Ceramide Signaling Research Articles

Sphingolipids Imbalanced in Brain Microvessel of Predisposed Reduced Uterine Perfusion Mice

Preeclampsia (PE), a hypertension disorder, is one of the most serious complications that can occur during pregnancy. It affects at least 2‐8% of pregnancies, causing up to 76,000 maternal deaths and 500,000 infant fatalities. PE negatively impacts the vasculature of multiple body systems and has significant neurovascular implications including reversible cerebral vasoconstriction syndrome and ischemic stroke. Although PE resolves after delivery, long term cerebrovascular effects remain. Women who have experienced PE are estimated to have an 80% increased risk of future stroke. Although the consequences of PE are extensive and prevalent, its full etiology is not yet known. It is suspected that cerebrovascular dysfunction plays a significant role in these critical ramifications of PE. Interestingly, the ceramide and sphingosine‐1‐phosphate (S1P) pathway is known to regulate many of the systems that are altered in PE. Specifically, ceramide and S1P are involved in regulation of blood pressure, vascular tone, and vessel permeability in addition to other cell and tissue processes. Because of the significant involvement of ceramide, S1P, and their signaling constituents in endothelial cell and vascular integrity, variations within this pathway may explain the link between PE and cerebrovascular disease. We hypothesize that the ceramide and S1P signaling pathway is linked to dysfunctional brain vasculature in mice that had a PE‐induced pregnancy. This study aims to prove the ceramide and S1P signaling pathway is altered in the cerebral microvasculature of PE murine models. C57BL female mice underwent reduced uterine perfusion pressure (RUPP) surgery at 10 weeks old to simulate PE or sham surgery. Brain microvessels (BMVs) were isolated from these mice dams nine months following delivery. Two step reverse transcription qPCR was performed to assess the mRNA expression of the various ceramide and S1P signaling components. It was found that RUPP mice BMVs express significantly less sphingosine kinase 1 (SphK1) in comparison to sham BMVs. RUPP mice BMVs also demonstrated significantly increased sphingosine‐1‐phosphate lyase 1 (Sgpl1) and phospholipid phosphatase 1 (Plpp1). RUPP mice BMVs exhibited decreased expression of ceramide kinase and sphingosine kinase 2 (Sphk2) as well. SphK1 and Sphk2 are key enzymes in producing S1P, an active signaling lipid responsible for maintaining the blood brain barrier, cerebrovascular integrity, and angiogenesis. Sgpl1 is responsible for the degradation of S1P into its inactive form, therefore contributing to endothelial apoptosis and diminished vessel integrity. Plpp1 catalyzes the production of pro‐apoptotic ceramide and was discovered to promote the metabolism of S1P. Ceramide kinase is a crucial enzyme in producing anti‐apoptotic ceramide‐1‐phosphate. These discrepancies in ceramide and S1P signaling pathway expression may contribute to impaired cerebrovascular health, providing insight into the increased incidence of stroke with PE.

Infusion of C20 ceramide induces depressive‐like behavior, increases microglia but not astrocyte expression

Depression is a disease affecting the population worldwide. Depressed patients have shown alteration in the hippocampus suggesting this region can be an important region to study the impact of the development of depressive‐like behavior. Literature has demonstrated depressed patients present an increased levels of long‐chain ceramides. Ceramide is a sphingolipid component of the cellular membrane and play an important role in its structural integrity. To better understand depression mechanisms it is important to assess the glial cells mechanisms, since these cells play an essential role in inflammation, which is increased in depressed patients. Literature has reported interaction between astrocytes and microglia, still their detailed mechanism, their individual response to ceramide signaling, and contribution to depressive‐like behavior development are not clearly understood. Some research has demonstrated that microglia are activated in the presence of C20 and C16 ceramide. Otherwise, data have shown that reactive astrocytes interact with C16 ceramide but not with C24 ceramides. Because of this, we hypothesize that the infusion of long‐chain ceramides (C20) in the ventral hippocampus will increase the development of depressive‐like behavior, will cause an increase in the level of microglia expression but not astrocyte expression. We performed seven infusions of long‐chain ceramides into the ventral hippocampus followed by behavior analysis to measure the development of depressive‐like behavior and tissue collection to analyze inflammatory profile. Results show that rats infused with long‐chain ceramides present development of short‐term anhedonia‐like behavior twenty‐four hours after infusions but no depressive‐like behavior was assessed five days after the last infusion of ceramides. Also, infusion of ceramides induce an increase in microglia expression but no significant differences were assessed in astrocyte expression. These results suggest that C20 ceramide activates the microglia inflammatory pathway but not astrocyte mediated inflammation. There might be different mechanisms inducing inflammation in microglia and astrocytes. This preliminary data can also suggest that microglia mediated inflammation can contribute more to depressive‐like behavior than astrocytes. These results bring speculative significance, but more comprehensive studies can show a higher understanding of ceramide signaling in inflammation and a better understanding of the contribution of microglia and astrocytes to the development of depressive‐like behavior.

Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle

The endoplasmic reticulum (ER) regulates cellular protein and lipid biosynthesis. ER dysfunction leads to protein misfolding and the unfolded protein response (UPR), which limits protein synthesis to prevent cytotoxicity. Chronic ER stress in skeletal muscle is a unifying mechanism linking lipotoxicity to metabolic disease. Unidentified signals from cells undergoing ER stress propagate paracrine and systemic UPR activation. Here, we induce ER stress and lipotoxicity in myotubes. We observe ER stress-inducing lipid cell non-autonomous signal(s). Lipidomics identifies that palmitate-induced cell stress induces long-chain ceramide 40:1 and 42:1 secretion. Ceramide synthesis through the ceramide synthase 2 de novo pathway is regulated by UPR kinase Perk. Inactivation of CerS2 in mice reduces systemic and muscle ceramide signals and muscle UPR activation. The ceramides are packaged into extracellular vesicles, secreted and induce UPR activation in naïve myotubes through dihydroceramide accumulation. This study furthers our understanding of ER stress by identifying UPR-inducing cell non-autonomous signals.

Associations of NAFLD with circulating ceramides and impaired glycemia

AimDetermine the association of circulating ceramides with NAFLD and glycemic impairment. MethodsSample: 669 participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort aged 40–84 years without cardiovascular disease, cirrhosis, or significant alcohol intake. Clinical measuresComputed tomography scans at baseline for hepatic attenuation. Fasting serum specimens at baseline and after 5 years. Lipidomics: LC-MS-based analysis of 19 known ceramide signals. Statistical analysisLinear and logistic regression models of log-transformed ceramides, hepatic attenuation and glucose adjusted for age, sex, calories, study site, BMI, exercise, diet quality, alcohol, saturated fat, lipid-lowering medications and fasting glucose. ResultsAverage age was 55 years, 44% were women, mean BMI was 25.9 kg/m2, and 8% had NAFLD. In adjusted models, Cer(d16:1/20:0) and Cer(d18:1/18:0) were associated with lower mean hepatic attenuation (increased liver fat) (β −4.29; 95% CI [-5.98, −2.59]) and (β −3.40; 95% CI [-5.11, −1.70]), and LacCer(d18:1/16:0) with higher attenuation (β 4.44; 95% CI [2.15, 6.73]). All three ceramides partially mediated the relationship between hepatic attenuation and fasting glucose by 16%, 11% and 5%, respectively, after 5-years. ConclusionsThree circulating ceramides were strongly associated with NAFLD and fasting glucose after 5 years, and partially mediated this association.

Sphingolipid Metabolism and Signaling in Endothelial Cell Functions.

The endothelium, inner layer of blood vessels, constitutes a metabolically active paracrine, endocrine, and autocrine organ, able to sense the neighboring environment and exert a variety of biological functions important to preserve the health of vasculature, tissues, and organs. Sphingolipids are both fundamental structural components of the eukaryotic membranes and signaling molecules regulating a variety of biological functions. Ceramide and sphingosine-1-phosphate (S1P), bioactive sphingolipids, have emerged as important regulators of cardiovascular functions in health and disease. In this review we discuss recent insights into the role of ceramide and S1P biosynthesis and signaling in regulating endothelial cell functions, in health and diseases. We also highlight advances into the mechanisms regulating serine palmitoyltransferase, the first and rate-limiting enzyme of de novo sphingolipid biosynthesis, with an emphasis on its inhibitors, ORMDL and NOGO-B. Understanding the molecular mechanisms regulating the sphingolipid de novo biosynthesis may provide the foundation for therapeutic modulation of this pathway in a variety of conditions, including cardiovascular diseases, associated with derangement of this pathway.

Sortilin deletion in the prefrontal cortex and hippocampus ameliorates depressive-like behaviors in mice via regulating ASM/ceramide signaling.

Major depressive disorder (MDD) is a common psychiatric disorder characterized by persistent mood despondency and loss of motivation. Although numerous hypotheses have been proposed, the possible pathogenesis of MDD remains unclear. Several recent studies show that a classic transporter protein, sortilin, is closely associated with depression. In the present study, we investigated the role of sortilin in MDD using a well-established rodent model of depression. Mice were subjected to chronic unpredictable mild stress (CUMS) for 6 weeks. We showed that the expression levels of sortilin were significantly increased in the prefrontal cortex and hippocampus of CUMS mice. The depressive-like behaviors induced by CUMS were alleviated by specific knockdown of sortilin in the prefrontal cortex and hippocampus. We revealed that sortilin facilitated acid sphingomyelinase (ASM)/ceramide signaling, which activated RhoA/ROCK2 signaling, ultimately causing the transformation of dendritic spine dynamics. Specific overexpression of sortilin in the prefrontal cortex and hippocampus induced depressive-like behaviors, which was mitigated by injection of ASM inhibitor SR33557 (4 µg/μL) into the prefrontal cortex and hippocampus. In conclusion, sortilin knockdown in the prefrontal cortex and hippocampus plays an important role in ameliorating depressive-like behavior induced by CUMS, which is mainly evidenced by decreasing the trafficking of ASM from the trans-Golgi network to the lysosome and reducing the ceramide levels. Our results provide a new insight into the pathology of depression, and demonstrate that sortilin may be a potential therapeutic target for MDD.

Links between ceramides and cardiac function.

Total ceramide levels in cardiac tissue relate to cardiac dysfunction in animal models. However, emerging evidence suggests that the fatty acyl chain length of ceramides also impacts their relationship to cardiac function. This review explores evidence regarding the relationship between ceramides and left ventricular dysfunction and heart failure. It further explores possible mechanisms underlying these relationships. In large, community-based cohorts, a higher ratio of specific plasma ceramides, C16 : 0/C24 : 0, related to worse left ventricular dysfunction. Increased left ventricular mass correlated with plasma C16 : 0/C24 : 0, but this relationship became nonsignificant after adjustment for multiple comparisons. Decreased left atrial function and increased left atrial size also related to C16 : 0/C24 : 0. Furthermore, increased incident heart failure, overall cardiovascular disease (CVD) mortality and all-cause mortality were associated with higher C16 : 0/C24 : 0 (or lower C24 : 0/C16 : 0). Finally, a number of possible biological mechanisms are outlined supporting the link between C16 : 0/C24 : 0 ceramides, ceramide signalling and CVD. High cardiac levels of total ceramides are noted in heart failure. In the plasma, C16 : 0/C24 : 0 ceramides may be a valuable biomarker of preclinical left ventricular dysfunction, remodelling, heart failure and mortality. Continued exploration of the mechanisms underlying these profound relationships may help develop specific lipid modulators to combat cardiac dysfunction and heart failure.

Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis.

Doxorubicin (Dox) is a chemotherapeutic agent with cardiotoxicity associated with profibrotic effects. Dox increases ceramide levels with pro-inflammatory effects, cell death, and fibrosis. The purpose of our study was to identify the underlying ceramide signaling pathways. We aimed to characterize the downstream effects on cell survival, metabolism, and fibrosis. Human fibroblasts (hFSF) were treated with 0.7 µM of Dox or transgenically overexpressed ceramide synthase 2 (FLAG-CerS2). Furthermore, cells were pre-treated with MitoTempo (MT) (2 h, 20 µM) or Fumonisin B1 (FuB) (4 h, 100 µM). Protein expression was measured by Western blot or immunofluorescence (IF). Ceramide levels were determined with mass spectroscopy (MS). Visualizations were conducted using laser scanning microscopy (LSM) or electron microscopy. Mitochondrial activity was measured using seahorse analysis. Dox and CerS2 overexpression increased CerS2 protein expression. Coherently, ceramides were elevated with the highest peak for C24:0. Ceramide- induced mitochondrial ROS production was reduced with MT or FuB preincubation. Mitochondrial homeostasis was reduced and accompanied by reduced ATP production. Our data show that the increase in pro-inflammatory ceramides is an essential contributor to Dox side-effects. The accumulation of ceramides resulted in a lipotoxic shift and subsequently mitochondrial structural and functional damage, which was partially reversible following inhibition of ceramide synthesis.

Central ceramide signaling mediates obesity-induced precocious Puberty

Cell Metab. 2020 Dec 1;32(6):951–966.e8. 10.1016/j.cmet.2020.10.001. PMID: 33080217. https://www.sciencedirect.com/science/article/pii/S1550413120305349?via%3Dihub

Network Pharmacology Analysis of the Identification of Phytochemicals and Therapeutic Mechanisms of Paeoniae Radix Alba for the Treatment of Asthma.

BackgroundPaeoniae Radix Alba (PRA), the root of the plant Paeonia lactiflora Pall., has been suggested to play an important role for the treatment of asthma. A biochemical understanding of the clinical effects of Paeoniae Radix Alba is needed. Here, we explore the phytochemicals and therapeutic mechanisms via a systematic and comprehensive network pharmacology analysis. Methods Through TCMSP, PubChem, GeneCards database, and SwissTargetPrediction online tools, potential targets of active ingredients from PRA for the treatment of asthma were obtained. Cytoscape 3.7.2 was used to determine the target of active ingredients of PRA. Target protein interaction (PPI) network was constructed through the STRING database. The Gene Ontology (GO) biological process and Kyoto Encyclopedia of Genes and Genes (KEGG) pathway enrichment analysis were analyzed through the biological information annotation database (DAVID). Results Our results indicate that PRA contains 21 candidate active ingredients with the potential to treat asthma. The enrichment analysis of GO and KEGG pathways found that the treatment of asthma by PRA may be related to the process of TNF (tumor necrosis factor) release, which can regulate and inhibit multiple signaling pathways such as ceramide signaling. Conclusions Our work provides a phytochemical basis and therapeutic mechanisms of PRA for the treatment of asthma, which provides new insights on further research on PRA.

Effect of Gegen Qinlian Decoction on Hepatic Gluconeogenesis in ZDF Rats with Type 2 Diabetes Mellitus Based on the Farnesol X Receptor/Ceramide Signaling Pathway Regulating Mitochondrial Metabolism and Endoplasmic Reticulum Stress.

Background Type 2 diabetes mellitus (T2DM) is a kind of disorder of glucose and lipid metabolism with the main clinical manifestation of long‐term higher blood glucose level than the normal value. Farnesol X receptor (FXR)/ceramide signaling pathway plays an important role in regulating cholesterol metabolism, lipid homeostasis, and the absorption of fat and vitamins in diet. Gegen Qinlian Decoction (GQD) is a classical herbal formula, which has a good clinical therapeutic effect on diabetes-related metabolic syndrome. Objective To investigate the effect of Gegen Qinlian Decoction (GQD) on hepatic gluconeogenesis in obese T2DM rats based on the FXR/ceramide signaling pathway regulating mitochondrial metabolism and endoplasmic reticulum stress (ERS). Methods ZDF (fa/fa) rats were fed with high-fat diet to establish the T2DM model; GQD was given to T2DM model rats by gavage; changes of the general state and body weight of rats were recorded; fasting blood glucose was detected; blood insulin, blood ceramide, glycosylated hemoglobin in blood, acetyl CoA in liver mitochondria, and bile salt lyase in intestinal tissue were detected by ELISA. The content of T-β-MCA in blood was detected by LC-MS; the content of glycogen in liver tissue was detected by PAS staining; the expression of FXR, Sptlc2, and Smpd3 in ileum tissue, P-PERK, ATF6α, GRP78 BIP, and P-IRE1 in the liver, and CS and PC protein in liver mitochondria was detected by immunohistochemistry and western blot assay. The mRNA expression levels of FXR, Sptlc2, and Smpd3 in the ileum, PERK, ATF6α, GRP78 BIP, and IRE1 in the liver, and CS and PC in liver mitochondria were detected by qRT-PCR. Results GQD can improve the general state of T2DM rats, slow down their weight gain, reduce the levels of fasting blood glucose, fasting insulin, glycosylated hemoglobin, blood ceramide, bile salt hydrolase in intestinal tissue, and acetyl CoA in liver mitochondria of T2DM rats, and increase the contents of liver glycogen and T-β-MCA in blood of T2DM rats. At the molecular level, GQD can inhibit the expression levels of FXR, Sptlc2, and Smpd3 in the ileum of T2DM rats and the protein and mRNA expression levels of oxidative stress-related factors in the liver. At the same time, GQD can increase the expression of CS and reduce the expression of PC in liver mitochondria of T2DM rats. Conclusion GQD can inhibit the FXR/ceramide signaling pathway, regulate endoplasmic reticulum stress, enhance the CS activity of liver mitochondria, reduce the acetyl CoA level and PC activity of liver mitochondria, inhibit hepatic gluconeogenesis, protect islet β-cells, and control blood glucose.

Microglia modulate stable wakefulness via the thalamic reticular nucleus in mice

Microglia are important for brain homeostasis and immunity, but their role in regulating vigilance remains unclear. We employed genetic, physiological, and metabolomic methods to examine microglial involvement in the regulation of wakefulness and sleep. Microglial depletion decreased stable nighttime wakefulness in mice by increasing transitions between wakefulness and non-rapid eye movement (NREM) sleep. Metabolomic analysis revealed that the sleep-wake behavior closely correlated with diurnal variation of the brain ceramide, which disappeared in microglia-depleted mice. Ceramide preferentially influenced microglia in the thalamic reticular nucleus (TRN), and local depletion of TRN microglia produced similar impaired wakefulness. Chemogenetic manipulations of anterior TRN neurons showed that they regulated transitions between wakefulness and NREM sleep. Their firing capacity was suppressed by both microglial depletion and added ceramide. In microglia-depleted mice, activating anterior TRN neurons or inhibiting ceramide production both restored stable wakefulness. These findings demonstrate that microglia can modulate stable wakefulness through anterior TRN neurons via ceramide signaling.

The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy.

Simple SummarySphingolipids are membrane-associated lipids that are involved in signal transduction pathways regulating cell death, growth, and migration. In cancer cells, sphingolipids regulate pathways relevant to cancer therapy, such as invasion, metastasis, apoptosis, and lethal mitophagy. Notable sphingolipids include ceramide, a sphingolipid that induces death and lethal mitophagy, and sphingosine-1 phosphate, a sphingolipid that induces survival and chemotherapeutic resistance. These sphingolipids participate in regulating the process of mitophagy, where cells encapsulate damaged mitochondria in double-membrane vesicles (called autophagosomes) for degradation. Lethal mitophagy is an anti-tumorigenic mechanism mediated by ceramide, where cells degrade many mitochondria until the cancer cell dies in an apoptosis-independent manner.Sphingolipids are bioactive lipids responsible for regulating diverse cellular functions such as proliferation, migration, senescence, and death. These lipids are characterized by a long-chain sphingosine backbone amide-linked to a fatty acyl chain with variable length. The length of the fatty acyl chain is determined by specific ceramide synthases, and this fatty acyl length also determines the sphingolipid’s specialized functions within the cell. One function in particular, the regulation of the selective autophagy of mitochondria, or mitophagy, is closely regulated by ceramide, a key regulatory sphingolipid. Mitophagy alterations have important implications for cancer cell proliferation, response to chemotherapeutics, and mitophagy-mediated cell death. This review will focus on the alterations of ceramide synthases in cancer and sphingolipid regulation of lethal mitophagy, concerning cancer therapy.

Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response

SUMMARYWe lack a mechanistic understanding of aging-mediated changes in mitochondrial bioenergetics and lipid metabolism that affect T cell function. The bioactive sphingolipid ceramide, induced by aging stress, mediates mitophagy and cell death; however, the aging-related roles of ceramide metabolism in regulating T cell function remain unknown. Here, we show that activated T cells isolated from aging mice have elevated C14/C16 ceramide accumulation in mitochondria, generated by ceramide synthase 6, leading to mitophagy/mitochondrial dysfunction. Mechanistically, aging-dependent mitochondrial ceramide inhibits protein kinase A, leading to mitophagy in activated T cells. This aging/ceramide-dependent mitophagy attenuates the antitumor functions of T cells in vitro and in vivo. Also, inhibition of ceramide metabolism or PKA activation by genetic and pharmacologic means prevents mitophagy and restores the central memory phenotype in aging T cells. Thus, these studies help explain the mechanisms behind aging-related dysregulation of T cells’ antitumor activity, which can be restored by inhibiting ceramide-dependent mitophagy.

Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

Pancreatic β-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for β-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic β-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in β-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced β-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in β-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in β-cells. This inhibitory intervention may be due to an increase of membrane fluidity.

Unwrapping the mechanisms of ceramide and fatty acid-initiated signals leading to immune-inflammatory responses in obesity

Obesity is considered a global epidemic developed in part as a consequence of the overconsumption of high fat diets. One of the main negative outcomes of obesity is the development of low-grade chronic systemic inflammation, induced by dysregulated immune responses, which can lead to multiple obesity-related diseases. Ceramides are a group of bioactive lipids known to be elevated in obesity and obesity-associated conditions, including cardiovascular disease and type II diabetes. Ceramides may be key players in promoting an obesity–induced inflammatory environment due to their ability to activate key pathways such as Toll-like receptor 4 (TLR4) and NLR pyrin domain containing receptor 3 (Nlrp3), while studies have shown that inhibition of ceramide synthesis gives rise to an anti-inflammatory environment. N-3 polyunsaturated fatty acids (n-3 PUFA) have been of interest due to their anti-inflammatory actions and shown to have beneficial effects in obesity-related diseases. This review will highlight the impact of ceramides in promoting an obesity-induced inflammatory microenvironment and discuss how n-3 PUFA could potentially counteract these responses and have a regulatory effect promoting immune homeostasis.

The ceramide fast track to puberty

Diet-induced obesity triggers hypothalamic ceramide signaling that leads to precocious puberty in female rats.

Central Ceramide Signaling Mediates Obesity-Induced Precocious Puberty

Childhood obesity, especially in girls, is frequently bound to earlier puberty, which is linked to higher disease burden later in life. The mechanisms underlying this association remain elusive. Here we show that brain ceramides participate in the control of female puberty and contribute to its alteration in early-onset obesity in rats. Postnatal overweight caused earlier puberty and increased hypothalamic ceramide content, while pharmacological activation of ceramide synthesis mimicked the pubertal advancement caused by obesity, specifically in females. Conversely, central blockade of de novo ceramide synthesis delayed puberty and prevented the effects of the puberty-activating signal, kisspeptin. This phenomenon seemingly involves a circuit encompassing the paraventricular nucleus (PVN) and ovarian sympathetic innervation. Early-onset obesity enhanced PVN expression of SPTLC1, a key enzyme for ceramide synthesis, and advanced the maturation of the ovarian noradrenergic system. In turn, obesity-induced pubertal precocity was reversed by virogenetic suppression of SPTLC1 in the PVN. Our data unveil a pathway, linking kisspeptin, PVN ceramides, and sympathetic ovarian innervation, as key for obesity-induced pubertal precocity.

Cancer stem cells and ceramide signaling: the cutting edges of immunotherapy

The multipotent, self renewing "cancer stem cells" (CSCs), a small population within tumor microenvironment facilitates transformed cells to grow and propagate within the body. The CSCs are discovered as resistant to the chemotherapeutic drug with distinct immunological characteristics. In recent years, immunologically targeting CSCs have emerged as an integral part of effective and successful cancer therapy. CSCs notably exhibit dysregulation in conventional sub-cellular sphingolipid metabolism. Recently, ceramide decaying enzymes have been shown to activate alternative ceramide signaling pathways leading to reduction in efficacy of the chemotherapeutic drugs. Therefore, a control over ceramide mediated modulations of CSCs offers an attractive dimension of effective cancer treatment strategy in future. In this review, we focused on the recent findings on broad spectrum of ceramide mediated signaling in CSCs within the tumor niche and their role in potential cancer immunotherapy.

Ceramide induces MMP-9 expression through JAK2/STAT3 pathway in airway epithelium

BackgroundCeramide, a bioactive lipid, plays an essential role in the development of several pulmonary inflammatory diseases. Matrix metallopeptidase 9 (MMP-9) regulates the synthesis and degradation of extracellular matrix, and is associated with airway remodeling and tissue injury. This study was conducted to investigate the effects and underlying mechanisms of ceramide on MMP-9 expression in airway epithelium.MethodsBEAS-2B cells, normal human bronchial epithelium cell lines, were pretreated with AG490, a selective janus tyrosine kinase 2 (JAK2) inhibitor, or Stattic, a selective signal transducer and activator of transcription 3 (STAT3) inhibitor. The cells were then stimulated with C6-ceramide. The levels of MMP-9 were determined by ELISA and real-time quantitative PCR (RT-qPCR). JAK2, phosphorylated JAK2 (p-JAK2), STAT3, and phosphorylated STAT3 (p-STAT3) expression was examined by Western blotting. BALB/c mice were pretreated with AG490 or Stattic before intratracheally instillated with C6-ceramide. Pathological changes in lung tissues were examined by Hematoxylin and Eosin staining, Periodic-acid Schiff staining, and Masson’s trichrome staining. MMP-9, JAK2, p-JAK2, STAT3, and p-STAT3 expression in the lung tissues was examined by Western blotting.ResultsThe expression of MMP-9, p-JAK2 and p-STAT3 in BEAS-2B cells was significantly increased after the treatment of C6-ceramide. Furthermore, the increased expression of MMP-9 induced by C6-ceramide was inhibited by AG490 and Stattic. Similar results were obtained in the lung tissues of C6-ceramide-exposed mice which were treated with AG490 or Stattic.ConclusionsCeramide could up-regulate MMP-9 expression through the activation of the JAK2/STAT3 pathway in airway epithelium. Targeted modulation of the ceramide signaling pathway may offer a potential therapeutic approach for inhibiting MMP-9 expression. This study points to a potentially novel approach to alleviating airway remodeling in inflammatory airway diseases.