Familial idiopathic basal ganglia calcification (IBGC) is a genetic condition with a wide spectrum of neuropsychiatric symptoms, including parkinsonism and dementia. Here, we identified mutations in SLC20A2, encoding the type III sodium-dependent phosphate transporter 2 (PiT2), in IBGC-affected families of varied ancestry, and we observed significantly impaired phosphate transport activity for all assayed PiT2 mutants in Xenopus laevis oocytes. Our results implicate altered phosphate homeostasis in the etiology of IBGC.

Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE-/- mice. Transplantation with ATM-/- as compared to ATM+/+ bone marrow increased vascular disease. Jun N-terminal kinase (JNK) activity was increased in ATM-deficient cells. Treatment of ATM+/+apoE-/- mice with low-dose chloroquine, an ATM activator, decreased atherosclerosis. In an ATM-dependent manner, chloroquine decreased macrophage JNK activity, decreased macrophage lipoprotein lipase activity (a proatherogenic consequence of JNK activation), decreased blood pressure, and improved glucose tolerance. Chloroquine also improved metabolic abnormalities in ob/ob and db/db mice. These results suggest that ATM-dependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease.

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Endocannabinoids and ceramides have demonstrated growth inhibition, cell death induction and pro-apoptotic activity in cancer research. In the present study, we describe the profiles of two major endocannabinoids, ceramides, free fatty acids and relevant metabolic enzymes in 47 pairs of human colorectal cancer tissues and adjacent non-tumor tissues. Among them, anandamide (AEA) and its metabolite, arachidonic acid (AA), were markedly upregulated in cancer tissues particularly in those with lymphatic metastasis. The levels of C16 and C24 ceramides were significantly elevated in the colorectal tumor tissues, while levels of C18 and C20 ceramides showed opposite trends. Levels of two enzymes participating in the biosynthesis and degradation of AEA, N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NPLD) and fatty acid amide hydrolase (FAAH), together with the most abundant ceramide synthases (CerS1, CerS2, CerS5 and CerS6) in the colon were also determined. Quantitative-PCR analysis indicated that the mRNA levels of these enzymes were overexpressed in the tumor tissues. The activities of NPLD and FAAH were also upregulated. In addition, both gene and protein expression levels of cannabinoid receptor 1 (CB1) were elevated but not of CB2. Elevation of AEA and alteration of ceramides (C16, C24, C18, C20) may qualify as potential endogenous biomarkers and novel drug targets for colorectal cancer.

Inhibition of stearoyl-CoA desaturase 1 (SCD1) has been found to effectively suppress tumor cell proliferation and induce apoptosis in numerous neoplastic lesions. However, mechanism underlying SCD1-mediated anti-tumor effect has maintained unclear. Herein, we reported endo-lipid messenger ceramides played a critical role in tumor fate modulated by SCD1 inhibition. In vitro study in colorectal cancer cells demonstrated inhibition of SCD1 activity promoted apoptosis attributed to mitochondria dysfunctions, upregulation of reaction oxygen species (ROS), alteration of mitochondrial transmembrane potential and translocation of mitochondrial protein cytochrome C. While these effects were mediated by intracellular ceramide signals through induction of ceramide biosynthesis, rather than exclusive SFA accumulation. In vivo study in xenograft colorectal cancer mice showed pharmacologic administration of SCD1 inhibitor A939 significantly delayed tumor growth, which was reversed by L-cycloserine, an inhibitor of ceramide biosynthesis. These results depicted the cross-talk of SCD1-mediated lipid pathway and endo-ceramide biosynthesis pathway, indicating roles of ceramide signals in SCD1-mediated anti-tumor property.

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Background: Lactate greatly contributes to the regulation of intracellular communication within the tumor microenvironment (TME). However, the role of lactate in pituitary adenoma (PA) invasion is unclear. In this study, we aimed to clarify the effects of lactate on the TME and the effects of TME on PA invasion. Methods: To explore the correlation between TME acidosis and tumor invasion, LDHA and LAMP2 expression levels were quantified in invasive (n = 32) and noninvasive (n = 32) PA samples. The correlation between immune cell infiltration and tumor invasion was evaluated in 64 PAs. Critical chemokine and key signaling pathway components were detected by qPCR, Western blotting, siRNA knockdown, and specific inhibitors. The functional consequences of CCR4 signaling inhibition were evaluated in vitro and in vivo . Results: Lactate was positively associated with PA invasion. Of the 64 PA tissues, invasive PAs were related to high infiltration of M2-like tumor-associated macrophages (TAMs) (P < 0.05). Moreover, lactate secreted from PA cells facilitated M2 polarization via the mTORC2 and ERK signaling pathways, while activated TAMs secreted CCL17 to promote PA invasion via the CCL17/CCR4/mTORC1 axis. According to univariate analysis of clinical data, high CCL17 expression was associated with larger tumor size (P = 0.0438), greater invasion (P = 0.0334), and higher susceptibility to postoperative recurrence (P = 0.0195) in human PAs. Conclusion: This study illustrates the dynamics between PA cells and immune TME in promoting PA invasion via M2 polarization. CCL17 levels in the TME are related to the PA invasiveness and clinical prognosis, and the CCL17/CCR4/mTOCR1 axis may serve as potential therapeutic targets for Pas.

Oleoylethanolamide (OEA), an endocannabinoid-like molecule, was revealed to modulate lipid metabolism through a peroxisome proliferator-activated receptor-α (PPAR-α) mediated mechanism. In present study, we further investigated the activities and mechanisms of OEA in ameliorating hepatic fibrosis in Sv/129 mice induced by a methionine choline-deficient (MCD) diet or thioacetamide (TAA) treatment. Liver fibrosis development was assessed by Hematoxylin-eosin and Sirius red staining. Treatment with OEA (5 mg/kg/day, intraperitoneal injection, i.p.) significantly attenuated the progress of liver fibrosis in both two experimental animal models by blocking the activation of hepatic stellate cells (HSCs). Gene expression analysis of hepatic tissues indicated that OEA inhibited the expression of α-smooth muscle action (α-SMA) and collagen matrix, fibrosis markers, and genes involved in inflammation and extracellular matrix remodeling. In vitro studies showed that OEA inhibited transforming growth factor β1-stimulated HSCs activation through suppressing Smad2/3 phosphorylation, α-SMA expression and myofibroblast transformation. These improvements could not be observed in PPAR-α knockout mice models with OEA administration, which suggested all the anti-fibrotic effects of OEA in vivo and in vitro were mediated by PPAR-α activation. Collectively, our results suggested that OEA exerted a pharmacological effect on modulating hepatic fibrosis development through the inhibition of HSCs activation in liver and therefore may be a potential therapeutic agent for liver fibrosis.