The relevance of pathophysiological alterations in redox signaling of 4-hydroxynonenal for pharmacological therapies of major stress-associated diseases.

Modern analytical methods combined with the modern concepts of redox signaling revealed 4-hydroxy-2-nonenal (4-HNE) as particular growth regulating factor involved in redox signaling under physiological and pathophysiological circumstances. In this review current knowledge of the relevance of 4-HNE as "the second messenger of reactive oxygen species" (ROS) in redox signaling of representative major stress-associated diseases is briefly summarized. The findings presented allow for 4-HNE to be considered not only as second messenger of ROS, but also as one of fundamental factors of the stress- and age-associated diseases. While standard, even modern concepts of molecular medicine and respective therapies in majority of these diseases target mostly the disease-specific symptoms. 4-HNE, especially its protein adducts, might appear to be the bioactive markers that would allow better monitoring of specific pathophysiological processes reflecting their complexity. Eventually that could help development of advanced integrative medicine approach for patients and the diseases they suffer from on the personalized basis implementing biomedical remedies that would optimize beneficial effects of ROS and 4-HNE to prevent the onset and progression of the illness, perhaps even providing the real cure.

Amaranth oil reduces accumulation of 4-hydroxynonenal-histidine adducts in gastric mucosa and improves heart rate variability in duodenal peptic ulcer patients undergoing Helicobacter pylori eradication.

Helicobacter pylori-induced oxidative stress in gastric mucosa (GM) is a milieu for the development of chronic gastritis, duodenal peptic ulcer (DPU), gastric cancer, and a number of extragastric diseases. Because our previous study revealed the accumulation of the protein adducts of lipid peroxidation product 4-hydroxynonenal (HNE) in GM, which persists after eradication of H. pylori, the aim of the study was to test whether Amaranth oil supplementation in addition to standard anti-Helicobacter treatment could prevent such accumulation of HNE in GM in H. pylori-positive DPU patients. Seventy-five patients were randomly split into two groups: group 1 - standard treatment (n = 39) and group 2 - standard treatment with additional supplementation of 1 ml of concentrated oil from amaranth seeds (Amaranthus cruenthus L., n = 36). Clinical analysis, including endoscopy with biopsies from antrum and corpus of the stomach were performed before and after the treatment, as was heart rate variability (HRV) recorded, as parameter of systemic, extragastric pathophysiological alterations in DPU patients. Improvement of clinical, endoscopic and histologic manifestations, and successful ulcer healing were observed in both the groups. Moreover, supplementation of amaranth oil in addition to standard anti-H. pylori treatment significantly reduced accumulation of HNE-histidine adducts in GM and increased HRV in DPU patients (p < .05). Therefore, standard treatments of DPU require additional therapeutic approaches, in accordance with integrative medicine principles, aiming to reduce persistence of oxidative stress, as was successfully done in our study by the use of amaranth oil.

Antitumor effect of Croatian propolis as a consequence of diverse sex-related dihydropyrimidine dehydrogenase (DPD) protein expression.

The aim of this study was to detect the antitumor properties of Croatian propolis in BALB/c male and female mice injected with 4T1 mammary carcinoma. Furthermore, the gender-dependence of this effect and the possible involvement of combined effect of propolis and 5-Fluorouracil (5FU) on dihydropyrimidine dehydrogenase (DPD) transcriptional and translational level, were determined. In combination with 5FU propolis treatment induced gender-related effects. The results of the study revealed that pretreatment of mice with propolis combined with 5FU treatment prolonged the suppressive effect of 5FU on tumor growth and reduced the number of metastasis only in male mice. Only males pretreated with propolis prior to 5FU administration had decreased DPD protein level indicating higher sensitivity to 5FU. Thus, benefitial effects of propolis in male tumor-bearing mice treated with 5FU might be explained by increased sensitivity to 5FU as the result of translationally downregulated DPD.

A fish-oil-rich diet reduces vascular oxidative stress in apoE(-/-) mice.

Oxidative stress contributes to lipid peroxidation and decreases nitric oxide (NO) bioavailability in atherosclerosis. While long-chain (n-3) polyunsaturated fatty acids (PUFA) are easily oxidized in vitro, they improve endothelial function. Hence, this study postulates that long-chain (n-3) PUFA decrease atherogenic oxidative stress in vivo. To test this, apoE(-/-) mice were fed a corn oil- or a fish oil (FO)-rich diet for 8, 14 or 20 weeks and parameters related to NO and superoxide (O(2)(.-)) plus markers of lipid peroxidation and protein oxidative damage in the aortic root were evaluated. The FO-rich diet increased NO production and endothelial NO synthase (NOS) expression and lowered inducible NOS, p22(phox) expression and O(2)(.-)production after 14 and 20 weeks of diet. Protein lipoxidative damage (including 4-hydroxynonenal) was decreased after a long-term FO-diet. This supports the hypothesis that a FO-rich diet could counteract atherogenic oxidative stress, showing beneficial effects of long-chain (n-3) PUFA.

Mitochondrial alterations in aging rat brain: effective role of (-)-epigallo catechin gallate.

Aging is a multi-factorial process which involves deprivation in body's metabolism. Brain mitochondria are prone to oxidative damage owing to their high metabolic rate. The decline in antioxidant system during aging augments the neuronal damage to mitochondrial components like antioxidant system, Kreb's cycle enzymes and electron transport chain complexes. Since brain is an organ rich in fatty acids, lipid peroxidation products like hydroxynonenal are predominant. Those lipid peroxidation products conjugate with amino acids to form adducts which alter their structural and functional properties. Epigallo catechin gallate is a potent antioxidant which is rich in green tea extract. This study elucidated the antioxidant potential of epigallo catechin gallate to counteract the mitochondrial oxidative damage in brain. The study comprised of young (3-4 months old; 150+/-20 g) and aged (above 24 months; 420+/-20 g) male albino rats of Wistar strain in Groups I and II. Groups III and IV comprised of young and aged rats supplemented with epigallo catechin gallate (2mg/kg body weight) for 30 days. Antioxidants, Kreb's cycle enzymes and electron transport chain complexes were assayed in the mitochondrial fraction. Hydroxynonenal expression was carried out using immunohistochemical analysis. Epigallo catechin gallate supplementation decreased the expression of hydroxynonenal in aged brain, up-regulated the antioxidant system and augmented the activities of Kreb's cycle enzymes and electron transport chain complexes in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria.

Unusual cause of dementia in an immunocompetent host: toxoplasmic encephalitis.

A 69-year-old male was presented with a 2-month history of cognitive decline. The most profound deficit was observed in short-term verbal and visual memory and recognition. He was otherwise healthy, apart from atrial fibrillation diagnosed 5 months before. Brain MRI revealed T2 hyperintensities in the left thalamus, right pulvinar thalami, both putamina and right head of caudate nucleus without diffusion restriction on DWI sequences. CSF examination revealed elevated proteins. He was HIV negative. The course of the disease was complicated with gram negative sepsis and the patient died 14 days later. Autopsy revealed the brain lesions to have been caused by toxoplasmic encephalitis. Toxoplasmic encephalitis is an extremely rare cause of rapidly progressive dementia in immunocompetent patients. In patients with multiple lesions, hyperintense on T2 and hypointense on T1 weighted sequences, without diffusion restriction and some expansive effect, infectious causes should be considered, even in the absence of classical signs of infectious diseases and CSF pleocythosis.

Bilateral thalamic astrocytoma.

We present a 68-year-old woman who presented with symptoms of frontotemporal dementia. Brain MRI revealed tumor mass in both thalami and according to WHO classification, the tumor corresponded to diffuse fibrillary astrocytoma grade II. This case points to the role of neuroimaging in patients presenting with classical symptoms of dementia.