Obesity is considered to be a risk factor for neurodegenerative- and psychiatric- diseases including Alzheimer's disease, schizophrenia, and depression. A high-lard diet is widely used to induce ...obesity in model animal experiments, which also leads to anxiety-like and depression-like behaviors. However, the contribution of dietary fat source to these abnormal behaviors in obesity is largely unknown.
Sprague-Dawley rats were treated with different types of high-fat (lard and olive oil) diet with high sucrose for more than 8 weeks. Anxiety-like behavior (open-field and social interaction tests) and cognitive function (Y-maze test) after the treatment were analyzed. The expression of mRNA related to neurotransmitter and nutrient transporters in the prefrontal cortex were determined using real-time PCR. Serum lipid species were determined using liquid chromatography with tandem mass spectrometry.
Both high-fat/high-sucrose diets increased body weight (BW), adipose tissue, and serum leptin level. However, the high-lard/high-sucrose (HL/HS), but not high-olive oil/HS, diet induced anxiety-like behavior in open field and social interaction tests. BW and endocrine hormones such as leptin and insulin were not correlated to anxiety-like behavior. HL/HS diet induced an increase in glutamate transporter and a decrease of glutamate receptor mRNA expressions in the prefrontal cortex. Further, serum lysophosphatidyl choline conjugated with several fatty acids was decreased by HL/HS diet. LPC conjugated with eicosapentaenoic acid (EPA) was strongly correlated with anxiety-like behavior.
These results suggest that lipid composition, rather than obesity per se, is a major cause of anxiety-like behavior in high-fat diet-induced obesity. Decreased levels of peripheral LPC conjugated with EPA and altered glutamate system in the prefrontal cortex might be involve in the pathophysiology of the behavioral change.
Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator that, along with its chemically stabilized analogue 2-carba-cyclic phosphatidic acid (2ccPA), induces various biological ...activities in vitro and in vivo. Although cPA is similar to lysophosphatidic acid (LPA) in structure and synthetic pathway, some of cPA biological functions apparently differ from those reported for LPA. We previously investigated the pharmacokinetic profile of 2ccPA, which was found to be rapidly degraded, especially in acidic conditions, yielding an unidentified compound. Thus, not only cPA but also its degradation compound may contribute to the biological activity of cPA, at least for 2ccPA. In this study, we determined the structure and examined the biological activities of 2-carba-lysophosphatidic acid (2carbaLPA) as a 2ccPA degradation compound, which is a type of β-LPA analogue. Similar to LPA and cPA, 2carbaLPA induced the phosphorylation of the extracellular signal-regulated kinase and showed potent agonism for all known LPA receptors (LPA
) in the transforming growth factor-α (TGFα) shedding assay, in particular for LPA
and LPA
. 2carbaLPA inhibited the lysophospholipase D activity of autotaxin (ATX) in vitro similar to other cPA analogues, such as 2ccPA, 3-carba-cPA, and 3-carba-LPA (α-LPA analogue). Our study shows that 2carbaLPA is a novel β-LPA analogue with high potential for the activation of some LPA receptors and ATX inhibition.
A humanized anti‐HER2 monoclonal antibody pertuzumab (Omnitarg, 2C4), binding to a different HER2 epitope than trastuzumab, is known as an inhibitor of heterodimerization of the HER receptors. Potent ...antitumor activity against HER2‐expressing breast and prostate cancer cell lines has been clarified, but this potential is not clear against lung cancers. The authors investigated the in vitro anti‐tumor activity of pertuzumab against eight non‐small cell lung cancer cells expressing various members of the HER receptors. A lung cancer 11_18 cell line expressed a large amount of HER2 and HER3, and its cell growth was stimulated by an HER3 ligand, heregulin (HRG)‐α. Pertuzumab significantly inhibited the HRG‐α‐stimulated cellular growth of the 11_18 cells. Pertuzumab blocked HRG‐α‐stimulated phosphorylation of HER3, mitogen‐activated protein kinase (MAPK), and Akt. In contrast, pertuzumab failed to block epidermal growth factor (EGF)‐stimulated phosphorylation of EGF receptor (EGFR) and MAPK. Immunoprecipitation showed that pertuzumab inhibited HRG‐α‐stimulated HER2/HER3 heterodimer formation. HRG‐α‐stimulated HER3 phosphorylation was also observed in the PC‐9 cells co‐overexpressing EGFR, HER2, and HER3, but the cell growth was neither stimulated by HRG‐α nor inhibited by pertuzumab. The present results suggest that pertuzumab is effective against HRG‐α‐dependent cell growth in lung cancer cells through inhibition of HRG‐α‐stimulated HER2/HER3 signaling. (Cancer Sci 2007; 98: 1498–1503)
•Oleic acid strongly induced astrocytic lipid droplet (LD) accumulation.•Lipid composition of cellular LDs reflected to extracellular fatty acids.•Inhibition of LDs accumulation caused lipotoxicity ...in astrocytes.
Astrocytes exhibit an important role in neural lipid metabolism for the regulation of energy balance to supply fatty acids (FAs) and ketone bodies to other neural cells. Lipid droplets (LDs) consisting of neutral- and phospho-lipids increase in the brains of patients with neurodegenerative diseases, such as Alzheimer’s disease and multiple sclerosis. However, the role of LDs and its lipid source remains largely unexplored. Here, we found that oleic acid (OA) was a potent inducer of astrocytic LD accumulation among various FAs. Lipidomic analysis using liquid chromatography equipped with tandem mass spectrometry revealed that the cellular triacylglycerol and phospholipid compositions in astrocytes during LD accumulation reflected the condition of extracellular FAs. Furthermore, the inhibition of diacylglycerol acyltransferase blocked OA-induced LD accumulation and caused lipotoxicity-induced cell death in astrocytes. The present study demonstrated that the formation of LDs, caused due to the increased extracellular OA, facilitated survival against lipotoxic condition.
Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of ...hereditary colon cancer syndromes such as Lynch syndrome. Long‐term chronic inflammation is also a key risk factor, responsible for colitis‐associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation‐induced colon carcinogenesis in DNA mismatch repair‐proficient and repair‐deficient mice. Male and female Mlh1−/− and Mlh1+/+ mice were irradiated with 2 Gy X‐rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X‐rays and/or DSS treatment in Mlh1+/+ mice. Colon tumors developed after DSS treatment alone in Mlh1−/− mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well‐to‐moderately differentiated adenocarcinomas with tumor‐infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and β‐catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis‐associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency.
In this study, we examined the effect of X‐rays in combination with dextran sodium sulfate (DSS)‐induced inflammatory colitis on colon carcinogenesis in C57BL/6 Mlh1+/+ and Mlh1−/− mice. No colon tumors were observed in Mlh1+/+ mice with any treatment. Colon lesions developed after DSS alone, or in combination with X‐rays in Mlh1−/− mice. Incidence and multiplicity of colon lesions were generally higher when DSS treatment was combined with X‐ray exposure, particularly in male Mlh1−/− mice.
Lysophosphatidic acid (LPA) and LPA1 receptor signaling play a crucial role in the initiation of peripheral nerve injury-induced neuropathic pain through the alternation of pain-related ...genes/proteins expression and demyelination. However, LPA and its signaling in the brain are still poorly understood. In the present study, we revealed that the LPA5 receptor expression in corpus callosum elevated after the initiation of demyelination, and the hyperalgesia through Aδ-fibers following cuprizone-induced demyelination was mediated by LPA5 signaling. These data suggest that LPA5 signaling may play a key role in the mechanisms underlying neuropathic pain following demyelination in the brain.
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•Astrocyte conditioned media (2ccPA-ACM) was collected from 2ccPA-treated astrocytes.•2ccPA-ACM decreased the ratio of M1 phenotype microglia.•2ccPA-ACM increased the ratio of M2 ...phenotype microglia.•2ccPA-ACM suppressed the expression of pro-inflammatory cytokines in microglia.
2-carba-cyclic phosphatidic acid (2ccPA) suppresses microglial and astrocyte inflammation for neuronal survival following traumatic brain injury. However, it remains unknown how 2ccPA regulates microglial activation. In this study, to elucidate the 2ccPA behavior in glial communication, we collected the astrocyte conditioned media (ACM) from primary astrocyte cultures that were treated by lipopolysaccharide (LPS) and 2ccPA and analyzed the alteration of microglial inflammation caused by the ACM treatment. The addition of the ACM derived from LPS- and 2ccPA-double treated astrocytes to microglia decreased the CD86+ pro-inflammatory M1 microglia, which were upregulated with the ACM collected from astrocytes treated by LPS without 2ccPA, while the direct addition of LPS and 2ccPA to microglia failed to decrease the CD86+ microglia to the basal level. We confirmed that the ACM from LPS- and 2ccPA-treated astrocytes increased the ratio of CD206+ anti-inflammatory M2 microglia to total microglia, whereas direct treatment of microglia with LPS and 2ccPA had no effect on the CD206+ microglia ratio, demonstrating the importance of astrocyte intervention in microglial polarization. In addition, we examined whether astrocytes modulate the 2ccPA-regulated proinflammatory cytokine production derived from microglia. The addition of the ACM from LPS- and 2ccPA-treated astrocytes to microglia remarkably canceled the LPS-induced upregulation of IL-1β, IL-6, and TNF-α secreted from microglia, while the direct addition of LPS and 2ccPA to microglia showed no affect. Therefore, our results indicate that astrocytes mediate the 2ccPA function to shift microglia towards the M2 phenotype by interfering with the polarization of M1 microglia and to suppress cytokine production.
•2ccPA increased glial cell proliferation through the activation of LPA receptor.•2ccPA treatment enhanced cell survival against oxidative stress.•ERK pathway was required for 2ccPA-induced glial ...cell growth.
Lysophosphatidic acid (LPA) and cyclic phosphatidic acid (cPA) are one of the lipid mediators regulating cell proliferation and differentiation through the activation of LPA receptors. An LPA receptor-mediated signal is important for the development of the central nervous system, while it has been demonstrated that LPA caused microglial activation and astroglial dysfunction. Previously, we have reported that cPA and carba analog of cPA, 2-O-carba-cPA (2ccPA), protected neural damage caused by transient ischemia. However, little is known about the target cell of cPA/2ccPA in the central nervous systems. Here, we examined the effect of 2ccPA on glial proliferation and differentiation using the primary astrocytes and oligodendrocyte precursor cells (OPCs) cultures. 2ccPA increased the DNA synthesis of astrocytes and OPCs, but it did not reduce the formazan production in the mitochondria. Further, 2ccPA increased the cell number and cell survival against oxidative stress. The inhibition of LPA receptors by ki16425 abolished 2ccPA-induced DNA synthesis. Extracellular signal-regulated kinase (ERK) was activated by 2ccPA, which contributed to the astroglial DNA synthesis. These results suggest that 2ccPA is a beneficial regulator of glial population through the activation of LPA receptor without reduction of mitochondrial activity.
We examined the mechanism how 2-carba-cyclic phosphatidic acid (2ccPA), a lipid mediator, regulates neuronal apoptosis in traumatic brain injury (TBI). First, we found 2ccPA suppressed neuronal ...apoptosis after the injury, and increased the immunoreactivity of tenascin-C (TN-C), an extracellular matrix protein by 2ccPA in the vicinity of the wound region. 2ccPA increased the mRNA expression levels of Tnc in primary cultured astrocytes, and the conditioned medium of 2ccPA-treated astrocytes suppressed the apoptosis of cortical neurons. The neuroprotective effect of TN-C was abolished by knockdown of TN-C. These results indicate that 2ccPA contributes to neuroprotection via TN-C from astrocytes in TBI.
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•2ccPA has neuroprotective function in acute phase after the stab wound injury.•2ccPA regulates the expression of TN-C via astrocyte in acute phase.•The expression of TN-C by 2ccPA is contributed to neuroprotection after injury
Lipid-protein interactions play essential roles in many biological phenomena. Lysophospholipid mediators, such as cyclic phosphatidic acid (cPA), have been recognized as secondary messengers, yet few ...cellular targets for cPA have been identified to date. Furthermore, the molecular mechanism that activates these downstream signaling events remains unknown. In this study, using metabolically stabilized cPA carba-derivative (2ccPA)-immobilized magnetic beads, we identified adenine nucleotide translocase 2 (ANT2) as a 2ccPA-interacting protein in microglial cells. 2ccPA was tested for its ability to inhibit apoptosis caused by phenylarsine oxide in microglial cells. This damage was significantly improved upon 2ccPA treatment, along with cell proliferation, apoptosis, reactive oxygen species production, and intracellular ATP levels. This is the first report to suggest the direct binding of 2ccPA to ANT2 in microglial cells and provides evidence for a new benefit of 2ccPA in protecting microglial cells from apoptotic death induced by the ANT2-mediated signaling pathway.
•ANT2 as a 2ccPA-interacting protein in BV-2 cells.•2ccPA inhibited PAO-induced depolarization and apoptosis in BV-2 cells.•PAO mediated ROS generation was blocked by 2ccPA.•2ccPA decreased the PAO-induced intracellular ATP concentration.•PAO-induced phosphorylation of p38 MAPK was blocked by 2ccPA.
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