Sildenafil reduces signs of oxidative stress in pulmonary arterial hypertension: Evaluation by fatty acid composition, level of hydroxynonenal and heart rate variability

AbstractPulmonary arterial hypertension (PAH) is a rare multifactorial disease with an unfavorable prognosis. Sildenafil therapy can improve functional capacity and pulmonary hemodynamics in PAH patients. Nowadays, it is increasingly recognized that the effects of sildenafil are pleiotropic and may also involve changes of the pro-/antioxidant balance, lipid peroxidation and autonomic control. In present study we aimed to assess the effects of sildenafil on the fatty acids (FAs) status, level of hydroxynonenal (HNE) and heart rate variability (HRV) in PAH patients. Patients with PAH were characterized by an increase in HNE and changes in the FAs composition with elevation of linoleic, oleic, docosahexanoic acids in phospholipids as well as reduced HRV with sympathetic predominance. Sildenafil therapy improved exercise capacity and pulmonary hemodynamics and reduced NT-proBNP level in PAH. Antioxidant and anti-inflammatory effects of sildenafil were noted from the significant lowering of HNE level and reduction of the phopholipid derived oleic, linoleic, docosahexanoic, docosapentanoic FAs. That was also associated with some improvement of HRV on account of the activation of the neurohumoral regulatory component. Incomplete recovery of the functional metabolic disorders in PAH patients may be assumed from the persistent increase in free FAs, reduced HRV with the sympathetic predominance in the spectral structure after treatment comparing to control group. The possibilities to improve PAH treatment efficacy through mild stimulation of free radical reactions and formation of hormetic reaction in the context of improved NO signaling are discussed

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.The EU-ROS consortium (COST Action BM1203) was supported by the European Cooperation in Science and Technology (COST). The present overview represents the final Action dissemination summarizing the major achievements of COST Action BM1203 (EU-ROS) as well as research news and personal views of its members. Some authors were also supported by COST Actions BM1005 (ENOG) and BM1307 (PROTEOSTASIS), as well as funding from the European Commission FP7 and H2020 programmes, and several national funding agencies

Persistent accumulation of 4-hydroxynonenal-protein adducts in gastric mucosa after Helicobacter pylori eradication [Povećano nakupljanje 4-hidroksinonenal-proteinskih konjugata u želučanoj sluznici zaostaje nakon izlječenja Helicobacter pylori]

Recent studies indicate that oxidative stress caused by Helicobacter pylori and insufficient host antioxidant defense could play important role in pathogenesis of gastrointestinal ulcerations. By specific monoclonal antibodies we have detected weak presence of the major lipid peroxidation bioactive marker 4-hydroxynonenal (HNE) in healthy human gastric mucosa, which strongly increased in case of H. pylori-associated peptic ulcer. Considering physiological presence of HNE on one hand, and high prevalence of H. pylori associated disorders on the other, evaluation of oxidative stress after treatment is important. Therefore, in current study immunohistochemical accumulation and distribution of HNE-protein adducts in gastric mucosa was evaluated with 21 patients having H. pylori-associated duodenal peptic ulcer (DPU) before and one month after eradication of H. pylori. Although dramatic decrease in histological manifestations of inflammation was demonstrated after eradication of H. pylori, initially high immunopositivity for the HNE-protein adducts remained elevated in antrum and even increased in stomach corpus. The observed accumulation and redistribution to higher grades of HNE-immunopositivity in nuclei of glandular cells in gastric corpus indicate augmentation of oxidative stress after treatment and open possibilities for adjuvant antioxidant treatments to protect gastric mucosa from progressive oxidative stress after eradication of H. pylori infection

Interval hypoxic training in complex treatment of Helicobacter pylori-associated peptic ulcer disease

This study was aimed to demonstrate the efficacy of interval hypoxic training (IHT) in complex treatment of Helicobacter pylori-associated duodenal peptic ulcer disease (DPUD) by parameters of aerobic metabolism and indexes of heart rate variability (HRV). Eighty patients with H. pylori-associated DPUD were included into the study, mean age 32±1.8 yrs, duration of the disease up to 10 years (66.3 %). IHT was modulated using Frolov's hypoxicator (TDI-01) for 30 days after standard eradication therapy. Daily hypoxic sessions consisted of three one-minute sessions, one two-minute, and one three-minute sessions separated by one-minute intervals of room-air breathing. Use of IHT resulted in more efficient elimination of clinical symptoms, histological hallmarks of inflammation and signs of oxidative stress in glandulocytes of the gastric mucosa as determined by 4-hydroxynonenal accumulation. Moderate prooxidant activity of IHT was demonstrated by the increased level of TBARS and oxidatively modified products, normalization of hydroperoxides, middle mass molecules and atherogenic beta-lipoproteins with simultaneous increase in catalase activity and mild decline of SOD activity. Therefore, IHT appeared to be accompanied by higher intensity of redox reactions and enhanced regeneratory processes in cells and tissues. Significant increase in HRV was also noted. Such changes were associated with reduction of inflammation signs and modulation of the autonomic homeostasis in DPUD patients. In general, use of IHT in complex treatment of H. pylori in DPUD patients can be recommended to increase resistance to oxidative stress and to modulate autonomic balance and oxidative homeostasis

Persistent Accumulation of 4-Hydroxynonenal-Protein Adducts in Gastric Mucosa after Helicobacter Pylori Eradication

Recent studies indicate that oxidative stress caused by Helicobacter pylori and insufficient host antioxidant defense could play important role in pathogenesis of gastrointestinal ulcerations. By specific monoclonal antibodies we have detected weak presence of the major lipid peroxidation bioactive marker 4-hydroxynonenal (HNE) in healthy human gastric mucosa, which strongly increased in case of H. pylori-associated peptic ulcer. Considering physiological presence of HNE on one hand, and high prevalence of H. pylori associated disorders on the other, evaluation of oxidative stress after treatment is important. Therefore, in current study immunohistochemical accumulation and distribution of HNE-protein adducts in gastric mucosa was evaluated with 21 patients having H. pylori-associated duodenal peptic ulcer (DPU) before and one month after eradication of H. pylori. Although dramatic decrease in histological manifestations of inflammation was demonstrated after eradication of H. pylori, initially high immunopositivity for the HNE-protein adducts remained elevated in antrum and even increased in stomach corpus. The observed accumulation and redistribution to higher grades of HNE-immunopositivity in nuclei of glandular cells in gastric corpus indicate augmentation of oxidative stress after treatment and open possibilities for adjuvant antioxidant treatments to protect gastric mucosa from progressive oxidative stress after eradication of H. pylori infection

European contribution to the study of ROS:a summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)

Abstract The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed