Membrane Phospholipid Metabolism Research Articles

Role of neurochemistry in amyloid pathology using 5xFAD transgenic mouse model of AD: A single‐voxel Magnetic Resonance Spectroscopy (MRS) study

AbstractBackgroundChanges in cerebral metabolic concentrations are markers of aging and are also associated with various neurological disorders. Neurotransmitter and membrane metabolisms are affected in Alzheimer’s disease (AD). These metabolic alterations are suggested to occur in the hippocampus and rhinal cortex during the early stages of AD pathology. Higher levels of glutamine (Gln) in the blood and cerebral spinal fluid are associated with an increased risk of developing AD. Since Gln is capable of crossing the blood‐brain barrier and is involved in the metabolic cycle with glutamate (Glu), elevated levels of Gln in the presence of Aβ pathology may suggest a protective role of Gln in the early stage of the disease. Therefore, alteration in Glu/Gln cycle may serve as an early biomarker in the pathogenesis of AD. Choline‐containing compounds (tCho) are essential for phospholipid synthesis and degradation of cell membranes. Abnormal alterations of tCho levels are indicative of imbalanced cell membrane phospholipid metabolism. At the early stage of Aβ pathology, high levels of tCho in conjunction with elevated levels of Gln may suggest the involvement of compensatory mechanisms to counter declining acetylcholine. Thus, investigating metabolic changes in the hippocampus may improve our understanding of metabolic mechanisms associated with Aβ pathology.MethodMale 5xFAD mice (N=4) at 6‐months‐old and age‐matched littermates (N=5) were used in this study. Single‐voxel MRS was acquired on a 9.4T Biospec micro‐MRI system equipped with a H1 cryogenic surface coil. STEAM spectra was acquired from a 2mm3 voxel positioned on the left hippocampus region. Glu, Gln, tCho and total Creatine (tCr) levels were estimated with LC Model. A general linear model (GLM) was used to estimate group‐wise differences in Glu/Gln ratio, tCho.Gln and tCr.ResultCerebral metabolic concentration levels suggest group‐level differences between wild‐type (WT) and 5xFAD mice. Glu/Gln ratio was significantly higher in WT mice than 5xFAD (pFWE<0.05; d=3.4) and tCho.Gln was significantly lower in WT than 5xFAD (pFWE<0.05; d=2.8).ConclusionSingle‐voxel MRS in the hippocampus region can identify the neurochemical profile of multiple cerebral metabolites, which may be sensitive to the Aβ burden at the early stages of the pathology.

PEGylated 2D-nanomaterials alleviate Parkinson's disease by shielding PIP2 lipids to inhibit IP3 second messenger signaling

Researches on nano-bio interfaces have revealed that two-dimensional (2D) nanomaterials can form functionally impactful architectures upon interaction with biological membranes. These biological impacts may drive various changes of membrane phospholipids, raising the possibility of alleviating neurodegenerative disorders by specifically altering metabolism of membrane phospholipids. Here, we demonstrate that PEGylated 2D nanomaterials including graphene oxide and poly-L-lactic acid sheets (denoted as P-sheet) alleviate behavioral and neuronal degeneration of Parkinson's disease (PD). Upon this finding, we experimentally identify enrichment for the phosphatidylinositol-4,5-bisphosphate (PIP2) lipid interacting with P-sheet and reveal the underlying mechanism by molecular dynamics simulations: a flip-flop orientation shift of PIP2 lipids within the membrane restricts the hydrolysis site, preventing cleavage-mediated inositol 1,4,5-trisphosphate. As a result, Ca2+-related endoplasmic reticulum stress can be reduced to protect the neurons of PD mice. These results together support P-sheet nanomaterials as a new type of drug-free agent for selective modulation of neurodegenerative-disorder-associated membrane-lipid dysregulation and potential PD therapy.

Altered high-energy phosphate and membrane metabolism in Pelizaeus-Merzbacher disease using phosphorus magnetic resonance spectroscopy.

Pelizaeus–Merzbacher disease is an X-linked recessive leucodystrophy of the central nervous system caused by mutations affecting the major myelin protein, proteolipid protein 1. The extent of the altered in vivo neurochemistry of protein, proteolipid protein 1 duplications, the most common form of Pelizaeus–Merzbacher disease, is, however, poorly understood. Phosphorus magnetic resonance spectroscopy is the only in vivo technique that can assess the biochemistry associated with high-energy phosphate and membrane phospholipid metabolism across different cortical, subcortical and white matter areas. In this cross-sectional study, whole-brain, multi-voxel phosphorus magnetic resonance spectroscopy was acquired at 3 T on 14 patients with Pelizaeus–Merzbacher disease with protein, proteolipid protein 1 duplications and 23 healthy controls (all males). Anabolic and catabolic levels of membrane phospholipids (phosphocholine and phosphoethanolamine, and glycerophosphoethanolamine and glycerophosphocholine, respectively), as well as phosphocreatine, inorganic orthophosphate and adenosine triphosphate levels relative to the total phosphorus magnetic resonance spectroscopy signal from 12 different cortical and subcortical areas were compared between the two groups. Independent of brain area, phosphocholine, glycerophosphoethanolamine and inorganic orthophosphate levels were significantly lower (P = 0.0025, P < 0.0001 and P = 0.0002) and phosphocreatine levels were significantly higher (P < 0.0001) in Pelizaeus–Merzbacher disease patients compared with controls. Additionally, there was a significant group-by-brain area interaction for phosphocreatine with post-hoc analyses demonstrating significantly higher phosphocreatine levels in patients with Pelizaeus–Merzbacher disease compared with controls across multiple brain areas (anterior and posterior white matter, superior parietal lobe, posterior cingulate cortex, hippocampus, occipital cortex, striatum and thalamus; all P ≤ 0.0042). Phosphoethanolamine, glycerophosphoethanolamine and adenosine triphosphate levels were not significantly different between groups. For the first-time, widespread alterations in phosphorus magnetic resonance spectroscopy metabolite levels of Pelizaeus–Merzbacher disease patients are being reported. Specifically, increased high-energy phosphate storage levels of phosphocreatine concomitant with decreased inorganic orthophosphate across multiple areas suggest a widespread reduction in the high-energy phosphate utilization in Pelizaeus–Merzbacher disease, and the membrane phospholipid metabolite deficits suggest a widespread degradation in the neuropil content/maintenance of patients with Pelizaeus–Merzbacher disease which includes axons, dendrites and astrocytes within cortex and the myelin microstructure and oligodendrocytes within white matter. These results provide greater insight into the neuropathology of Pelizaeus–Merzbacher disease both in terms of energy expenditure and membrane phospholipid metabolites. Future longitudinal studies are warranted to investigate the utility of phosphorus magnetic resonance spectroscopy as surrogate biomarkers in monitoring treatment intervention for Pelizaeus–Merzbacher disease.

In vivo magnetic resonance spectrometry imaging demonstrates comparable adaptation of brain energy metabolism to metabolic stress induced by 72 h of fasting in depressed patients and healthy volunteers

Major depressive disorder (MDD) is characterized by dysregulation of stress systems and by abnormalities in cerebral energy metabolism. Stress induction has been shown to impact neurometabolism in healthy individuals. Contrarily, neurometabolic changes in response to stress are insufficiently investigated in MDD patients. Metabolic stress was induced in MDD patients (MDD, N = 24) and in healthy individuals (CTRL, N = 22) by application of an established fasting protocol in which calorie intake was omitted for 72 h. Both study groups were comparable regarding age, gender distribution, and body mass index (BMI). Fasting-induced effects on brain high-energy phosphate levels and membrane phospholipid metabolism were assessed using phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Two-way repeated measures ANOVAs did not reveal significant interaction effects (group x fasting) or group differences in adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters (PME), phosphodiesters (PDE), or pH levels between MDD and CTRL. Fasting, independent of group, significantly increased ATP and decreased Pi levels and an overall increase in PME/PDE ratio as marker for membrane turnover was observed. Overall these results indicate reactive changes in cerebral energetics and in membrane phospholipid metabolism in response to fasting. The observed effects did not significantly differ between CTRL and MDD, indicating that neurometabolic adaptation to metabolic stress is preserved in MDD patients.

Evidence of altered metabolism of cellular membranes in bipolar disorder comorbid with post-traumatic stress disorder

In proton magnetic resonance spectroscopy (¹H MRS) studies, aberrant levels of choline-containing compounds that include glycerophosphocholine plus phosphocholine (GPC+PC), can signify alterations in the metabolism of cellular membrane phospholipids (MPLs) from a healthy baseline. In a recent ¹H MRS study, we reported increased GPC+PC in cortical and subcortical areas of adult patients with bipolar disorder I (BP-I). Post-traumatic stress disorder (PTSD) can worsen the severity of BP-I, but it is unclear whether the effect of a PTSD comorbidity in BP-I is associated with altered MPL metabolism. The purpose of this study was to re-investigate the ¹H MRS data to determine whether the regional extent of elevated GPC+PC was greater in BP-I patients with PTSD (BP-I/wPTSD) compared to BP-I without comorbid PTSD (BP-I/woPTSD) patients and healthy controls. GPC+PC levels from four brain areas [the anterior cingulate cortex (ACC), anterior-dorsal ACC, caudate, and putamen] were measured in 14 BP-I/wPTSD, 36 BP-I/woPTSD, and 44 healthy controls using a multi-voxel 1H MRS approach on a 3 Tesla system with high spatial resolution and absolute quantification. Results show a significant increase in GPC+PC levels from the caudate and putamen of BP-I/wPTSD patients compared to healthy controls (P<0.05) and in the putamen compared to BP-I/woPTSD patients (P<0.05). These findings are consistent with evidence of elevated degradation of MPLs in the neuropil that is more pronounced in BP-I patients with comorbid PTSD.

Anterior cingulate cortex neuro-metabolic changes underlying lithium-induced euthymia in bipolar depression: A longitudinal 1H-MRS study

The diagnosis and treatment of bipolar depression (BDep) poses complex clinical challenges for psychiatry. Proton magnetic resonance spectroscopy (1H-MRS) is a useful imaging tool for investigating in vivo levels of brain neuro-metabolites, critical to understanding the process of mood dysregulation in Bipolar Disorder. Few studies have evaluated longitudinal clinical outcomes in BDep associated with 1H-MRS metabolic changes. This study aimed to longitudinally assess brain 1H-MRS metabolites in the anterior cingulate cortex (ACC) correlated with improvement in depression (from BDep to euthymia) after lithium treatment in BDep patients versus matched healthy controls (HC). Twenty-eight medication-free BDep patients and 28 HC, matched for age and gender, were included in this study. All subjects were submitted to a 3-Tesla brain 1H-MRS scan in the ACC using a single-voxel (8cm3) PRESS sequence at baseline. At follow-up (6 weeks), 14 BDep patients repeated the exam in euthymia. Patients with current BDep had higher baseline Myo-inositol/Cr (mI/Cr) and Choline/Cr (Cho/Cr) compared to HC. After six weeks, mI/Cr or Cho/Cr levels in subjects that achieved euthymia no longer differed to levels in HC, while high Cho/Cr levels persisted in non-responders . Elevated ACC mI/Cr and Cho/Cr in BDep might indicate increased abnormal membrane phospholipid metabolism and phosphatidylinositol (PI) cycle activity. Return of mI/Cr and Cho/Cr to normal levels after lithium-induced euthymia suggests a critical regulatory effect of lithium targeting the PI cycle involved in mood regulation.

Increased PLA2 activity in individuals at ultra-high risk for psychosis

Phospholipase A2 is the main enzyme in the metabolism of membrane phospholipids. It comprises a family of enzymes divided into iPLA2, cPLA2 and sPLA2. Studies have reported increased PLA2 activity in psychotic patients, which suggests an accelerated breakdown of membrane phospholipids. In the present study we investigated whether increased PLA2 activity is also present in individuals at ultra-high risk (UHR) for psychosis. One-hundred fifty adults were included in this study (85 UHR and 65 controls). UHR was assessed using the "structured interview for prodromal syndromes". PLA2 activity was determined in platelets by a radio-enzymatic assay. We found in UHR individuals increased activities of iPLA2 (p < 0.001) and cPLA2 (p = 0.012) as compared to controls. No correlations were found between socio-demographic and clinical parameters and PLA2 activity. Our findings suggest that increased PLA2 activities may be useful as a biological risk-marker for psychotic disorders.

Lysolipids in Vascular Development, Biology, and Disease.

Membrane phospholipid metabolism forms lysophospholipids, which possess unique biochemical and biophysical properties that influence membrane structure and dynamics. However, lysophospholipids also function as ligands for G-protein-coupled receptors that influence embryonic development, postnatal physiology, and disease. The 2 most well-studied species-lysophosphatidic acid and S1P (sphingosine 1-phosphate)-are particularly relevant to vascular development, physiology, and cardiovascular diseases. This review summarizes the role of lysophosphatidic acid and S1P in vascular developmental processes, endothelial cell biology, and their roles in cardiovascular disease processes. In addition, we also point out the apparent connections between lysophospholipid biology and the Wnt (int/wingless family) pathway, an evolutionarily conserved fundamental developmental signaling system. The discovery that components of the lysophospholipid signaling system are key genetic determinants of cardiovascular disease has warranted current and future research in this field. As pharmacological approaches to modulate lysophospholipid signaling have entered the clinical sphere, new findings in this field promise to influence novel therapeutic strategies in cardiovascular diseases.

Brain NAD Is Associated With ATP Energy Production and Membrane Phospholipid Turnover in Humans.

The brain requires a large amount of energy, mostly derived from the metabolism of glucose, which decreases substantially with age and neurological diseases. While mounting evidence in model organisms illustrates the central role of brain nicotinamide adenine dinucleotide (NAD) for maintaining energy homeostasis, similar data are sparse in humans. This study explores the correlations between brain NAD, energy production and membrane phospholipid metabolism by 31-phosphorous magnetic resonance spectroscopy (31P-MRS) across 50 healthy participants including a young (mean age 27.1-year-old) and middle-aged (mean age 56.4-year-old) group. The analysis revealed that brain NAD level and NAD+/NADH redox ratio were positively associated with ATP level and the rate of energy production, respectively. Moreover, a metabolic network linking NAD with membrane phospholipid metabolism, energy production, and aging was identified. An inverted trend between age and NAD level was detected. These results pave the way for the use of 31P-MRS as a powerful non-invasive tool to support the development of new therapeutic interventions targeting NAD associated phospho-metabolic pathways in brain aging and neurological diseases.

Spatial Lipidomic Profiling of Mouse Joint Tissue Demonstrates the Essential Role of PHOSPHO1 in Growth Plate Homeostasis.

Lipids play a crucial role in signaling and metabolism, regulating the development and maintenance of the skeleton. Membrane lipids have been hypothesized to act as intermediates upstream of orphan phosphatase 1 (PHOSPHO1), a major contributor to phosphate generation required for bone mineralization. Here, we spatially resolve the lipid atlas of the healthy mouse knee and demonstrate the effects of PHOSPHO1 ablation on the growth plate lipidome. Lipids spanning 17 subclasses were mapped across the knee joints of healthy juvenile and adult mice using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS), with annotation supported by shotgun lipidomics. Multivariate analysis identified 96 and 80 lipid ions with differential abundances across joint tissues in juvenile and adult mice, respectively. In both ages, marrow was enriched in phospholipid platelet activating factors (PAFs) and related metabolites, cortical bone had a low lipid content, whereas lysophospholipids were strikingly enriched in the growth plate, an active site of mineralization and PHOSPHO1 activity. Spatially-resolved profiling of PHOSPHO1-knockout (KO) mice across the resting, proliferating, and hypertrophic growth plate zones revealed 272, 306, and 296 significantly upregulated, and 155, 220, and 190 significantly downregulated features, respectively, relative to wild-type (WT) controls. Of note, phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, lysophosphatidylethanolamine, and phosphatidylethanolamine derived lipid ions were upregulated in PHOSPHO1-KO versus WT. Our imaging pipeline has established a spatially-resolved lipid signature of joint tissues and has demonstrated that PHOSPHO1 ablation significantly alters the growth plate lipidome, highlighting an essential role of the PHOSPHO1-mediated membrane phospholipid metabolism in lipid and bone homeostasis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Multimodal Magnetic Resonance Imaging and Therapeutic Intervention With Yi-nao-jie-yu Decoction in a Rat Model of Post-stroke Depression.

Post-stroke depression (PSD) is the most common neuropsychiatric complication after a stroke, though its neuropathological characteristics have not been fully elucidated. Comprehensive and non-invasive magnetic resonance (MR) assessment techniques are urgently needed for current research, as diffusion tensor imaging (DTI), arterial spin labeling (ASL), and magnetic resonance spectroscopy (MRS) can allow for a comprehensive assessment of neuropathological changes in the brain. These techniques can provide information about microscopic tissue integrity, cerebral perfusion, and cerebral metabolism, and can serve as powerful tools for investigating neurophysiological changes associated with PSD. Yi-nao-jie-yu decoction (YNJYD) is a Chinese herbal formulation based on the theory of traditional Chinese medicine, with demonstrated clinical efficacy in the treatment of PSD. The aim of this study was to use these MR techniques to evaluate changes in PSD and YNJYD-treated rats. This is the first experimental study in animals to investigate neuropathological changes associated with PSD using a combination of multiple MR techniques, including DTI, ASL, and MRS. In addition, we investigated the effect of YNJYD in a rat model of PSD by assessing changes in brain tissue microstructure, brain metabolism, and cerebral perfusion. First, depressive-like behaviors of PSD rats were assessed by the open field test (OFT), sucrose preference test (SPT), and Morris water maze (MWM) test, and then the integrity of the rats' microstructure was assessed by DTI, the levels of regional cerebral perfusion were assessed by ASL, and changes in the relative concentrations of brain metabolites were determined by MRS. The results showed that OFT and SPT scores were significantly reduced in PSD rats, as was performance in the MWM; these PSD-associated changes were attenuated in rats administered YNJYD, with improved depressive-like behaviors evidenced by increased OFT and SPT scores and improved performance in the MWM task. Furthermore, we found that PSD rats had lower perfusion levels in the prefrontal cortex (PFC) and hippocampus (HP), microstructural damage, and abnormal changes in the concentrations of brain metabolites; YNJYD exerted therapeutic effects on PSD rats by improving microcirculation in the PFC and HP, regulating glutamatergic systems and membrane phospholipid metabolism, and repairing microstructural damage.

FORGETTER2 protein phosphatase and phospholipase D modulate heat stress memory in Arabidopsis.

Plants can mitigate environmental stress conditions through acclimation. In the case of fluctuating stress conditions such as high temperatures, maintaining a stress memory enables a more efficient response upon recurring stress. In a genetic screen for Arabidopsis thaliana mutants impaired in the memory of heat stress (HS) we have isolated the FORGETTER2 (FGT2) gene, which encodes a type 2C protein phosphatase (PP2C) of the D-clade. Fgt2 mutants acquire thermotolerance normally; however, they are defective in the memory of HS. FGT2 interacts with phospholipase D α2 (PLDα2), which is involved in the metabolism of membrane phospholipids and is also required for HS memory. In summary, we have uncovered a previously unknown component of HS memory and identified the FGT2 protein phosphatase and PLDα2 as crucial players, suggesting that phosphatidic acid-dependent signaling or membrane composition dynamics underlie HS memory.

Use of peroxiredoxin for preconditioning of heterotopic heart transplantation in a rat

Peroxiredoxin 6 (Prdx6) is an antioxidant enzyme in the human body that performs a number of important functions in the cell. Prdx6 restores a wide range of peroxide substrates, thus playing a leading role in maintaining redox homeostasis in mammalian cells. In addition to peroxidase activity, Prdx6 has an activity of phospholipase A2, thus taking part in membrane phospholipid metabolism. Due to its peroxidase and phospholipase activity, Prdx6 participates in intracellular and intercellular signal transmission, thereby facilitating the initiation of regenerative processes in the cell, suppression of apoptosis and activation of cell proliferation. Given the functions performed, Prdx6 can effectively deal with oxidative stress caused by various factors, including ischemia-reperfusion injury. On an animal model of rat heterotopic heart transplantation, we showed the cardioprotective potential of exogenous recombinant Prdx6, introduced before transplantation and subsequent reperfusion injury of the heart. It has been demonstrated that exogenous Prdx6 effectively alleviates the severity of ischemia-reperfusion injury of the heart by 2–3 times, providing normalization of its structural and functional state during heterotopic transplantation. The use of recombinant Prdx6 can be an effective approach in preventing/alleviating ischemia-reperfusion injury of the heart, as well as in maintaining an isolated heart during transplantation.

Pentalinonsterol exhibits the immunomodulatory action in macrophages through activation of Phospholipase A2

Leishmaniasis, a protozoan parasitic disease, is caused by the infection with the parasite, Leishmania spp. Pentalinonsterol (cholest‐4,20,24‐trien‐3‐one) (PEN) is a natural product recently isolated from the roots of Pentalinon andrieuxii. Previous in vitro and in vivo studies have demonstrated that P. andrieuxii root extracts possess potent immunomodulatory properties, which markedly increase the activity of macrophages and dendritic cells. Given the beneficial characteristics of this root extract, the objective of this study was to elucidate the mechanism of action of the immunomodulatory action(s) of PEN in macrophages on membrane phospholipid metabolism towards the anti‐leishmanial action of PEN. Phospholipase A2 (PLA2), plays an important role in membrane phospholipid homeostasis, cell signaling and generation of the eicosanoid inflammatory bioactive lipids. Therefore, in this study, we investigated PEN‐mediated modulation of PLA2 activity in RAW 264.7 macrophages and the bone marrow‐derived primary macrophages (BMDMs) from mice in vitro and how the upstream PLA2 activation would modulate the downstream cytokine release in the macrophages. Our results demonstrated that, (1) PEN induced PLA2 activation (arachidonic acid release), in a dose‐ and time‐dependent manner that was regulated upstream by mitogen‐activated protein kinases (MAPKs): (2) the PEN induced activation of PLA2 was attenuated by the cPLA2‐specific pharmacological inhibitors; and (3) cPLA2‐specific pharmacological inhibitors attenuated the release of the inflammatory cytokines from macrophages. We also observed that PEN enhances the Leishmania‐induced cPLA2 activation in the RAW macrophages. Our study demonstrated that PEN exerted immunomodulatory actions through cPLA2 activation in macrophages, which is advantageous for vaccine development against Leishmaniasis.Support or Funding InformationSupported by the U.S. Army/Department of Defense and Center for Clinical and Translational Science, Ohio State University.

Regionally Distinct Alterations in Membrane Phospholipid Metabolism in Schizophrenia: A Meta-analysis of Phosphorus Magnetic Resonance Spectroscopy Studies

BackgroundExisting data on altered membrane phospholipid metabolism in schizophrenia are diverse. We conducted a meta-analysis of studies of phosphorus magnetic resonance spectroscopy, a noninvasive imaging approach that can assess molecular biochemistry of cortex by measuring phosphomonoester (PME) and phosphodiester (PDE) levels, which can provide evidence of altered biochemical processes involved in neuropil membrane expansion and contraction in schizophrenia. MethodsWe analyzed PME and PDE data in the frontal and temporal lobes in subjects with schizophrenia from 24 peer-reviewed publications using the MAVIS package in R by building random- and fixed-effects models. Heterogeneity of effect sizes, effects of publication bias, and file drawer analysis were also assessed. ResultsSubjects with schizophrenia showed lower PME levels in the frontal regions (p = .008) and elevated PDE levels in the temporal regions (p < .001) with significant heterogeneity. We noted significant publication bias and file drawer effect for frontal PME and PDE and temporal PDE levels, but not for temporal PME levels. Fail-safe analysis estimated that a high number of negative studies were required to provide nonsignificant results. ConclusionsDespite methodological differences, these phosphorus magnetic resonance spectroscopy studies demonstrate regionally specific imbalance in membrane phospholipid metabolism related to neuropil in subjects with schizophrenia compared with control subjects reflecting neuropil contraction. Specifically, decreased PME levels in the frontal regions and elevated PDE levels in the temporal regions provide evidence of decreased synthesis and increased degradation of neuropil membrane, respectively. Notwithstanding significant heterogeneity and publication bias, a large number of negative studies are required to render the results of this meta-analysis nonsignificant. These findings warrant further postmortem and animal studies.

Reduced Annexin A3 in schizophrenia.

The cellular and molecular mechanisms underlying onset and development of schizophrenia have not yet been completely elucidated, but the association of disturbed neuroplasticity and inflammation has gained particular relevance recently. These mechanisms are linked to annexins functions. ANXA3, particularly, is associated to inflammation and membrane metabolism cascades. The aim was to determine the ANXA3 levels in first-onset drug-naïve psychotic patients. We investigated by western blot the protein expression of annexin A3 in platelets of first-onset, drug-naïve psychotic patients (diagnoses according to DSM-IV: 28 schizophrenia, 27 bipolar disorder) as compared to 30 age- and gender-matched healthy controls. Annexin A3 level was lower in schizophrenia patients as compared to healthy controls (p < 0.001) and to bipolar patients (p < 0.001). Twenty out of 28 schizophrenic patients had undetectable annexin A3 levels, as compared to none from the bipolar and none from the control subjects. ANXA3 was reduced in drug-naïve patients with schizophrenia. ANXA3 affects neuroplasticity, inflammation and apoptosis, as well as it modulates membrane phospholipid metabolism. All these processes have been discussed in regard to the biology of schizophrenia. In face of these data, we feel that further studies with larger samples are warranted to investigate the possible role of reduced ANXA3 as a possible risk marker for schizophrenia.

Protective role of exogenous recombinant peroxiredoxin 6 under ischemia-reperfusion injury of kidney.

Peroxiredoxin 6 (Prx6) is an important antioxidant enzyme with various functions in the cell. Prx6 reduces a wide range of peroxide substrates, playing a leading role in maintaining the redox homeostasis of mammalian cells. In addition to the peroxidase activity, a phospholipase A2-like activity was demonstrated for Prx6, which plays an important role in the metabolism of membrane phospholipids. Besides that, due to its peroxidase and phospholipase activities, Prx6 participates in intracellular and intercellular signal transduction, thus triggering regenerative processes in the cell, suppressing apoptosis caused by various factors, including ischemia-reperfusion injuries. A nephroprotective effect of exogenous recombinant Prx6 administered before ischemia-reperfusion injury was demonstrated on an animal model. Exogenous Prx6 effectively alleviates the severeness of renal ischemia-reperfusion injuries and facilitates normalization of their structural and functional conditions. Infusion of exogenous Prx6 increases the survival rate of experimental animals by almost 3 times. Application of exogenous Prx6 can be an effective approach in the prevention and treatment of renal ischemia-reperfusion kidney lesions and in preserving isolated kidneys during transplantation.

Radioprotective Role of Peroxiredoxin 6.

Peroxiredoxin 6 (Prdx6) is a member of an evolutionary ancient family of peroxidase enzymes with diverse functions in the cell. Prdx6 is an important enzymatic antioxidant. It reduces a wide range of peroxide substrates in the cell, thus playing a leading role in the maintenance of the redox homeostasis in mammalian cells. Beside peroxidase activity, Prdx6 has been shown to possess an activity of phospholipase A2, an enzyme playing an important role in membrane phospholipid metabolism. Moreover, Prdx6 takes part in intercellular and intracellular signal transduction due to its peroxidase and phospholipase activity, thus facilitating the initiation of regenerative processes in the cell, suppression of apoptosis, and activation of cell proliferation. Being an effective and important antioxidant enzyme, Prdx6 plays an essential role in neutralizing oxidative stress caused by various factors, including action of ionizing radiation. Endogenous Prdx6 has been shown to possess a significant radioprotective potential in cellular and animal models. Moreover, intravenous infusion of recombinant Prdx6 to animals before irradiation at lethal or sublethal doses has shown its high radioprotective effect. Exogenous Prdx6 effectively alleviates the severeness of radiation lesions, providing normalization of the functional state of radiosensitive organs and tissues, and leads to a significant elevation of the survival rate of animals. Prdx6 can be considered as a potent and promising radioprotective agent for reducing the pathological effect of ionizing radiation on mammalian organisms. The radioprotective properties and mechanisms of radioprotective action of Prdx6 are discussed in the current review.

Molecular mechanisms underlying daptomycin resistance

Due to potent bactericidal activity and low rate of drug-resistance, daptomycin is recognized as first line antibiotic to treat serious infections caused by drug-resistant Gram-positive pathogens. However, the incidence of daptomycin resistance is increasing due to its widespread application. Alteration of cell wall homeostasis and membrane phospholipid metabolism is involved in daptomycin resistance. The unique mode of action underlying daptomycin resistance in important pathogens, including Staphylococcus aureus and Enterococci, is presented in this paper.

Lysophosphatidic acid enhances neointimal hyperplasia following vascular injury through modulating proliferation, autophagy, inflammation and oxidative stress.

Lysophosphatidic acid (LPA), which is one of the intermediate products of membrane phospholipid metabolism, is a bioactive phospholipid that possesses diverse activities. In the present study, the effects of LPA on neointimal formation following vascular injury were investigated. A carotid artery balloon injury model was employed in the present study, and following vascular injury, rats received an intraperitoneal injection of 1 mg/kg LPA. Subsequently, histopathological alterations were assessed by hematoxylin and eosin staining, the expression levels of proliferating cell nuclear antigen (PCNA) were detected by immunohistochemistry, apoptosis was assessed via a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and the expression levels of apoptosis-associated and autophagy-associated proteins were detected by western blotting. In addition, inflammatory and oxidative stress-associated factors were assessed by reverse transcription-quantitative polymerase chain reaction or corresponding kits. The results of the present study demonstrated that LPA enhanced vascular injury-induced neointimal hyperplasia. LPA further elevated the expression levels of PCNA in the injured carotid artery tissues. LPA exhibited no effect on apoptosis in carotid artery tissues, whereas it modulated autophagy in the injured carotid artery tissues. Furthermore, LPA enhanced vascular injury-induced inflammation and oxidative stress. The present study demonstrated that LPA may enhance neointimal hyperplasia following vascular injury by modulating proliferation, autophagy, inflammation and oxidative stress, but not apoptosis. Furthermore LPA may contribute to the pathology of atherosclerosis and may be considered a promising therapeutic target for the treatment of atherosclerosis.