060589

  19. The Role of Inspiratory Muscle Training in Sickle Cell Anemia Related Pulmonary Damage due to Recurrent Acute Chest Syndrome Attacks.

    PubMed

    Camcıoğlu, Burcu; Boşnak-Güçlü, Meral; Karadallı, Müşerrefe Nur; Akı, Şahika Zeynep; Türköz-Sucak, Gülsan

    2015-01-01

    Background. The sickling of red blood cells causes a constellation of musculoskeletal, cardiovascular, and pulmonary manifestations. A 32-year-old gentleman with sickle cell anemia (SCA) had been suffering from recurrent acute chest syndrome (ACS). Aim. To examine the effects of inspiratory muscle training (IMT) on pulmonary functions, respiratory and peripheral muscle strength, functional exercise capacity, and quality of life in this patient with SCA. Methods. Functional exercise capacity was evaluated using six-minute walk test, respiratory muscle strength using mouth pressure device, hand grip strength using hand-held dynamometer, pain using Visual Analogue Scale, fatigue using Fatigue Severity Scale, dyspnea using Modified Medical Research Council Scale, and health related quality of life using European Organization for Research and Treatment of Cancer QOL measurement. Results. A significant improvement has been demonstrated in respiratory muscle strength, functional exercise capacity, pain, fatigue, dyspnea, and quality of life. There was no admission to emergency department due to acute chest syndrome in the following 12 months after commencing regular erythrocytapheresis. Conclusion. This is the first report demonstrating the beneficial effects of inspiratory muscle training on functional exercise capacity, respiratory muscle strength, pain, fatigue, dyspnea, and quality of life in a patient with recurrent ACS. PMID:26060589

  20. Cell kinetics during regeneration in the sponge Halisarca caerulea: how local is the response to tissue damage?

    PubMed Central

    Achlatis, Michelle; Osinga, Ronald; van der Geest, Harm G.; Cleutjens, Jack P.M.; Schutte, Bert; de Goeij, Jasper M.

    2015-01-01

    Sponges have a remarkable capacity to rapidly regenerate in response to wound infliction. In addition, sponges rapidly renew their filter systems (choanocytes) to maintain a healthy population of cells. This study describes the cell kinetics of choanocytes in the encrusting reef sponge Halisarca caerulea during early regeneration (0–8 h) following experimental wound infliction. Subsequently, we investigated the spatial relationship between regeneration and cell proliferation over a six-day period directly adjacent to the wound, 1 cm, and 3 cm from the wound. Cell proliferation was determined by the incorporation of 5-bromo-2′-deoxyuridine (BrdU). We demonstrate that during early regeneration, the growth fraction of the choanocytes (i.e., the percentage of proliferative cells) adjacent to the wound is reduced (7.0 ± 2.5%) compared to steady-state, undamaged tissue (46.6 ± 2.6%), while the length of the cell cycle remained short (5.6 ± 3.4 h). The percentage of proliferative choanocytes increased over time in all areas and after six days of regeneration choanocyte proliferation rates were comparable to steady-state tissue. Tissue areas farther from the wound had higher rates of choanocyte proliferation than areas closer to the wound, indicating that more resources are demanded from tissue in the immediate vicinity of the wound. There was no difference in the number of proliferative mesohyl cells in regenerative sponges compared to steady-state sponges. Our data suggest that the production of collagen-rich wound tissue is a key process in tissue regeneration for H. caerulea, and helps to rapidly occupy the bare substratum exposed by the wound. Regeneration and choanocyte renewal are competing and negatively correlated life-history traits, both essential to the survival of sponges. The efficient allocation of limited resources to these life-history traits has enabled the ecological success and diversification of sponges. PMID:25780772

  1. Sitting can cause ischaemia in the subcutaneous tissue of the buttocks, which implicates multilayer tissue damage in the development of pressure ulcers.

    PubMed

    Thorfinn, Johan; Sjoberg, Folke; Lidman, Disa

    2009-01-01

    A better understanding of how pressure ulcers develop in the buttocks will improve prophylactic measures. Our aim was to investigate signs of reduced perfusion and ischaemia in the subcutaneous fat in the buttocks during sitting. A microelectrode was used to quantify oxygen (pO(2)). Metabolites that indicate aerobic or anaerobic metabolism (glucose, lactate, pyruvate, and glycerol) were quantified using microdialysis. Sixteen healthy people were studied while they sat on a wheel chair cushion, and a hard surface. Sitting pressures were mapped, and the thickness of the subcutaneous fatty layer was measured. The results showed that pO(2) and glucose were significantly reduced during sitting, and for pO(2) the effect is significantly more profound during sitting on a hard surface. After loading, both glucose and pO(2) increased significantly. We conclude that the subcutaneous adipose tissue covering the ischial tuberosities becomes ischaemic during sitting. This finding supports the theory that not only is the skin involved in early development of pressure ulcers, but also the deeper tissues.

  2. Perception Versus Actual Performance in Timely Tissue Plasminogen Activation Administration in the Management of Acute Ischemic Stroke

    PubMed Central

    Lin, Cheryl B; Cox, Margueritte; Olson, DaiWai M; Britz, Gavin W; Constable, Mark; Fonarow, Gregg C; Schwamm, Lee; Peterson, Eric D; Shah, Bimal R

    2015-01-01

    Background Timely thrombolytic therapy can improve stroke outcomes. Nevertheless, the ability of US hospitals to meet guidelines for intravenous tissue plasminogen activator (tPA) remains suboptimal. What is unclear is whether hospitals accurately perceive their rate of tPA “door-to-needle” (DTN) time within 60 minutes and how DTN rates compare across different hospitals. Methods and Results DTN performance was defined by the percentage of treated patients who received tPA within 60 minutes of arrival. Telephone surveys were obtained from staff at 141 Get With The Guidelines hospitals, representing top, middle, and lowDTN performance. Less than one-third (29.1%) of staff accurately identified their DTN performance. Among middle- and low-performing hospitals (n=92), 56 sites (60.9%) overestimated their performance; 42% of middle performers and 85% of low performers overestimated their performance. Sites that overestimated tended to have lower annual volumes of tPA administration (median 8.4 patients [25th to 75th percentile 5.9 to 11.8] versus 10.2 patients [25th to 75th percentile 8.2 to 17.3], P=0.047), smaller percentages of eligible patients receiving tPA (84.7% versus 89.8%, P=0.008), and smaller percentages of DTN ≤60 minutes among treated patients (10.6% versus 16.6%, P=0.002). Conclusions Hospitals often overestimate their ability to deliver timely tPA to treated patients. Our findings indicate the need to routinely provide comparative provider performance rates as a key step to improving the quality of acute stroke care. PMID:26201547

  3. Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism

    PubMed Central

    Valencia, C. Alexander; Wang, Xinjian; Wang, Jin; Peters, Anna; Simmons, Julia R.; Moran, Molly C.; Mathur, Abhinav; Husami, Ammar; Qian, Yaping; Sheridan, Rachel; Bove, Kevin E.; Witte, David; Huang, Taosheng; Miethke, Alexander G.

    2016-01-01

    Background & Aims The etiology of acute liver failure (ALF) remains elusive in almost half of affected children. We hypothesized that inherited mitochondrial and fatty acid oxidation disorders were occult etiological factors in patients with idiopathic ALF and impaired energy metabolism. Methods Twelve patients with elevated blood molar lactate/pyruvate ratio and indeterminate etiology were selected from a retrospective cohort of 74 subjects with ALF because their fixed and frozen liver samples were available for histological, ultrastructural, molecular and biochemical analysis. Results A customized next-generation sequencing panel for 26 genes associated with mitochondrial and fatty acid oxidation defects revealed mutations and sequence variants in five subjects. Variants involved the genes ACAD9, POLG, POLG2, DGUOK, and RRM2B; the latter not previously reported in subjects with ALF. The explanted livers of the patients with heterozygous, truncating insertion mutations in RRM2B showed patchy micro- and macrovesicular steatosis, decreased mitochondrial DNA (mtDNA) content <30% of controls, and reduced respiratory chain complex activity; both patients had good post-transplant outcome. One infant with severe lactic acidosis was found to carry two heterozygous variants in ACAD9, which was associated with isolated complex I deficiency and diffuse hypergranular hepatocytes. The two subjects with heterozygous variants of unknown clinical significance in POLG and DGUOK developed ALF following drug exposure. Their hepatocytes displayed abnormal mitochondria by electron microscopy. Conclusion Targeted next generation sequencing and correlation with histological, ultrastructural and functional studies on liver tissue in children with elevated lactate/pyruvate ratio expand the spectrum of genes associated with pediatric ALF. PMID:27483465

  4. Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis.

    PubMed

    Strand, S; Hofmann, W J; Grambihler, A; Hug, H; Volkmann, M; Otto, G; Wesch, H; Mariani, S M; Hack, V; Stremmel, W; Krammer, P H; Galle, P R

    1998-05-01

    Wilson's disease can result in fulminant liver failure due to hepatic copper overload. The CD95 system mediates apoptosis and has been demonstrated to be involved in liver disease. In this study CD95 mediated apoptosis was investigated in patients with fulminant hepatic failure in the course of Wilson's disease and in an in vitro model of copper treated human hepatoma cells. In patients, hepatic expression of CD95 and CD95L mRNA and apoptosis were detected. Copper overload in vitro resulted in hepatocytic apoptosis which could be reduced with a neutralizing anti-CD95L antibody. Copper treatment of hepatocytes results in activation of the CD95 system and induction of apoptosis which is operative during the course of hepatic failure in acute Wilson's disease.

  5. Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats.

    PubMed

    King, Tristan J; Shandala, Tetyana; Lee, Alice M; Foster, Bruce K; Chen, Ke-Ming; Howe, Peter R; Xian, Cory J

    2015-08-06

    Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage.

  6. Malondialdehyde-derived epitopes in human skin result from acute exposure to solar UV and occur in nonmelanoma skin cancer tissue.

    PubMed

    Williams, Joshua D; Bermudez, Yira; Park, Sophia L; Stratton, Steven P; Uchida, Koji; Hurst, Craig A; Wondrak, Georg T

    2014-03-01

    Cutaneous exposure to solar ultraviolet radiation (UVR) is a causative factor in photoaging and photocarcinogenesis. In human skin, oxidative stress is widely considered a key mechanism underlying the detrimental effects of acute and chronic UVR exposure. The lipid peroxidation product malondialdehyde (MDA) accumulates in tissue under conditions of increased oxidative stress, and the occurrence of MDA-derived protein epitopes, including dihydropyridine-lysine (DHP), has recently been substantiated in human skin. Here we demonstrate for the first time that acute exposure to sub-apoptogenic doses of solar simulated UV light (SSL) causes the formation of free MDA and protein-bound MDA-derived epitopes in cultured human HaCaT keratinocytes and healthy human skin. Immunohistochemical staining revealed that acute exposure to SSL is sufficient to cause an almost twenty-fold increase in general MDA- and specific DHP-epitope content in human skin. When compared to dose-matched solar simulated UVA, complete SSL was more efficient generating both free MDA and MDA-derived epitopes. Subsequent tissue microarray (TMA) analysis revealed the prevalence of MDA- and DHP-epitopes in nonmelanoma skin cancer (NMSC). In squamous cell carcinoma tissue, both MDA- and DHP-epitopes were increased more than threefold as compared to adjacent normal tissue. Taken together, these date demonstrate the occurrence of MDA-derived epitopes in both solar UVR-exposed healthy human skin and NMSC TMA tissue; however, the potential utility of these epitopes as novel biomarkers of cutaneous photodamage and a functional role in the process of skin photocarcinogenesis remain to be explored.

  7. Histopathology of Incontinence-Associated Skin Lesions: Inner Tissue Damage Due to Invasion of Proteolytic Enzymes and Bacteria in Macerated Rat Skin

    PubMed Central

    Mugita, Yuko; Minematsu, Takeo; Huang, Lijuan; Nakagami, Gojiro; Kishi, Chihiro; Ichikawa, Yoshie; Nagase, Takashi; Oe, Makoto; Noguchi, Hiroshi; Mori, Taketoshi; Abe, Masatoshi; Sugama, Junko; Sanada, Hiromi

    2015-01-01

    A common complication in patients with incontinence is perineal skin lesions, which are recognized as a form of dermatitis. In these patients, perineal skin is exposed to digestive enzymes and intestinal bacterial flora, as well as excessive water. The relative contributions of digestive enzymes and intestinal bacterial flora to skin lesion formation have not been fully shown. This study was conducted to reveal the process of histopathological changes caused by proteases and bacterial inoculation in skin maceration. For skin maceration, agarose gel containing proteases was applied to the dorsal skin of male Sprague-Dawley rats for 4 h, followed by Pseudomonas aeruginosa inoculation for 30 min. Macroscopic changes, histological changes, bacterial distribution, inflammatory response, and keratinocyte proliferation and differentiation were examined. Proteases induced digestion in the prickle cell layer of the epidermis, and slight bleeding in the papillary dermis and around hair follicles in the macerated skin without macroscopic evidence of erosion. Bacterial inoculation of the skin macerated by proteolytic solution resulted in the formation of bacteria-rich clusters comprising numerous microorganisms and inflammatory cells within the papillary dermis, with remarkable tissue damage around the clusters. Tissue damage expanded by day 2. On day 3, the proliferative keratinocyte layer was elongated from the bulge region of the hair follicles. Application of proteases and P. aeruginosa induced skin lesion formation internally without macroscopic erosion of the overhydrated area, suggesting that the histopathology might be different from regular dermatitis. The healing process of this lesion is similar to transepidermal elimination. PMID:26407180

  8. Histopathology of Incontinence-Associated Skin Lesions: Inner Tissue Damage Due to Invasion of Proteolytic Enzymes and Bacteria in Macerated Rat Skin.

    PubMed

    Mugita, Yuko; Minematsu, Takeo; Huang, Lijuan; Nakagami, Gojiro; Kishi, Chihiro; Ichikawa, Yoshie; Nagase, Takashi; Oe, Makoto; Noguchi, Hiroshi; Mori, Taketoshi; Abe, Masatoshi; Sugama, Junko; Sanada, Hiromi

    2015-01-01

    A common complication in patients with incontinence is perineal skin lesions, which are recognized as a form of dermatitis. In these patients, perineal skin is exposed to digestive enzymes and intestinal bacterial flora, as well as excessive water. The relative contributions of digestive enzymes and intestinal bacterial flora to skin lesion formation have not been fully shown. This study was conducted to reveal the process of histopathological changes caused by proteases and bacterial inoculation in skin maceration. For skin maceration, agarose gel containing proteases was applied to the dorsal skin of male Sprague-Dawley rats for 4 h, followed by Pseudomonas aeruginosa inoculation for 30 min. Macroscopic changes, histological changes, bacterial distribution, inflammatory response, and keratinocyte proliferation and differentiation were examined. Proteases induced digestion in the prickle cell layer of the epidermis, and slight bleeding in the papillary dermis and around hair follicles in the macerated skin without macroscopic evidence of erosion. Bacterial inoculation of the skin macerated by proteolytic solution resulted in the formation of bacteria-rich clusters comprising numerous microorganisms and inflammatory cells within the papillary dermis, with remarkable tissue damage around the clusters. Tissue damage expanded by day 2. On day 3, the proliferative keratinocyte layer was elongated from the bulge region of the hair follicles. Application of proteases and P. aeruginosa induced skin lesion formation internally without macroscopic erosion of the overhydrated area, suggesting that the histopathology might be different from regular dermatitis. The healing process of this lesion is similar to transepidermal elimination. PMID:26407180

  9. Histopathology of Incontinence-Associated Skin Lesions: Inner Tissue Damage Due to Invasion of Proteolytic Enzymes and Bacteria in Macerated Rat Skin.

    PubMed

    Mugita, Yuko; Minematsu, Takeo; Huang, Lijuan; Nakagami, Gojiro; Kishi, Chihiro; Ichikawa, Yoshie; Nagase, Takashi; Oe, Makoto; Noguchi, Hiroshi; Mori, Taketoshi; Abe, Masatoshi; Sugama, Junko; Sanada, Hiromi

    2015-01-01

    A common complication in patients with incontinence is perineal skin lesions, which are recognized as a form of dermatitis. In these patients, perineal skin is exposed to digestive enzymes and intestinal bacterial flora, as well as excessive water. The relative contributions of digestive enzymes and intestinal bacterial flora to skin lesion formation have not been fully shown. This study was conducted to reveal the process of histopathological changes caused by proteases and bacterial inoculation in skin maceration. For skin maceration, agarose gel containing proteases was applied to the dorsal skin of male Sprague-Dawley rats for 4 h, followed by Pseudomonas aeruginosa inoculation for 30 min. Macroscopic changes, histological changes, bacterial distribution, inflammatory response, and keratinocyte proliferation and differentiation were examined. Proteases induced digestion in the prickle cell layer of the epidermis, and slight bleeding in the papillary dermis and around hair follicles in the macerated skin without macroscopic evidence of erosion. Bacterial inoculation of the skin macerated by proteolytic solution resulted in the formation of bacteria-rich clusters comprising numerous microorganisms and inflammatory cells within the papillary dermis, with remarkable tissue damage around the clusters. Tissue damage expanded by day 2. On day 3, the proliferative keratinocyte layer was elongated from the bulge region of the hair follicles. Application of proteases and P. aeruginosa induced skin lesion formation internally without macroscopic erosion of the overhydrated area, suggesting that the histopathology might be different from regular dermatitis. The healing process of this lesion is similar to transepidermal elimination.

  10. Dendritic cell-mediated vaccination relies on interleukin-4 receptor signaling to avoid tissue damage after Leishmania major infection of BALB/c mice.

    PubMed

    Masic, Anita; Hurdayal, Ramona; Nieuwenhuizen, Natalie E; Brombacher, Frank; Moll, Heidrun

    2012-01-01

    Prevention of tissue damages at the site of Leishmania major inoculation can be achieved if the BALB/c mice are systemically given L. major antigen (LmAg)-loaded bone marrow-derived dendritic cells (DC) that had been exposed to CpG-containing oligodeoxynucleotides (CpG ODN). As previous studies allowed establishing that interleukin-4 (IL-4) is involved in the redirection of the immune response towards a type 1 profile, we were interested in further exploring the role of IL-4. Thus, wild-type (wt) BALB/c mice or DC-specific IL-4 receptor alpha (IL-4Rα)-deficient (CD11c(cre)IL-4Rα(-/lox)) BALB/c mice were given either wt or IL-4Rα-deficient LmAg-loaded bone marrow-derived DC exposed or not to CpG ODN prior to inoculation of 2×10⁵ stationary-phase L. major promastigotes into the BALB/c footpad. The results provide evidence that IL4/IL-4Rα-mediated signaling in the vaccinating DC is required to prevent tissue damage at the site of L. major inoculation, as properly conditioned wt DC but not IL-4Rα-deficient DC were able to confer resistance. Furthermore, uncontrolled L. major population size expansion was observed in the footpad and the footpad draining lymph nodes of CD11c(cre)IL-4Rα(-/lox) mice immunized with CpG ODN-exposed LmAg-loaded IL-4Rα-deficient DC, indicating the influence of IL-4Rα-mediated signaling in host DC to control parasite replication. In addition, no footpad damage occurred in BALB/c mice that were systemically immunized with LmAg-loaded wt DC doubly exposed to CpG ODN and recombinant IL-4. We discuss these findings and suggest that the IL4/IL4Rα signaling pathway could be a key pathway to trigger when designing vaccines aimed to prevent damaging processes in tissues hosting intracellular microorganisms.

  11. A prospective strategy to restore the tissue damage in malaria infection: Approach with chitosan-trypolyphosphate conjugated nanochloroquine in Swiss mice.

    PubMed

    Tripathy, Satyajit; Das, Sabyasachi; Dash, Sandeep Kumar; Mahapatra, Santanu Kar; Chattopadhyay, Sourav; Majumdar, Subrata; Roy, Somenath

    2014-08-15

    Accumulating evidence indicates that wide range of polymer based nanoconjugated drug have the ability to overcome the microbial infection. The present study was to evaluate the effects of nanoconjugated chloroquine (Nch) against Plasmodium berghei NK65 (P. berghei) infection on selective makers of oxidative damage, antioxidant status, pro-inflammatory and anti-inflammatory cytokines in liver and spleen. P. berghei infected Swiss mice were treated with Nch (250mg/kg bw for 15 days) compared with chloroquine. The stress markers, pro-inflammatory cytokines were increased significantly (P<0.05) and the anti-oxidant enzymes level, redox ratio (GSH/GSSG), anti-inflammatory markers were decreased significantly (P<0.05) in liver and spleen of infected mice compared with uninfected mice. Chloroquine and Nch effectively decreased the stress markers, pro-inflammatory cytokines, as well as, increased antioxidants level in liver and spleen of the infected mice. Moreover, the favorable effect Nch is better than the chloroquine defending the tissue damage during malarial infection. These findings suggested that the potential use and prospective role of Nch than only chloroquine against P. berghei induced pathology as well as oxidative damage in liver and spleen.

  12. Effect of sample size on multi-parametric prediction of tissue outcome in acute ischemic stroke using a random forest classifier

    NASA Astrophysics Data System (ADS)

    Forkert, Nils Daniel; Fiehler, Jens

    2015-03-01

    The tissue outcome prediction in acute ischemic stroke patients is highly relevant for clinical and research purposes. It has been shown that the combined analysis of diffusion and perfusion MRI datasets using high-level machine learning techniques leads to an improved prediction of final infarction compared to single perfusion parameter thresholding. However, most high-level classifiers require a previous training and, until now, it is ambiguous how many subjects are required for this, which is the focus of this work. 23 MRI datasets of acute stroke patients with known tissue outcome were used in this work. Relative values of diffusion and perfusion parameters as well as the binary tissue outcome were extracted on a voxel-by- voxel level for all patients and used for training of a random forest classifier. The number of patients used for training set definition was iteratively and randomly reduced from using all 22 other patients to only one other patient. Thus, 22 tissue outcome predictions were generated for each patient using the trained random forest classifiers and compared to the known tissue outcome using the Dice coefficient. Overall, a logarithmic relation between the number of patients used for training set definition and tissue outcome prediction accuracy was found. Quantitatively, a mean Dice coefficient of 0.45 was found for the prediction using the training set consisting of the voxel information from only one other patient, which increases to 0.53 if using all other patients (n=22). Based on extrapolation, 50-100 patients appear to be a reasonable tradeoff between tissue outcome prediction accuracy and effort required for data acquisition and preparation.

  13. Systems Biology Model of Interactions Between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFbeta and ATM Signaling

    SciTech Connect

    O'Neill, Peter; Anderson, Jennifer

    2014-10-02

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to cross- talk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  14. Tissue damage by laser radiation: an in vitro comparison between Tm:YAG and Ho:YAG laser on a porcine kidney model.

    PubMed

    Huusmann, Stephan; Wolters, Mathias; Kramer, Mario W; Bach, Thorsten; Teichmann, Heinrich-Otto; Eing, Andreas; Bardosi, Sebastian; Herrmann, Thomas R W

    2016-01-01

    The understanding of tissue damage by laser radiation is very important for the safety in the application of surgical lasers. The objective of this study is to evaluate cutting, vaporization and coagulation properties of the 2 µm Tm:YAG laser (LISA Laser Products OHG, GER) in comparison to the 2.1 µm Ho:YAG laser (Coherent Medical Group, USA) at different laser power settings in an in vitro model of freshly harvested porcine kidneys. Laser radiation of both laser generators was delivered by using a laser fiber with an optical core diameter of 550 µm (RigiFib, LISA Laser GER). Freshly harvested porcine kidneys were used as tissue model. Experiments were either performed in ambient air or in aqueous saline. The Tm:YAG laser was adjusted to 5 W for low and 120 W for the high power setting. The Ho:YAG laser was adjusted to 0.5 J and 10 Hz (5 W average power) for low power setting and to 2.0 J and 40 Hz (80 W average power) for high power setting, accordingly. The specimens of the cutting experiments were fixed in 4 % formalin, embedded in paraffin and stained with Toluidin blue. The laser damage zone was measured under microscope as the main evaluation criteria. Laser damage zone consists of an outer coagulation zone plus a further necrotic zone. In the ambient air experiments the laser damage zone for the low power setting was 745 ± 119 µm for the Tm:YAG and 614 ± 187 µm for the Ho:YAG laser. On the high power setting, the damage zone was 760 ± 167 µm for Tm:YAG and 715 ± 142 µm for Ho:YAG. The incision depth in ambient air on the low power setting was 346 ± 199 µm for Tm:YAG, 118 ± 119 µm for Ho:YAG. On the high power setting incision depth was 5083 ± 144 µm (Tm:YAG) and 1126 ± 383 µm (Ho:YAG) respectively. In the saline solution experiments, the laser damage zone was 550 ± 137 µm (Tm:YAG) versus 447 ± 65 µm (Ho:YAG), on the low power setting and 653 ± 137 µm (Tm:YAG) versus 677 ± 134 µm (Ho

  15. Tissue damage by laser radiation: an in vitro comparison between Tm:YAG and Ho:YAG laser on a porcine kidney model.

    PubMed

    Huusmann, Stephan; Wolters, Mathias; Kramer, Mario W; Bach, Thorsten; Teichmann, Heinrich-Otto; Eing, Andreas; Bardosi, Sebastian; Herrmann, Thomas R W

    2016-01-01

    The understanding of tissue damage by laser radiation is very important for the safety in the application of surgical lasers. The objective of this study is to evaluate cutting, vaporization and coagulation properties of the 2 µm Tm:YAG laser (LISA Laser Products OHG, GER) in comparison to the 2.1 µm Ho:YAG laser (Coherent Medical Group, USA) at different laser power settings in an in vitro model of freshly harvested porcine kidneys. Laser radiation of both laser generators was delivered by using a laser fiber with an optical core diameter of 550 µm (RigiFib, LISA Laser GER). Freshly harvested porcine kidneys were used as tissue model. Experiments were either performed in ambient air or in aqueous saline. The Tm:YAG laser was adjusted to 5 W for low and 120 W for the high power setting. The Ho:YAG laser was adjusted to 0.5 J and 10 Hz (5 W average power) for low power setting and to 2.0 J and 40 Hz (80 W average power) for high power setting, accordingly. The specimens of the cutting experiments were fixed in 4 % formalin, embedded in paraffin and stained with Toluidin blue. The laser damage zone was measured under microscope as the main evaluation criteria. Laser damage zone consists of an outer coagulation zone plus a further necrotic zone. In the ambient air experiments the laser damage zone for the low power setting was 745 ± 119 µm for the Tm:YAG and 614 ± 187 µm for the Ho:YAG laser. On the high power setting, the damage zone was 760 ± 167 µm for Tm:YAG and 715 ± 142 µm for Ho:YAG. The incision depth in ambient air on the low power setting was 346 ± 199 µm for Tm:YAG, 118 ± 119 µm for Ho:YAG. On the high power setting incision depth was 5083 ± 144 µm (Tm:YAG) and 1126 ± 383 µm (Ho:YAG) respectively. In the saline solution experiments, the laser damage zone was 550 ± 137 µm (Tm:YAG) versus 447 ± 65 µm (Ho:YAG), on the low power setting and 653 ± 137 µm (Tm:YAG) versus 677 ± 134 µm (Ho

  16. Reduced Leukocyte Infiltration in Absence of Eosinophils Correlates with Decreased Tissue Damage and Disease Susceptibility in ΔdblGATA Mice during Murine Neurocysticercosis

    PubMed Central

    Mishra, Pramod K.; Li, Qun; Munoz, Luis E.; Mares, Chris A.; Morris, Elizabeth G.; Teale, Judy M.; Cardona, Astrid E.

    2016-01-01

    Neurocysticercosis (NCC) is one of the most common helminth parasitic diseases of the central nervous system (CNS) and the leading cause of acquired epilepsy worldwide. NCC is caused by the presence of the metacestode larvae of the tapeworm Taenia solium within brain tissues. NCC patients exhibit a long asymptomatic phase followed by a phase of symptoms including increased intra-cranial pressure and seizures. While the asymptomatic phase is attributed to the immunosuppressive capabilities of viable T. solium parasites, release of antigens by dying organisms induce strong immune responses and associated symptoms. Previous studies in T. solium-infected pigs have shown that the inflammatory response consists of various leukocyte populations including eosinophils, macrophages, and T cells among others. Because the role of eosinophils within the brain has not been investigated during NCC, we examined parasite burden, disease susceptibility and the composition of the inflammatory reaction in the brains of infected wild type (WT) and eosinophil-deficient mice (ΔdblGATA) using a murine model of NCC in which mice were infected intracranially with Mesocestoides corti, a cestode parasite related to T. solium. In WT mice, we observed a time-dependent induction of eosinophil recruitment in infected mice, contrasting with an overall reduced leukocyte infiltration in ΔdblGATA brains. Although, ΔdblGATA mice exhibited an increased parasite burden, reduced tissue damage and less disease susceptibility was observed when compared to infected WT mice. Cellular infiltrates in infected ΔdblGATA mice were comprised of more mast cells, and αβ T cells, which correlated with an abundant CD8+ T cell response and reduced CD4+ Th1 and Th2 responses. Thus, our data suggest that enhanced inflammatory response in WT mice appears detrimental and associates with increased disease susceptibility, despite the reduced parasite burden in the CNS. Overall reduced leukocyte infiltration due to

  17. Reduced Leukocyte Infiltration in Absence of Eosinophils Correlates with Decreased Tissue Damage and Disease Susceptibility in ΔdblGATA Mice during Murine Neurocysticercosis.

    PubMed

    Mishra, Pramod K; Li, Qun; Munoz, Luis E; Mares, Chris A; Morris, Elizabeth G; Teale, Judy M; Cardona, Astrid E

    2016-06-01

    Neurocysticercosis (NCC) is one of the most common helminth parasitic diseases of the central nervous system (CNS) and the leading cause of acquired epilepsy worldwide. NCC is caused by the presence of the metacestode larvae of the tapeworm Taenia solium within brain tissues. NCC patients exhibit a long asymptomatic phase followed by a phase of symptoms including increased intra-cranial pressure and seizures. While the asymptomatic phase is attributed to the immunosuppressive capabilities of viable T. solium parasites, release of antigens by dying organisms induce strong immune responses and associated symptoms. Previous studies in T. solium-infected pigs have shown that the inflammatory response consists of various leukocyte populations including eosinophils, macrophages, and T cells among others. Because the role of eosinophils within the brain has not been investigated during NCC, we examined parasite burden, disease susceptibility and the composition of the inflammatory reaction in the brains of infected wild type (WT) and eosinophil-deficient mice (ΔdblGATA) using a murine model of NCC in which mice were infected intracranially with Mesocestoides corti, a cestode parasite related to T. solium. In WT mice, we observed a time-dependent induction of eosinophil recruitment in infected mice, contrasting with an overall reduced leukocyte infiltration in ΔdblGATA brains. Although,