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Multiple myeloma (MM) is characterized by the clonal proliferation of malignant plasma cells and refractoriness to traditional therapies. It has been shown that exosomes are involved in modulating the progression and the metastasis of cancers through microRNAs (miRs). Ceramide is a type of sphingolipid; the ceramide pathway of exosomal secretion has been shown to affect the apoptosis of cancer cells. But the role of this pathway in MM cell function, exosome function and miR regulation remains unknown. In this study, we showed that C6 ceramide (an exogenous ceramide supplement, 1.25-40 μmol/L) dose-dependently inhibited the proliferation and promoted the apoptosis in human MM OPM2 cell line, which were associated with elevated caspase 3/9 and PARP cleavage. We also found that C6 ceramide (5-20 μmol/L) dose-dependently stimulated exosome secretion and increased exosomal levels of tumor-suppressive miRs (miR 202, miR 16, miR 29b and miR 15a). Of note, exosomes from C6 ceramide-treated OPM2 cells could influence the proliferation and apoptosis of the recipient OPM2 cells, which correlated with increased tumor-suppressive exosomal miRs. In contrast, GW4869 (a ceramide inhibitor, 5-20 μmol/L) exerted the opposite effects on the regulation of MM function, exosome secretion and miR levels in MM exosomes. However, exosomes from GW4869-treated OPM2 cells had no effect on these miRs and the survival of targeted OPM2 cells. Taken together, our findings reveal that the ceramide pathway modulates MM survival, probably directly via the caspase pathway and indirectly via exosomal miR mechanisms.

ABSTRACT Background Changes in the level or profile of ceramides are associated with decreased stratum corneum (SC) barrier function. Topical application of a pseudo‐ceramide (pCer)‐containing moisturizer can improve barrier function. Additionally, pCer that absorbs into the SC may improve ceramide profiles. Aim We investigated the relationship between pCer absorption into the SC and SC properties and determined the efficacy of a pCer‐containing spray compared with that of a commercial spray without pCer. Patients/Methods Patients with self‐perceived dry and sensitive skin and decreased barrier function (transepidermal water loss [TEWL] > 10 g/m2h) were randomized into two groups to topically apply a pCer‐containing spray (test group; N = 33) or commercial spray without pCer (control group; N = 19) twice daily as a single‐blind study. SC function and ceramide properties were investigated before and after 4 weeks of application. Results In the test group, the ceramide (NP)/(NS) ratio proportionally increased with the pCer application level after 4 weeks of pCer‐containing spray application. In the control group, there were no changes in SC function after topical application of the commercially available spray without pCer; however, the SC water content, TEWL, SC cell area, and scaling score improved in the test group. Furthermore, the changes in TEWL in the test group were significantly negatively correlated with the pCer application level. Conclusions The efficacy of pCer‐containing sprays for those who have sensitive skin with impaired barrier function was demonstrated. Furthermore, the improvement in SC barrier function induced by pCer may contribute to normalizing the SC ceramide profile.

Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase 1 (DES1), which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals or tissue-specific deletion in the liver and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and metabolic disorders.

Mass spectrometry-based lipidomics approaches offer valuable tools for the detection and quantification of various lipid species, including sphingolipids. The present study aimed to develop a new method to simultaneously detect various sphingolipid species that applies to diverse biological samples. We developed and validated a measurement system by employing a single-column liquid chromatography-mass spectrometry system utilizing a normal-phase separation mode with positive ionization. The measurement system provided precision with a coefficient of variant below 20% for sphingolipids in all types of samples, and we observed good linearity in diluted serum samples. This system can measure the following sphingolipids: sphingosine 1-phosphate (S1P), sphingosine (Sph), dihydroS1P (dhS1P), dihydroSph (dhSph), ceramide 1-phosphate (Cer1P), hexosylceramide (HexCer), lactosylceramide (LacCer), dh-ceramide, deoxy-ceramide, deoxy-dh-ceramide, and sphingomyelin (SM). By measuring these sphingolipids in cell lysates where S1P lyase expression level was modulated, we could observe significant and dynamic modulations of sphingolipids in a comprehensive manner. Our newly established and validated measurement system can simultaneously measure many kinds of sphingolipids in biological samples. It holds great promise as a valuable tool for laboratory testing applications to detect overall modulations of sphingolipids, which have been proposed to be involved in pathogenesis processes in a series of elegant basic research studies.

The skin consists of the epidermis, dermis and subcutis. The epidermis is primarily comprised of keratinocytes and is separated into four layers according to the stage of differentiation of the keratinocytes. Corneocytes are terminally differentiated keratinocytes that closely interact with other corneocytes through corneodesmosomes, and synthesize lamellar bodies and the intercellular multilamellar barrier, which protects the body from the external environment. As ceramides are the principal components of lamellar bodies and the multilamellar barrier, it is important to understand the biosynthesis of ceramides and their functions in skin. Ceramides are synthesized by amide bond-mediated interactions between sphingoid bases, long-chain amino alcohols [long-chain base] and fatty acids through a de novo pathway, a sphingomyelin (SM) hydrolysis pathway and a catabolic pathway. The majority of ceramides produced by the de novo pathway form the epidermal barrier. Ceramides used as signaling molecules are synthesized by the SM and catabolic pathways. Synthesized ceramides are released from corneocytes and form the multilamellar barrier. Additionally, ceramides and their metabolites regulate the apoptosis, proliferation and differentiation of skin cells as well as the formation of the skin barrier. Thus, the study of ceramides and their metabolites is crucial to understanding the function and regulation of the skin barrier.

Ceramides are a heterogeneous group of bioactive membrane sphingolipids that play specialized regulatory roles in cellular metabolism depending on their characteristic fatty acyl chain lengths and subcellular distribution. As obesity progresses, certain ceramide molecular species accumulate in metabolic tissues and cause cell-type-specific lipotoxic reactions that disrupt metabolic homeostasis and lead to the development of cardiometabolic diseases. Several mechanisms for ceramide action have been inferred from studies in vitro, but only recently have we begun to better understand the acyl chain length specificity of ceramide-mediated signaling in the context of physiology and disease in vivo. New discoveries show that specific ceramides affect various metabolic pathways and that global or tissue-specific reduction in selected ceramide pools in obese rodents is sufficient to improve metabolic health. Here, we review the tissue-specific regulation and functions of ceramides in obesity, thus highlighting the emerging concept of selectively inhibiting production or action of ceramides with specific acyl chain lengths as novel therapeutic strategies to ameliorate obesity-associated diseases.

Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in the PM. SMPDL3b excess affects the production of active sphingolipids resulting in decreased ceramide-1-phosphate (C1P) content as observed in human podocytes in vitro and in kidney cortexes of diabetic db/db mice in vivo. Podocyte-specific Smpdl3b deficiency in db/db mice is sufficient to restore kidney cortex C1P content and to protect from DKD. Exogenous administration of C1P restores IR signaling in vitro and prevents established DKD progression in vivo. Taken together, we identify SMPDL3b as a modulator of insulin signaling and demonstrate that supplementation with exogenous C1P may represent a lipid therapeutic strategy to treat diabetic complications such as DKD. Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme known to affect membrane lipid composition. Here, Mitrofanova et al. show that increased expression of SMPDL3b in diabetes impairs insulin signaling and ceramide-1-phosphate (C1P) availability in podocytes, and that C1P supplementation protects mice from diabetic kidney disease.

[beta]-Sitosterol 3-O-d-glucoside (BSG) is known to act as an agonist by binding to estrogen receptors, and estrogen has been reported to enhance the activity of [beta]-glucocerebrosidase, an epidermal ceramide metabolizing enzyme. In this study, we determined whether BSG up-regulates ceramide levels in the stratum corneum (SC) of a reconstructed human epidermal keratinization (RHEK) model. Treatment with BSG significantly increased the total ceramide content by 1.2-fold compared to that in the control in the SC of the RHEK model, accompanied by a significant increase of the ceramide species, Cer[EOS] by 2.1-fold compared to that in the control. RT-PCR analysis demonstrated that BSG significantly up-regulated the mRNA expression levels of serine palmitoyltransferase (SPT)2, ceramide synthase (CerS)3, glucosylceramide synthase (GCS) and acid sphingomyelinase by 1.41-1.89, 1.35-1.44, 1.19 and 2.06-fold, respectively, compared to that in the control in the RHEK model. Meanwhile, BSG significantly down-regulated the mRNA expression levels of sphingomyelin synthase (SMS)2 by 0.87-0.89-fold. RT-PCR analysis also demonstrated that BSG significantly up-regulated the mRNA expression levels of CerS3 and GCS by 1.19-1.55 and 1.20-fold, respectively, but not of SPT2 and significantly down-regulated that of SMS2 by 0.74-fold in HaCaT keratinocytes. Western blotting analysis revealed that BSG significantly increased the protein expression levels of CerS3 and GCS by 1.78 and 1.28-1.32-fold, respectively, compared to that in the control in HaCaT cells. These findings indicate that BSG stimulates ceramide synthesis via the up-regulated expression levels of CerS3 and GCS in the glucosylceramide pathway, which results in a significantly increased level of total ceramides in the SC accompanied by significantly increased levels of acylceramide species such as Cer[EOS].

The outer most layer of the skin, the stratum corneum, consists of corneocytes which are coated by a cornified envelope and embedded in a lipid matrix of ordered lamellar structure. It is responsible for the skin barrier function. Ceramides (CERs) are the backbone of the intercellular lipid membranes. Skin diseases such as atopic dermatitis and psoriasis and aged skin are characterized by dysfunctional skin barrier and dryness which are associated with reduced levels of CERs. Previously, the effectiveness of supplementation of synthetic and animal-based CERs in replenishing the depleted natural skin CERs and restoring the skin barrier function have been investigated. Recently, however, the barrier function improving effect of plant-derived CERs has attracted much attention. Phyto-derived CERs (phytoCERs) are preferable due to their assumed higher safety as they are mostly isolated from dietary sources. The beneficial effects of phytoCER-based oral dietary supplements for skin hydration and skin barrier reinforcement have been indicated in several studies involving animal models as well as human subjects. Ingestible dietary supplements containing phytoCERs are also widely available on the market. Nonetheless, little effort has been made to investigate the potential cosmetic applications of topically administered phytoCERs. Therefore, summarizing the foregoing investigations and identifying the gap in the scientific data on plant-derived CERs intended for skin-health benefits are of paramount importance. In this review, an attempt is made to synthesize the information available in the literature regarding the effects of phytoCER-based oral dietary supplements on skin hydration and barrier function with the underlying mechanisms.