Cerebral blood flow characteristics in patients with post-lumbar puncture headache

The aim of this study was to verify if diagnostic lumbar puncture (DLP) in post-lumbar puncture headache (PLPH) patients is related to significant changes in cerebral blood flow which could be visualized by transcranial Doppler (TCD). Sixty-six patients were enrolled in this study. TCD was performed 24 h before DLP and repeated within 24 h after the procedure. The measurements included mean velocity (Vmean), peak systolic velocity (Vmax), and Gosling’s pulsatility index (PI), in the left and right middle cerebral artery (MCA). PLPH was observed in 21 patients (32%). No significant differences were noted in Vmean, Vmax and PI between the right and left MCAs—both before DLP and following this procedure. In patients who developed PLPH, bilateral pre-puncture values of Vmean and Vmax were significantly higher and PI was significantly lower compared to unaffected individuals. No significant differences were observed between these groups in terms of post-puncture Vmean and Vmax, but the post-puncture PI was still significantly lower in PLPH cases. In PLPH cases, the post-puncture values of Vmean and Vmax were significantly lower than the respective baseline parameters. A significant inverse correlation was present between PLPH severity and bilateral pre-puncture PI. In conclusion, this study revealed that higher baseline values of Vmean and Vmax and low PI in bilateral MCAs predispose patients to PLPH

Profile of Lipid and Protein Autacoids in Diabetic Vitreous Correlates With the Progression of Diabetic Retinopathy

OBJECTIVE: This study was aimed at obtaining a profile of lipids and proteins with a paracrine function in normal and diabetic vitreous and exploring whether the profile correlates with retinal pathology. RESEARCH DESIGN AND METHODS: Vitreous was recovered from 47 individuals undergoing vitreoretinal surgery: 16 had nonproliferative diabetic retinopathy (NPDR), 15 had proliferative diabetic retinopathy, 7 had retinal detachments, and 9 had epiretinal membranes. Protein and lipid autacoid profiles were determined by protein arrays and mass spectrometry-based lipidomics. RESULTS: Vitreous lipids included lipoxygenase (LO)- and cytochrome P450 epoxygenase (CYP)-derived eicosanoids. The most prominent LO-derived eicosanoid was 5-hydroxyeicosate traenoic acid (HETE), which demonstrated a diabetes-specific increase (P = 0.027) with the highest increase in NPDR vitreous. Vitreous also contained CYP-derived epoxyeicosatrienoic acids; their levels were higher in nondiabetic than diabetic vitreous (P < 0.05). Among inflammatory, angiogenic, and angiostatic cytokines and chemokines, only vascular endothelial growth factor (VEGF) showed a significant diabetes-specific profile (P < 0.05), although a similar trend was noted for tumor necrosis factor (TNF)-alpha. Soluble VEGF receptors R1 and R2 were detected in all samples with lowest VEGF-R2 levels (P < 0.05) and higher ratio of VEGF to its receptors in NPDR and PDR vitreous. CONCLUSIONS: This study is the first to demonstrate diabetes-specific changes in vitreous lipid autacoids including arachidonate and docosahexanoate-derived metabolites indicating an increase in inflammatory versus anti-inflammatory lipid mediators that correlated with increased levels of inflammatory and angiogenic proteins, further supporting the notion that inflammation plays a role the pathogenesis of this disease

The FPR2-induced rise in cytosolic calcium in human neutrophils relies on an emptying of intracellular calcium stores and is inhibited by a gelsolin-derived PIP2-binding peptide

<p>Abstract</p> <p>Background</p> <p>The molecular basis for neutrophil recognition of chemotactic peptides is their binding to specific G-protein-coupled cell surface receptors (GPCRs). Human neutrophils express two pattern recognition GPCRs, FPR1 and FPR2, which belong to the family of formyl peptide receptors. The high degree of homology between these two receptors suggests that they share many functional and signal transduction properties, although they exhibit some differences with respect to signaling. The aims of this study were to determine whether FPR2 triggers a unique signal that allows direct influx of extracellular calcium without the emptying of intracellular calcium stores, and whether the gelsolin-derived PIP₂-binding peptide, PBP10, selectively inhibits FPR2-mediated transient rise in intracellular Ca²⁺.</p> <p>Results</p> <p>The transient rise in intracellular Ca²⁺induced by agonists for FPR1 or FPR2 in human neutrophils occurred also in the presence of a chelator of Ca²⁺(EGTA). PBP10 inhibited not only FPR2-induced oxidase activity, but also the transient rise in intracellular Ca²⁺.</p> <p>Conclusions</p> <p>Ca²⁺signaling mediated <it>via </it>FPR2 follows the same route as FPR1, which involves initial emptying of the intracellular stores. PBP10 inhibits selectively the signals generated by FPR2, both with respect to NADPH-oxidase activity and the transient rise in intracellular Ca²⁺induced by agonist exposure.</p

Epoxyeicosatrienoic acids and heme oxygenase-1 interaction attenuates diabetes and metabolic syndrome complications

MSCs are considered to be the natural precursors to adipocyte development through the process of adipogenesis. A link has been established between decreased protective effects of EETs or HO-1 and their interaction in metabolic syndrome. Decreases in HO-1 or EET were associated with an increase in adipocyte stem cell differentiation and increased levels of inflammatory cytokines. EET agonist (AKR-I-27-28) inhibited MSC-derived adipocytes and decreased the levels of inflammatory cytokines. We further describe the role of CYP-epoxygenase expression, HO expression, and circulating cytokine levels in an obese mouse, ob/ob−/− mouse model. Ex vivo measurements of EET expression within MSCs derived from ob/ob−/− showed decreased levels of EETs that were increased by HO induction. This review demonstrates that suppression of HO and EET systems exist in MSCs prior to the development of adipocyte dysfunction. Further, adipocyte dysfunction can be ameliorated by induction of HO-1 and CYP-epoxygenase, i.e. EET

Heme oxygenase‐2 deletion impairs macrophage function: implication in wound healing

Heme oxygenase (HO)-2 deficiency impairs wound healing and exacerbates inflammation following injury. We examine the impact of HO-2 deficiency on macrophage function and the contribution of macrophage HO-2 to inflammatory and repair responses to injury. Corneal epithelial debridement was performed in control and macrophage-depleted HO-2(−/−) and wild-type (WT) mice and in bone marrow chimeras. Peritoneal macrophages were collected for determination of phagocytic activity and classically activated macrophage (M1)-alternatively activated macrophage (M2) polarization. Depletion of macrophages delayed corneal healing (13.2%) and increased neutrophil infiltration (54.1%) by day 4 in WT mice, whereas in HO-2(−/−) mice, it did not worsen the already impaired wound healing and exacerbated inflammation. HO-2(−/−) macrophages displayed an altered M1 phenotype with no significant expression of M2 or M2-like activated cells and a 31.3% reduction in phagocytic capacity that was restored by inducing HO-1 activity or supplementing biliverdin. Macrophage depletion had no effect, whereas adoptive transfer of WT bone marrow improved wound healing (34% on day 4) but did not resolve the exaggerated inflammatory response in HO-2(−/−) mice. These findings indicate that HO-2–deficient macrophages are dysfunctional and that macrophage HO-2 is required for proper macrophage function but is insufficient to correct the impaired healing of the HO-2(−/−) cornea, suggesting that corneal epithelial expression of HO-2 is a key to resolution and repair in wound healing.—Bellner, L., Marrazzo, G., van Rooijen, N., Dunn, M. W., Abraham, N. G., Schwartzman, M. L. Heme oxygenase-2 deletion impairs macrophage function: implication in wound healing

Epoxyeicosatrienoic intervention improves NAFLD in leptin receptor deficient mice by an increase in PGC1α-HO-1-PGC1α-mitochondrial signaling

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and is considered to be an inflammatory disorder characterized by fatty acid accumulation, oxidative stress, and lipotoxicity. We have previously reported that epoxyeicosatrienoic acid-agonist (EET-A) has multiple beneficial effects on cardiac, renal and adipose tissue function while exhibiting both anti-inflammatory and anti-oxidant activities. We hypothesized that EET-A intervention would play a central role in attenuation of obesity-induced steatosis and hepatic fibrosis that leads to NAFLD. METHODS: We studied the effect of EET-A on fatty liver using db/db mice as a model of obesity. Mice were fed a high fat diet (HFD) for 16 weeks and administered EET-A twice weekly for the final 8 weeks. RESULTS: db/db mice fed HFD significantly increased hepatic lipid accumulation as manifested by increases in NAS scores, hepatic fibrosis, insulin resistance, and inflammation, and decreases in mitochondrial mitofusin proteins (Mfn 1/2) and anti-obesity genes Fibroblast growth factor 21 (FGF21) and Cellular Repressor of E1A-Stimulated Genes 1 (CREG1). EET-A administration reversed the decrease in these genes and reduced liver fibrosis. Knockout of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in EET-A treated mice resulted in a reversal of the beneficial effects of EET-A administration. CONCLUSIONS: EET-A intervention diminishes fatty acid accumulation, fibrosis, and NFALD associated with an increase in HO-1-PGC1α and increased insulin receptor phosphorylation. A pharmacological strategy involving EETs may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NAFLD