Cerebrospinal Fluid and Plasma Oxidative Stress Biomarkers in Different Clinical Phenotypes of Neuroinflammatory Acute Attacks. Conceptual Accession: From Fundamental to Clinic

Oxidative stress is revealed as the main contributor in the pathophysiology of neuroinflammation. Analyzing plasma and cerebrospinal fluid (CSF) of patients with different clinical phenotypes of neuroinflammation, defined as clinically isolated syndrome (CIS), and those defined as relapsing remitting multiples sclerosis (RRMS), we tested peripheral and CNS oxidative stress intensity in these neuroinflammatory acute attacks. All obtained values changes were assessed regarding clinical and radiological features of CNS inflammation. The obtained results revealed an increase in malondialdehyde levels in plasma and CSF in CIS and RRMS patients compared to control values (p < 0.05). The obtained values were most prevailed in both study group, CIS and RRMS, in patients with severe clinical presentation (p < 0.05). Measured activities of catalase and total superoxide dismutase were higher in CIS and RRMS patients in plasma compared to control values (p < 0.05), parallel with an increased catalase activity and decrease in superoxide dismutase activity in CSF regarding values obtained in control group (p < 0.05). The positive correlations regarding clinical score were obtained for all tested biomarkers (p < 0.01). Although the positive correlations were observed in MDA levels in plasma and CSF, for both study patients, and their radiological findings (p < 0.01), and a negative correlation in plasma SOD activity and CIS patients’ radiological findings (p < 0.01), no other similar correlations were obtained. These findings might be useful in providing the earliest antioxidative treatment in neuroinflammation aimed to preserve total and CNS antioxidative capacity parallel with delaying irreversible, later neurological disabilities.     

Chronic hypoxia leads to a glycolytic phenotype and suppressed HIF-2 signaling in PC12 cells

Background

Along with other regulators of cell metabolism, hypoxia-inducible factors HIF-1 and HIF-2 differentially regulate cell adaptation to hypoxia. Switches in HIF-1/HIF-2 signaling in chronic hypoxia have not been fully investigated.

Methods

Proliferation, viability, apoptosis, neuronal and bioenergetic markers, mitochondrial function, respiration, glycolysis, HIF signalling, responses to O₂ and glucose deprivation (OGD) were examined using tumor PC12 and SH-SY5Y cells continuously grown at 3% O₂.

Results

Hypoxic PC12 cells (H-cells) exhibit reduced proliferation and histone H4 acetylation, NGF-independent differentiation, activation of AMPK, inhibition of Akt, altered mitochondria and response to NGF. Cellular cytochrome c is increased with no effect on apoptosis. Reduction in respiration has minor effect on cellular ATP which is maintained through activated uptake (GLUT1) and utilization (HK2, PFK2) of glucose. H-cells exhibit resistance to OGD linked to increased glycogen stores. HIF-2alpha protein is decreased without changes in mRNA. Unlike HIF-1alpha, HIF-2alpha is not stabilized pharmacologically or by O₂ deprivation. Capacity for HIF-2alpha stabilization is partly restored when H-cells are cultured at normoxia. In low-respiring SH-SY5Y cells cultured under the same conditions HIF-2alpha stabilization and energy budget are not affected.

Conclusions

In chronically hypoxic PC12 cells glycolytic energy budget, increased energy preservation and low susceptibility to OGD are observed. HIF-2alpha no longer orchestrates adaptive responses to anoxia.

General significance

Demonstrated switch in HIF-1/HIF-2 signaling upon chronic hypoxia can facilitate cell survival in energy crisis, by regulating balance between energy saving and decrease in proliferation, on one hand and active cell growth and tumor expansion, on the other.     

Sources and donors of resistance to wheat spot blotch caused by Bipolaris sorokiniana Shoem. (Cochliobolus sativus Drechs. ex Dastur)

The resistance of wheat lines and cultivars from the Institute of Crop Breeding (Harbin, China) and synthetic, hexaploid wheat lines derived from T. durum and T. tauschii (CIMMYT) were screened for resistance to spot blotch Bipolaris sorokiniana Shoem. using field and laboratory tests. The highly and moderately resistant wheat samples were determined. The satisfactory coincidence of data obtained from evaluation of type reaction of seedlings and disease severity in adult plant stage was demonstrated. The genetics of resistance in Chinese lines Long 98-4554, Long 98-4546, Long mai 24, Long mai 23 and Canadian line 181-5 was studied using hybridological analysis. The resistance in these lines was inherited as quantitative traits and was conditioned by a few (one or two) genes. The absence of susceptible plants in F₂ in crosses of resistant lines Long 98-4554, Long 98-4546, Long mai 24 and 181-5 can testify to the presence of a common gene of resistance. Our data reveals the poor genetic diversity for spot blotch resistance in studying wheat genotypes.     

Lipids in the daubed shanny (Teleostei: Leptoclinus maculatus) in Svalbard waters

The daubed shanny, Leptoclinus maculatus, is a common fish species in Arctic and North Atlantic waters and has an important role in high-latitude ecosystems as a link between lower trophic levels and many fish, marine mammal and seabird species. Its biology and ecology have, however, remained largely unstudied. The primary aim of this study was to increase the knowledge about the daubed shanny by analysing total lipids, lipid-classes and the fatty acid composition of liver, muscle and female gonads in adults from the high Arctic archipelago of Svalbard. In female gonads, the triacylglycerols and wax esters in addition to cholesterol esters were dominant among the stored lipids. Triacylglycerols dominated in the liver, whereas structural lipids, such as phospholipids and cholesterols, were the most important lipids in muscles. Phosphatidylcholine and phosphatidylethanolamine were major phospholipids in all organs studied. The fatty acid spectrum of the investigated organs was characterized by a high amount of monounsaturated fatty acids, particularly in the liver. Polyunsaturated fatty acids, particularly 22:6(n-3) and 20:4(n-6), were prevalent in muscle tissues. The lipid and fatty acid spectra in the organs during this period of life are tightly connected with the activation of the liver metabolism and the storage of lipids in the developed female gonads. Lipid accumulation and distribution in gonads are transferred to optimal development of embryos and larvae in Arctic waters.     

The different morphs of Undaria pinnatifida (Phaeophyceae, Laminariales) in Peter the Great Bay (Sea of Japan) are phenotypic variants: direct evidence

Previous study elicited three morphologically distinct forms of Undaria pinnatifida in Peter the Great Bay (Sea of Japan), which were represented by one or more populations. It was supposed that their specific morphology is plastic response to the local environment. In the present study, we used molecular data in order to examine directly the degree of genetic similarity between these morphs. We performed amplified fragment length polymorphism and microsatellite analyses. In addition, offspring of these forms were cultivated in the same environments. It was shown that genetic polymorphism of U. pinnatifida in Peter the Great Bay is low. The genetic distance among five populations representing three forms of U. pinnatifida did not exceed 0.2. The offspring of three forms grown in the same environmental conditions became, in general, morphologically similar. Combination of genetic analysis and cultivation in the same environmental conditions of three morphologically different forms of U. pinnatifida from Peter the Great Bay suggested that their specific morphology is not genetically fixed and is the result of ontogenetic adaptation to the local environment.     

Synthesis and structure–activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors

A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure–activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development.     

New directions in ER stress-induced cell death

Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of many diseases including heart disease, cancer and neurodegenerative diseases such as Alzheimer’s and Huntington’s. Prolonged or excessive ER stress results in the initiation of signaling pathways resulting in cell death. Over the past decade much research investigating the onset and progression of ER stress-induced cell death has been carried out. Owing to this we now have a better understanding of the signaling pathways leading to ER stress-mediated cell death and have begun to appreciate the importance of ER localized stress sensors, IRE1α, ATF6 and PERK in this process. In this article we provide an overview of the current thinking and concepts concerning the various stages of ER stress-induced cell death, focusing on the role of ER localized proteins in sensing and triggering ER stress-induced death signals with particular emphasis on the contribution of calcium signaling and Bcl-2 family members to the execution phase of this process. We also highlight new and emerging directions in ER stress-induced cell death research particularly the role of microRNAs, ER-mitochondria cross talk and the prospect of mitochondria-independent death signals in ER stress-induced cell death.     

Supplementary studies and molecular data on Henneguya cerebralis Pronin, 1972 (Myxozoa: Myxosporea), a parasite from Kosogol grayling Thymallus arcticus nigrescens in Mongolia

Henneguya cerebralis Pronin, 1972 (Myxozoa) was described from Kosogol graylings Thymallus arcticus nigrescens Dorogostaisky, 1923 in Lake Khovsgol (Mongolia) in 1972.H. cerebralis was redescribed using critical morphological features and 18S ribosomal DNA (rDNA) gene sequence. Parasite infects cranial cartilage of fish host. Plasmodia are white rounded or ovoid, by 0.1 to 2 mm in size, containing large quantities of spores. Spore body is ovoid or rounded, 11.18 ± 0.13 μm (range 9,71–12,56) in length and 9.06 ± 0.16 μm (range 7.22–10,06) in width with equal polar capsules (4.7 × 2.6 μm). The two caudal appendages have different lengths (one of them was shorter in 20%).Phylogenetic position inferred by 18S rDNA shows that H. cerebralis is closely related with H. zschokkei, H. nuesslini, H. salminicola and H. cartilaginis which are histozoic parasites of salmonid fish.