Growing evidence implicates aberrant lipid signaling in Alzheimer's disease (AD). While phospholipases A2 and C have been recentlyshown to mediate key actions of amyloid ␤-peptide (A␤) through a dysregulation of arachidonic acid and phosphatidylinositol-4,5-bisphosphate metabolism, respectively, the role of phospholipase D (PLD) has so far remained elusive. PLD produces phosphatidic acid (PA), a bioactive lipid involved in multiple aspects of cell physiology, including signaling and membrane trafficking processes. Here we show that oligomeric A␤ enhances PLD activity in cultured neurons and that this stimulatory effect does not occur upon ablation of PLD2 via gene targeting. A␤ fails to suppress long-term potentiation in PLD2-deficient hippocampal slices, suggesting that PLD2 is required for the synaptotoxic action of this peptide. In vivo PLD activity, as assessed by detection of phosphatidylethanol levels using mass spectrometry (MS) following ethanol injection, is also increased in the brain of a transgenic mouse model of AD (SwAPP). Furthermore, Pld2 ablation rescues memory deficits and confers synaptic protection in SwAPP mice despite a significant A␤ load. MS-based lipid analysis of Pld2 mutant brains in the presence or absence of the SwAPP transgene unmasks striking crosstalks between different PA species. This lipid analysis shows an exquisite acyl chain specificity and plasticity in the perturbation of PA metabolism. Collectively, our results point to specific molecular species of PA as key modulators of AD pathogenesis and identify PLD2 as a novel potential target for therapeutics.

While macroautophagy is known to be an essential degradative process whereby autophagosomes mediate the engulfment and delivery of cytoplasmic components into lysosomes, the lipid changes underlying autophagosomal membrane dynamics are undetermined. Here we show that phospholipase D1 (PLD1), which is primarily associated with the endosomal system, partially relocalizes to the outer membrane of autophagosome-like structures upon nutrient starvation. The localization of PLD1, as well as the starvation-induced increase in PLD activity, are altered by wortmannin, a phosphatidylinositol 3-kinase inhibitor, suggesting PLD1 may act downstream of Vps34. Pharmacological inhibition of PLD and genetic ablation of PLD1 in the mouse decrease the starvation-induced expansion of LC3-positive compartments, consistent with a role of PLD1 in the regulation of autophagy. Furthermore, inhibition of PLD results in higher levels of tau and p62 aggregates in organotypic brain slices. Our in vitro and in vivo findings establish a novel role for PLD1 in autophagy.

Angiogenesis inhibitors confer only short-term benefits on tumor growth. We report that ablation of the lipid signaling enzyme phospholipase D1 (PLD1) in the tumor environment compromises neovascularization and growth of tumors. PLD1 deficiency suppressed activation of AKT and mitogen-activated protein kinase signaling pathways by vascular endothelial growth factor (VEGF) in vascular endothelial cells, resulting in decreased integrin-dependent cell adhesion to and migration on extracellular matrixes and reduced tumor angiogenesis in a xenograft model. In addition, mice lacking PLD1 incurred significantly fewer lung metastases. Bone marrow transplantation and binding studies identified a platelet-derived mechanism involving decreased tumor cell:platelet interaction due to impaired activation of platelet αIIbβ3 integrin, which decreased seeding of tumor cells into the lung parenchyma. Treatment with a small molecule inhibitor of PLD1 phenocopied PLD1 deficiency, efficiently suppressing both tumor growth and metastasis in mice. These findings reveal that PLD1 in the tumor environment promotes tumor growth and metastasis, and taken together with prior reports of PLD1 roles in tumor cell intrinsic adaptations to stress, suggest potential utility for PLD1 inhibitors as cancer therapeutics.

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BackgroundMesenchymal stromal cells (MSCs) are a promising therapy for preventing chronic Graft-Versus-Host Disease (cGVHD) due to their potent immunomodulatory properties. However, the safety concerns regarding the use of MSCs remain unsolved, and conflicting effects are observed due to the heterogeneity of MSCs. Recently, exosomes were shown to mediate the paracrine effects of MSCs, making it a potential candidate for cell-free therapies. The aim of this study is to investigate the efficacy and safety of MSCs-derived exosomes (MSCs-exo) in an established cGVHD mouse model.MethodsBone marrow (BM)-derived MSCs were cultured, and the supernatants of these cultures were collected to prepare exosomes using ultracentrifugation. Exosomes from human dermal fibroblasts (Fib-exo) were used as a negative control. The cGVHD model was established, and tail vein injections of MSCs-exo or Fib-exo were administered once per week for 6 weeks. The symptoms and signs of cGVHD were monitored, and histopathological changes were detected by hematoxylin and eosin and Masson staining. The effects of MSCs-exo on Th17, Th1, and Treg were evaluated by flow cytometry, qPCR, and Luminex. In addition, human peripheral blood mononuclear cells (PBMCs) were stimulated and treated with MSCs-exo in vitro. IL-17-expressing Th17 and IL-10-expressing Treg were evaluated by flow cytometry, qPCR, and ELISA.ResultsWe found that MSCs-exo effectively prolonged the survival of cGVHD mice and diminished the clinical and pathological scores of cGVHD. Fibrosis in the skin, lung, and liver was significantly ameliorated by MSCs-exo application. In MSCs-exo treated mice, activation of CD4+ T cells and their infiltration into the lung were reduced. Of note, MSCs-exo exhibited potent immunomodulatory effects via the inhibition of IL-17-expressing pathogenic T cells and induction of IL-10-expressing regulatory cells during cGVHD. The expressions of Th17 cell-relevant transcription factors and pro-inflammatory cytokines was markedly reduced after MSCs-exo treatment. In vitro, MSCs-exo blocked Th17 differentiation and improved the Treg phenotype in PBMCs obtained from healthy donors and patients with active cGVHD, further indicating the regulatory effect of MSCs-exo on GVHD effector T cells.ConclusionsOur data suggested that MSCs-exo could improve the survival and ameliorate the pathologic damage of cGVHD by suppressing Th17 cells and inducing Treg. This finding provides a novel alternative approach for the treatment of cGVHD.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0680-7) contains supplementary material, which is available to authorized users.

The pathophysiology of psoriasis is complex and dynamic. Recently, the involvement of oxidative stress in the pathogenesis of psoriasis has been proposed. Oxidative stress is an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage. In this article, the published studies on the role of oxidative stress in psoriasis pathogenesis are reviewed, focusing on the impacts of oxidative stress on dendritic cells, T lymphocytes, and keratinocytes, on angiogenesis and on inflammatory signaling (mitogen-activated protein kinase, nuclear factor-κB, and Janus kinase/signal transducer and activator of transcription). As there is compelling evidence that oxidative stress is involved in the pathogenesis of psoriasis, the possibility of using this information to develop novel strategies for treatment of patients with psoriasis is of considerable interest. In this article, we also review the published studies on treating psoriasis with antioxidants and drugs with antioxidant activity.

High flow nasal cannula (HFNC) has been shown to improve extubation outcomes in patients with hypoxemia, but the role of HFNC in weaning patients with chronic obstructive pulmonary disease (COPD) with hypercapnia from invasive ventilation is unclear. We compared the effects of HFNC to noninvasive ventilation (NIV) on postextubation vital signs and arterial blood gases (ABGs) among patients with COPD. Other outcomes included comfort scores, need for bronchoscopy, use of pulmonary medications, and chest physiotherapy. Forty‐two COPD patients who had persistent hypercapnia at extubation were assigned randomly to receive HFNC (22) or NIV (20). Twenty patients in each group were enrolled for per‐protocol analysis with regard to primary outcomes. Vital signs and ABGs before extubation were similar between groups. At 3 hr after extubation, pH in the NIV group was lower than HFNC group (7.42 ± 0.06 vs. 7.45 ± 0.05, p = 0.01). At 24 hr after extubation, patients’ mean arterial pressure (82.97 ± 9.04 vs. 92.06 ± 11.11 mmHg, p = 0.05) and pH (7.42 ± 0.05 vs. 7.46 ± 0.03, p = 0.05) in the NIV group were lower than in the HFNC group. No significant differences were found at 48 hr after extubation. In the HFNC group, comfort scores were better (3.55 ± 2.01 vs. 5.15 ± 2.28, p = 0.02) and fewer patients needed bronchoscopy for secretion management within 48 hr after extubation (2/22 vs. 9/20, p = 0.03). HFNC is a potential alternative to NIV to wean hypercapnic COPD patients with regard to vital signs and ABGs, HFNC improved patients’ comfort and secretion clearance.

Previous studies have demonstrated that patients with traumatic brain injury (TBI) who also have progressive hemorrhagic injury (PHI), have a higher risk of clinical deterioration and worse outcomes than do TBI patients without PHI. Therefore, the early prediction of PHI occurrence is useful to evaluate the status of patients with TBI and to improve outcomes. The objective of this study was to develop and validate a prognostic model that uses information available at admission to determine the likelihood of PHI after TBI. Retrospectively collected data were used to develop a PHI prognostic model with a logistic regression analysis. The prediction model was validated in 114 patients from a separate hospital. Eight independent prognostic factors were identified: age ‡ 57 years (5 points), intra-axial bleeding/brain contusion (4 points), midline shift ‡ 5 mm (6 points), platelet (PLT) count < 100 · 10 9 /L (10 points), PLT count ‡ 100 but < 150 · 10 9 /L (4 points), prothrombin time > 14 sec (7 points), D-dimer ‡ 5 mg/L (12 points), and glucose ‡ 10 mmol/L (10 points). Each patient was assigned a number of points proportional to the regression coefficient. We calculated risk scores for each patient and defined three risk groups: low risk (0-13 points), intermediate risk (14-22 points), and high risk (23-54 points). In the development cohort, the PHI rates after TBI for these three groups were 10.3%, 47.3%, and 85.2%, respectively. In the validation cohort, the corresponding PHI rates were 10.9%, 47.3%, and 86.9%. The C-statistic for the point system was 0.864 ( p = 0.509 by the Hosmer-Lemeshow test) in the development cohort, and 0.862 ( p = 0.589 by the Hosmer-Lemeshow test) in the validation cohort. In conclusion, a relatively simple risk score using admission predictors accurately predicted the risk for PHI after TBI.