PLPP2: Potential therapeutic target of breast cancer in PLPP family

PLPPs (Phospholipid phosphatases) are widely expressed in different human tissues, regulate cell signal transduction, and are overexpressed in cancers such as gliomas, pancreatic adenocarcinoma, lung adenocarcinoma, and so on. As a member of the PLPP family, PLPP2 (phospholipid phosphatase 2) plays a vital role in the occurrence and development of breast cancer, but its mechanism is still unclear. Our research found that PLPP2 was overexpressed in breast cancer, and the higher expression level of PLPP2 showed a worse prognosis for breast cancer patients. Further analysis showed that overexpression of PLPP2 affected the expression of CDC34 (cell-division cycle 34), LSM7 (Like-Smith 7), and SGTA (small glutamine-rich tetratricopeptide repeat-containing protein alpha) through EMT (epigenetic-mesenchymal transition) related pathways to promote the occurrence and development of breast cancer. In vitro, silencing PLPP2 significantly reduced the proliferation, invasion, and migration abilities of human breast cancer cells MDA-MB-231. ER+ is a common subtype of breast cancer. Furthermore, we found that the overexpression of PLPP2 was significantly related to the poor prognosis of ER+ breast cancer. These results indicate that PLPP2 has value as a potential therapeutic target for breast cancer, especially for ER+ breast cancer.     

Differential effects of phospholipase inhibitors in long-term potentiation in the rat hippocampal mossy fiber synapses and Schaffer/commissural synapses

Bath application of the inhibitors of phospholipases, nordihydroguaiaretic acid (NDGA) and p-bromophenacyl bromide (BPB), to the rat hippocampal slices suppressed long-term potentiation (LTP) in Schaffer/commissural-CA1 pyramidal synapses. On the other hand, neither of the two inhibitors suppressed LTP in mossy fiber-CA3 pyramidal cell synapses. BPB did not suppress phosphatidylinositol-specific phospholipase C (PI-PLC) activity of the slices. These results suggested that the mechanisms of LTP were quite different in the CA1 and CA3 subfields of rat hippocampus: in CA1, the involvement of an arachidonate metabolism was strongly suggested, whereas in CA3, an arachidonic acid cascade may not be necessary for LTP.     

Treatment with silybin-vitamin E-phospholipid complex in patients with hepatitis C infection

The aim of this study was to evaluate the hepatoprotective and anti-inflammatory effects of silybin-phospholipids and vitamin E complex (SPV complex), by determining cytokine patterns and various markers of liver disease. Forty Caucasian patients with chronic HCV infection were recruited and divided into two groups: 30 were treated with SPV complex for 3 months, while the other 10 did not receive any treatment. Ten other subjects without HCV infection but with staeatosic diagnosis were recruited and treated with SPV complex. Biochemical and hepatic principal parameters were investigated at 0 (T0) and 3 months (T3). The group of HCV patients treated showed an improvement trend of hepatic indecises and viral load, and had a significant and persistent reduction of ALT (P = 0.02) and AST serum level (P = 0.01). In this group cytokines showed a statistically significant increase of IL-2 (P = 0.03) and IL-6 were significantly reduced (P = 0.02) at T0 and T3. After the treatment the group of hepatic steatosics showed a significant decrease in ALT (P = 0.02), AST (0.008), gammaGT (0.004) alkaline phosphatase (0.05), total cholesterol (P = 0.03), fasting glucose (P = 0.008), insulinemia (0.0006), HOMA value (0.002) and C-reactive protein (CRP; 0.04). There was a significant reduction of IFN-gamma, TNF-alpha, and IL-6 (P = 0.02, 0.05 and 0.04, respectively). The data suggest that the SPV complex exerts hepatoprotective, anti-inflammatory and antifibrotic effects. This new compound may therefore be useful in clinical practice in patients with chronic hepatitis C who cannot undergo conventional antiviral therapy.     

慢性肾功能衰竭红细胞变形能力与红细胞膜的研究

本文报道了慢性肾功能衰竭患者红细胞的变形能力、红细胞膜胆固醇与磷脂比值及膜微粘度。结果表明,红细胞可变形能力明显降低,膜胆固醇与磷脂比值及膜微粘度明显增加,提示红细胞变形能力可能与红细胞膜的流动性有关。     

Renewal of the membrane complex of Schistosoma mansoni is closely associated with lipid metabolism

Metabolic pathways leading to lipid biosynthesis in four different developmental stages of Schistosoma mansoni were explored and quantified by incubation in the presence of labeled precursors in a chemically defined medium. At the schistosomulum stage and in male, female, or paired worms, glycerol and oleate incorporation into neutral lipids, mainly in the form of triacylglycerols, was greater than into phospholipids, whereas in 11-and 15-day-old worms, synthesis mainly led to phospholipids. Incorporation into phospholipids was recovered largely in phosphatidylcholine, and distribution into other phospholipids depended on the developmental stage. Incorporation of choline and ethanolamine into their respective phospholipids represented up to 15% of the parasitic phospholipid content. The formation of phosphatidylcholine by phosphatidylethanolamine methylation occurred mainly in the immature parasitic stages. Inositol incorporation was also measurable, whereas [14C]serine incorporation was low or undetectable. Addition of 1-palmitoyl-2-[14C]oleyl phosphatidylcholine revealed a very high uptake of this phospholipid by the immature stages but further metabolism was not detectable. In contrast, adult S. mansoni were completely unable to take up or absorb this exogenous phospholipid. The most striking aspect of this study was the relatively high metabolic activity in 11-day-old worms and the lower but sustained activity on day 15 and at the schistosomulum stage. By comparison, biosynthetic activity in adult S. mansoni, on which research studies have been focused until now, was very low. We also discuss the participation of lipid metabolism in the constant renewal of the membrane complex which is essential to parasitism by S. mansoni.     

In vivo brain (31)P-MRS: measuring the phospholipid resonances at 4 Tesla from small voxels

An optimized phosphorous ((31)P) three-dimensional chemical-shift imaging (3D-CSI) protocol was developed at 4 T to study the phospholipid metabolism from discrete regions in the human brain without the need for (1)H-decoupling or nuclear Overhauser enhancement (NOE). In this study, a spherically bound, weighted average, random point omission 3D-CSI technique was developed and tested, based on methods proposed in the literature. The technique yields a significant (p < 0.001, two-tailed, 5% confidence level) increase in signal-to-noise (SNR) efficiency over conventional 3D-CSI (phantom 32%), without an increase in voxel bleedthrough. An automated time-domain fitting procedure utilizing prior spectral knowledge quantified the individual brain phospholipid metabolites from 15 cm(3) effective (8.0 cm(3) nominal) volumes from the left/right-parieto-occipital cortex and left/right thalamus in 10 normal volunteers. Individual constituents from the phosphomonoester (PME) region; phosphoethanolamine (PEth), phosphocholine (PCh) and the phosphodiester (PDE) region; glycerophosphoethanolamine (GPEth), glycerophosphocholine (GPCh) and membrane phospholipids (MP) were separately quantified to assess the precision of our method at 4 T against previous (1)H-decoupled (31)P-MRS brain studies at lower fields and much larger voxels. Derived concentrations (mM/l tissue) for PEth, PCh, GPEth, GPCh and MP in the left-parieto-occipital cortex were 0.81 +/- 0.21, 0.46 +/- 0.14, 0.74 +/- 0.30, 1.15 +/- 0.43 and 1.54 +/- 0.95 mM, respectively, and 0.94 +/- 0.16, 0.46 +/- 0.17, 0.83 +/- 0.22, 1.14 +/- 0.40 and 1.26 +/- 0.78 mM for the right parieto-occipital cortex. Derived concentrations (mM/l tissue) for PEth, PCh, GPEth, GPCh and MP in the left-thalamus were 0.69 +/- 0.18, 0.42 +/- 0.16, 0.63 +/- 0.20, 1.05 +/- 0.42 and 0.93 +/- 0.56 mM, respectively, and 0.68 +/- 0.24, 0.34 +/- 0.18, 0.60 +/- 0.23, 1.09 +/- 0.36 and 0.74 +/- 0.48 mM for the right-thalamus. This is the first study to our knowledge that has been able to quantify each of these individual phospholipid metabolites from such small voxels in the brain within a clinically reasonable scan time and without (1)H-decoupling or NOE.     

Clinical relevance of multiple antibody specificity testing in anti-phospholipid syndrome and recurrent pregnancy loss

We wanted to evaluate whether testing for anti-phosholipid antibodies other than anti-cardiolipin (aCL) and anti-beta-2 glycoprotein I (abeta2GPI) immunoglobulin (Ig)G and IgM identifies patients with recurrent pregnancy loss (RPL) who may be positive for anti-phospholipid syndrome (APS). In a cross-sectional study comprising 62 patients with APS, 66 women with RPL, 50 healthy blood donors and 24 women with a history of successful pregnancies, we tested IgM and IgG antibodies to phosphatidic acid, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl inositol and phosphatidyl serine with and without beta-2 glycoprotein I (beta2GPI) from a single manufacturer as well as aCL and abeta2GPI antibodies. Diagnostic accuracies of individual and combined anti-phospholipid (aPL) assays were assessed by computing sensitivities, specificities, positive predictive values and negative predictive values together with their 95% confidence intervals. There was a general trend for increased sensitivities in the presence of beta2GPI co-factor with significant effect for certain specificities. The overall combined sensitivity of the non-recommended aPL assays was not significantly higher than that of the aCL and aB2GPI tests. Multiple aPL specificities in RPL group is not significantly different from controls and therefore of no clinical significance.     

Anti-beta2-glycoprotein I (GPI) autoantibodies, annexin V binding and the anti-phospholipid syndrome

We examined the role of autoantibodies to beta2-GPI and prothrombin (PT) in the inhibition of annexin V binding to cardiolipin (CL) and the association with clinical manifestations of the anti-phospholipid syndrome (APS). Plasma samples from 59 patients with anti-phospholipid (aPL) antibodies were studied. Affinity purification of total IgG and IgG anti-ss2-GPI antibodies was performed using staphylococcal protein A and phospholipid liposomes. Annexin V binding to CL was significantly inhibited by 31/59 (53%) aPL+ plasma samples. There was a significant association between annexin V inhibition and elevated levels of IgG anti-cardiolipin (aCL) (r = -0.62; P < 0.001), IgG anti-ss2-GPI (r = -0.67; P < 0. 001) and a weaker association with lupus anti-coagulant (r = -0.27; P = 0.05). There was no association with other isotypes of aCL and anti-ss2-GPI or with anti-PT of any isotype. In patients with clinical manifestations of the APS there were higher levels of IgG aCL (median (range) Z score): 10.0 (0-17.6) versus 5.0 (0-16.1); P = 0.03), IgG anti-ss2-GPI (4.5 (0-11.3) versus 0.9 (0-9.7); P = 0.02) and greater inhibition of annexin V binding to CL (-3.4 (-11.4-0.6) versus -1.1 (-10.8-1.2); P = 0.22). Odds ratios for the laboratory assays and the presence of clinical manifestations of the APS varied between 0.38 and 4.16, with the highest values for IgG aCL (4.16), IgG anti-ss2-GPI (3.28) and annexin V inhibition (2.85). Additional experiments with affinity-purified IgG antibodies indicated that inhibition of annexin V binding was dependent upon the concentration of ss2-GPI and anti-ss2-GPI antibodies. These results indicate that inhibition of annexin V binding to procoagulant phospholipid surfaces is dependent upon anti-ss2-GPI antibodies and suggest a role for annexin V in the pathogenesis of the APS.     

Nanosized ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery against vitiligo: formulation optimization,in vitro evaluation and preclinical assessment

The present investigation aimed for the development and characterization of ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery and effective treatment against vitiligo. The ethosomes were prepared by central composite design (CCD) and characterized for various quality attributes like vesicle shape, size, zeta potential, lamellarity, drug entrapment and drug leaching. The optimized ethosomes were subsequently incorporated int Carbopol® 934 gel and characterized for drug content, rheological behavior, texture profile, in vitro release, ex vivo skin permeation and retention, skin photosensitization and histopathological examination. Ethosomes were found to be spherical and multilamellar in structures having nanometric size range with narrow size distribution, and high encapsulation efficiency. Ethosomal formulations showed significant skin permeation and accumulation in the epidermal and dermal layers. The fluorescence microscopy study using 123 Rhodamine exhibited enhanced permeation of the drug-loaded ethosomes in the deeper layers of skin. Also, the developed formulation showed insignificant phototoxicity and erythema vis-à-vis the conventional cream. The results were cross-validated using histopathological examination of skin segments. In a nutshell, the ethosomes-based hydrogel formulation was found to be a promising drug delivery system demonstrating enhanced percutaneous penetration of methoxsalen with reduced phototoxicity and erythema, thus leading to improved patient compliance for the treatment against vitiligo.     

Analysis of pulmonary surfactant in rat lungs after inhalation of nanomaterials: Fullerenes,nickel oxide and multi-walled carbon nanotubes

The health risks of inhalation exposure to engineered nanomaterials in the workplace are a major concern in recent years, and hazard assessments of these materials are being conducted. The pulmonary surfactant of lung alveoli is the first biological entity to have contact with airborne nanomaterials in inhaled air. In this study, we retrospectively evaluated the pulmonary surfactant components of rat lungs after a 4-week inhalation exposure to three different nanomaterials: fullerenes, nickel oxide (NiO) nanoparticles and multi-walled carbon nanotubes (MWCNT), with similar levels of average aerosol concentration (0.13–0.37?mg/m³). Bronchoalveolar lavage fluid (BALF) of the rat lungs stored after previous inhalation studies was analyzed, focusing on total protein and the surfactant components, such as phospholipids and surfactant-specific SP-D (surfactant protein D) and the BALF surface tension, which is affected by SP-B and SP-C. Compared with a control group, significant changes in the BALF surface tension and the concentrations of phospholipids, total protein and SP-D were observed in rats exposed to NiO nanoparticles, but not in those exposed to fullerenes. Surface tension and the levels of surfactant phospholipids and proteins were also significantly different in rats exposed to MWCNTs. The concentrations of phospholipids, total protein and SP-D and BALF surface tension were correlated significantly with the polymorphonuclear neutrophil counts in the BALF. These results suggest that pulmonary surfactant components can be used as measures of lung inflammation.