For efficient application of adjuvant chemotherapy after radical surgery for lung cancer, identifying recurrence high risk group is needed. However, predicting lung cancer recurrence after radical surgery is difficult even with numbers of histopathological prognostic factors reported ever. Because subjective judgements for the conventional histopathological prognostic factors are inevitable, novel prognostic factor with high objectivity is expected. Lipid metabolism alterations are known to contribute to cancer progression.

Background: Lipids are abundant in the white matter of brain and essential for brain function. Recent accumulated evidence showed optimizing motor performance via repetitive training is associated with increases in the white matter detected by MRI. However, it remains unknown whether the MRI signal is caused by changes in the lipids related to neuronal circuit function. We recently showed that myelin (major source of lipids) formation associated with learning was promoted by neuronal impulses. Our recent study using in vivo two-photon calcium imaging showed myelin are necessary for temporal regulation of neuronal firing required for motor learning in mouse motor cortex.

Background and purpose: The initial steps in the cascade leading to cell death are still unknown because of the limitations of the existing methodology, strategy, and modalities used. Methods: Imaging mass spectrometry (IMS) was used to measure dynamic molecular changes of phosphatidylcholine (PC) species in the rat hippocampus after transient global ischemia (TGI) for 6 min. Fresh frozen sections were obtained after euthanizing the rats on Days 1, 2, 4, 7, 10, 14, and 21. Histopathology and IMS of adjacent sections compared morphological and molecular changes, respectively. Results: Histopathological changes were absent immediately after TGI (at Day 1, superacute phase). At Days 2-21 after TGI (from subacute to chronic phases), histopathology revealed neuronal death associated with gliosis, inflammation, and accumulation of activated microglia in CA1. IMS detected significant molecular changes after TGI in the same CA1 domain: increase of PC (diacyl-16: 0/22: 6) in the superacute phase and increase of PC (diacyl-16:0/18:1) in the subacute to chronic phases. Conclusions: Histopathology and IMS can provide comprehensive and complementary information on cell death mechanisms in the hippocampal CA1 after global ischemia. IMS provided novel data on molecular changes in phospholipids immediately after TGI. Increased level of PC (diacyl-16: 0/22: 6) in the pyramidal cell layer of hippocampal CA1 prior to the histopathological change may represent an early step in delayed neuronal death mechanisms. (C) 2016 The Authors. Published by Elsevier Ltd. on behalf of IBRO.

In this study, we analyzed the spatiotemporal alterations of phospholipid composition in the spinal cord of an amyotrophic lateral sclerosis (ALS) mouse model (G93A-mutated human superoxide dismutase 1 transgenic mice [SOD1(G93A) mice]) using imaging mass spectrometry (IMS), a powerful method to visualize spatial distributions of various types of molecules in situ. Using this technique, we deciphered the phospholipid distribution in the pre-symptomatic stage, early stage after disease onset, and terminal stages of disease in female SOD1(G93A) mouse spinal cords. These experiments revealed a significant decrease in levels of docosahexaenoic acid (DHA)-containing phosphatidylcholines (PCs), such as PC (diacyl-16:0/22:6), PC (diacyl-18:0/22:6), and PC (diacyl-18:1/22:6) in the L5 anterior horns of terminal stage (22-week-old) SOD1(G93A) mice. The reduction in PC (diacyl-16:0/22:6) level could be reflecting the loss of motor neurons themselves in the anterior horn of the spinal cord in ALS model mice. In contrast, other PCs, such as PC (diacyl-16:0/16:0), were observed specifically in the L5 dorsal horn gray matter, and their levels did not vary between ALS model mice and controls. Thus, our study showed a significant decrease in DHA-containing PCs, but not other PCs, in the terminal stage of ALS in model mice, which is likely to be a reflection of neuronal loss in the anterior horns of the spinal cords. Given its enrichment in dorsal sensory regions, the preservation of PC (diacyl-16:0/16:0) may be the result of spinal sensory neurons being unaffected in ALS. Taken together, these findings suggest that ALS spinal cords show significant alterations in PC metabolism only at the terminal stage of the disease, and that these changes are confined to specific anatomical regions and cell types.

The interleukin (IL)-6 pathway plays an important role in recovery after spinal cord injury (SCI). The anti-IL-6 receptor antibody MR16-1 has been shown to suppress inflammation after SCI and promote recovery of motor function. The purpose of this study was to analyze the effects of MR16-1 on the expression patterns of phospholipids in the spinal cord in a mouse model of SCI. Eight-week-old C57BL/6JJmsSlc mice were used in this study. Laminectomy was performed at the ninth and tenth thoracic levels (T9-T10), and contusion injury of the spinal cord was induced at level T10. Immediately after SCI, mice were intraperitoneally injected with a single dose of MR16-1 (MR16-1 group) or a single dose of phosphate-buffered saline of the same volume (control group). Imaging mass spectrometry was performed to visualize phosphatidylcholine (PC) expression in the spinal cord 7 days after SCI. We found that MR16-1 treatment suppressed the infiltration of immune cells after SCI, and was able to increase the locomotor function post-injury. Phospholipid imaging revealed that the MR16-1 was able to prevent the reduction of docosahexaenoic acid (DHA)-containing PC in comparison with the control group. We also observed high levels of glial fibrillary acidic protein (GFAP) at the site of DHA-containing PC expression in the MR16-1 group. These results suggest that MR16-1 treatment influences the DHA-containing PC composition of GFAP-positive cells at the injury site as early as 7 days post-SCI.

Genetic and epidemiologic evidence suggests that cellular energy homeostasis is critically associated with Parkinson's disease (PD) pathogenesis. Here we demonstrated that genetic deletion of Poly (ADP-ribose) polymerase 1 completely blocked 6-hydroxydopamine-induced dopaminergic neurodegeneration and related PD-like symptoms. Hyperactivation of PARP-1 depleted ATP pools in dopaminergic (DA) neurons, thereby activating AMP-activated protein kinase (AMPK). Further, blockade of AMPK activation by viral infection with dominant-negative AMPK strongly inhibited DA neuronal atrophy with moderate suppression of nuclear translocation of apoptosis-inhibiting factor (AIF), whereas overactivation of AMPK conversely strengthened the 6-OHDA-induced DA neuronal degeneration. Collectively, these results suggest that manipulation of PARP-1 and AMPK signaling is an effective therapeutic approach to prevent PD-related DA neurodegeneration.

It has been recognized that ceramide levels are decreased in the epidermis of patients with atopic dermatitis and psoriasis. However, the underlying mechanism by which ceramide deficiency leads to skin inflammation still remains unclear. Here, we generated Sptlc2 targeted mice under control of the keratin 5 promoter (referred to as K5-SPT-KO mice), by which their keratinocytes were devoid of serine palmitoyltransferase (SPT), the rate-limiting enzyme for de novo sphingolipid synthesis. K5-SPT-KO mice have decreased levels of ceramide in the epidermis and these mice demonstrate barrier dysfunction. From 2 weeks of age, they develop skin inflammation, showing psoriasis-like histopathologic changes and inflammatory cell infiltrates in the dermis. While expression of IFN-γ was not observed in the inflamed skin and draining lymph nodes, increased levels of IL-17 and IL-22 were detected. Strikingly, K5-SPT-KO mice showed increased numbers of γδ-T cells that produce IL-17 (γδ-17) in the skin lesion and lymph nodes and most of them also produce IL-22, similar to Th17 cells. However, much fewer γδ-17 cells are detected in the skin and lymph nodes of wild-type mice. In vivo administration of anti-IL-12/23p40 antibody ameliorated the skin lesions and reduced the number of γδ-17 cells in K5-SPT-KO mice. Therefore, we conclude that ceramide deficiency in the epidermis results in the development of psoriasis-like lesions, likely mediated by IL-23-dependent γδ-17 cells in mice.

Tubulin, a main component of ciliary and flagellar axonemes, undergoes highly unique post-translational modifications, polyglutamylation and polyglycylation. Recent years, evidence accumulates that dysregulations of these two modifications lead to severe ciliary defects in a variety of model organisms, such as Chlamydomonas, Tetrahymena, C. elegans, Drosophila, and zebrafish. Previously, we have for the first time revealed that a reduction of tubulin polyglutamylation causes ciliopathy-related defects including severe respiratory problems, such as paranasal sinusitis and repetitive coughing or sneezing, and male infertility by means of a knockout mouse of a glutamate ligase (TTLL1KO) [Ikegami et al. 2010 PNAS]. Despite the clear ciliopathy-related defects by the loss of polyglutamylation-performing enzyme, it is still veiled whether over-polyglutamylation leads to ciliopathy-related phenotypes in mice. To address the question, we examined the retina of a spontaneous mutant of a glutamate-removing enzyme (pcd) mouse that displays late-onset retinal photoreceptor degeneration. The pcd mouse showed stronger polyglutamylation signals in the retinal cone and rod layer compared to wild-type animal. To test if the hyper-polyglutamylation leads to retinal degeneration, we generated a double mutant of pcd and TTLL1KO. The hyper-polyglutamylation observed in the cone and rod layer of pcd mice was neutralized in that of pcd/TTLL1KO double mutant. The retinal photoreceptor degeneration in pcd was almost completely rescued in the pcd/TTLL1KO double mutant. These results suggest that hyper-polyglutamylation underlies retinal photoreceptor degeneration. We would emphasize, in the conference, the importance of keeping narrow range of polyglutamylation level to maintain ciliary function.