Role of Lymphatic Embolization in Chylothorax Associated with Gorham-Stout Disease: A Case Report.

A 45-year-old male patient with spontaneous chylothorax and osteolysis in the right 1st and 2nd ribs was diagnosed with Gorham-Stout disease based on clinical manifestations and bone biopsy. The chylothorax temporarily decreased after a successful selective lymphatic embolization. The patient presented with recurrent chylothorax, mild chest discomfort, and progressive osteolysis (despite administering sirolimus) during the follow-up period of 15 months.

Association Between Dietary Fiber Intake and Low Muscle Strength Among Korean Adults.

The health benefits of dietary fiber are widely recognized, but its impact on muscle health remains unclear. Therefore, this study aimed to elucidate the relationship between dietary fiber intake and muscle strength through a cross-sectional analysis of data from the Korea National Health and Examination Survey (KNHANES). Data from a single 24-h dietary recall and handgrip strength tests of 10,883 younger adults aged 19 to 64 years and 3,961 older adults aged ≥ 65 years were analyzed. Low muscle strength was defined as handgrip strength < 28 kg for men and < 18 kg for women. Multivariable linear and logistic regression analyses were conducted to determine the association of dietary fiber intake with muscle strength. Approximately 43% of Korean adults met the recommended intake of dietary fiber, and those with higher dietary fiber consumption also had higher total energy and protein intake. After adjusting for confounding variables, dietary fiber intake was found to be positively associated with maximal handgrip strength in younger women aged 19 to 64 years (ß = 0.015; standard error [SE] = 0.006) and older men aged ≥ 65 years (ß = 0.035; SE = 0.014). For older women aged ≥ 65 years, those in the lowest quartile of dietary fiber intake had a higher risk of low muscle strength than those in the highest quartile after adjustment of confounders (odds ratio 1.709; 95% confidence interval 1.130-2.585). These results suggest that adequate dietary fiber intake may reduce the risk of sarcopenia in older Korean women.

Association between nut consumption and low muscle strength among Korean adults.

Nuts are an important component of a healthy diet, but little has been known about their effects on muscle health. Therefore, this study examined the association between nut consumption and low muscle strength among Korean adults. This cross-sectional analysis was conducted using single 24-h recall and handgrip strength data from 3962 younger adults 19-39 years, 6921 middle-aged adults 40-64 years and 3961 older adults ≥65 years participated in the seventh cycle (2016-2018) of the Korea National Health and Nutrition Examination Survey. Low muscle strength was defined as handgrip strength <28 kg for men and <18 kg for women. Sex-specific OR were obtained for younger, middle-aged and older adults using multivariable logistic regression analyses. About one in four Korean adults were consuming nuts (using a culinary definition) with peanut being the most frequently consumed type. After adjustment for age, BMI, total energy intake, household income, alcohol consumption, smoking, resistance exercise, medical history and dietary protein intake, nut consumption was associated with the lower risk of low muscle strength among older adults ≥65 years (men: OR 0·55, 95 % CI (0·38, 0·79); women: OR 0·69, 95 % CI (0·51, 0·93)); however, this association was not observed among younger adults 19-39 years or middle-aged adults 40-64 years. Our results suggest that consuming nuts might be beneficial in lowering the risk of low muscle strength among Korean older adults.

Anti-Inflammatory Activity of the Constituents from the Leaves of Perilla frutescens var. acuta.

Perilla frutense var. acuta (Lamiaceae) has been used to treat indigestion, asthma, and allergies in traditional medicine. In this study, luteolin 7-O-diglucuronide (1), apigenin 7-O-diglucuronide (2), and rosmarinic acid (3) were isolated from the leaves of P. frutescens var. acuta through various chromatographic purification techniques. Several approaches were used to investigate the anti-inflammatory activity of the constituents (1-3) and their working mechanisms. In silico docking simulation demonstrated that 1-3 would work as a PPAR-α/δ/γ agonist, and in vitro PPAR-α/δ/γ transcriptional assay showed that the Perilla water extract (PWE) and 3 increased PPAR-α luciferase activity (1.71 and 1.61 times of the control (PPAR-α + PPRE, p < 0.001)). In the NF-κB luciferase assay, 1 suppressed NF-κB activity the most (56.83% at 5 µM; 74.96% at 10 µM; 79.86% at 50 µM). In addition, 1 and 2 inhibited the mRNA expression of NF-κB target genes, including Il6, Mcp1, and Tnfa, at 50 µM, and 3 suppressed the genes at the mRNA level in a dose-dependent manner. We report that 1 and 2 exert anti-inflammatory effects through NF-κB inhibition, and the PPAR-α/NF-κB signaling pathway is related to the anti-inflammatory activity of 3.

Postnatal Tamoxifen Exposure Induces Long-Lasting Changes to Adipose Tissue in Adult Mice.

Tamoxifen (TAM) is commonly administered to a variety of inducible or conditional transgenic mice that contain Cre recombinase fused with ER. While the impacts of adult TAM treatment are well documented in the field of adipose biology, the long-term effects of postnatal TAM treatment on adult life are still understudied. In this study, we investigated whether postnatal TAM treatment had long-lasting effects on adult body composition and adiposity in male and female mice, fed either with chow or a high-fat diet (HFD). We found that postnatal, but not adult, TAM treatment had long-lasting impacts on female mice, resulting in lower body weight, lower fat mass, and smaller adipocytes. In contrast, postnatal exposure to TAM impaired male but not female cold-induced adipose beiging capacity. Interestingly, upon HFD feeding, the sex-dependent effects of TAM on adult life disappeared, and both female and male mice showed a more obese phenotype with impaired glucose tolerance. These findings suggest that postnatal TAM injection exerts a long-lasting impact on adipose tissue in adult life in a sex- and diet-dependent manner.

Role of heat shock protein 70 in regulation of anti-inflammatory response to curcumin in 3T3-L1 adipocytes.

BACKGROUND/OBJECTIVES: Curcumin is a well-known phytochemical with anti-inflammatory effects. Heat shock protein (HSP) 70, an intracellular chaperone, inhibits proinflammatory signaling activation. Although curcumin has been shown to induce HSP70 expression in various cell types, whether HSP70 mediates the anti-inflammatory effects of curcumin in mature adipocytes remains unclear. MATERIALS/METHODS: To assess the role of HSP70 in regulating the anti-inflammatory response to curcumin in adipocytes, fully differentiated 3T3-L1 adipocytes were treated with curcumin, lipopolysaccharide (LPS), and/or the HSP70 inhibitor pifithrin-µ (PFT-µ). The expression levels of HSP70 and proinflammatory cytokines were then measured. RESULTS: Curcumin upregulated HSP70 expression at both protein and mRNA levels and attenuated LPS-induced Il6, Ptx3, and Ccl2 mRNA upregulation. PFT-µ tended to exacerbate the LPS-induced upregulation of Il6, Ptx3, Ccl2, and Tnfa mRNA expression. However, on curcumin pretreatment, the tendency of PFT-µ to upregulate LPS-induced proinflammatory cytokine expression decreased or disappeared. CONCLUSION: These results indicate that HSP70 is involved in the regulation of inflammatory responses but may not be crucial for the anti-inflammatory effects of curcumin in 3T3-L1 adipocytes.

Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals drive aberrant microglia-mediated engulfment of synapses in AD is unclear. Here we report that secreted phosphoprotein 1 (SPP1/osteopontin) is upregulated predominantly by perivascular macrophages and, to a lesser extent, by perivascular fibroblasts. Perivascular SPP1 is required for microglia to engulf synapses and upregulate phagocytic markers including C1qa, Grn and Ctsb in presence of amyloid-ß oligomers. Absence of Spp1 expression in AD mouse models results in prevention of synaptic loss. Furthermore, single-cell RNA sequencing and putative cell-cell interaction analyses reveal that perivascular SPP1 induces microglial phagocytic states in the hippocampus of a mouse model of AD. Altogether, we suggest a functional role for SPP1 in perivascular cells-to-microglia crosstalk, whereby SPP1 modulates microglia-mediated synaptic engulfment in mouse models of AD.

Iron Homeostasis and Energy Metabolism in Obesity.

Iron plays a role in energy metabolism as a component of vital enzymes and electron transport chains (ETCs) for adenosine triphosphate (ATP) synthesis. The tricarboxylic acid (TCA) cycle and oxidative phosphorylation are crucial in generating ATP in mitochondria. At the mitochondria matrix, heme and iron-sulfur clusters are synthesized. Iron-sulfur cluster is a part of the aconitase in the TCA cycle and a functional or structural component of electron transfer proteins. Heme is the prosthetic group for cytochrome c, a principal component of the respiratory ETC. Regarding fat metabolism, iron regulates mitochondrial fat oxidation and affects the thermogenesis of brown adipose tissue (BAT). Thermogenesis is a process that increases energy expenditure, and BAT is a tissue that generates heat via mitochondrial fuel oxidation. Iron deficiency may impair mitochondrial fuel oxidation by inhibiting iron-containing molecules, leading to decreased energy expenditure. Although it is expected that impaired mitochondrial fuel oxidation may be restored by iron supplementation, its underlying mechanisms have not been clearly identified. Therefore, this review summarizes the current evidence on how iron regulates energy metabolism considering the TCA cycle, oxidative phosphorylation, and thermogenesis. Additionally, we relate iron-mediated metabolic regulation to obesity and obesity-related complications.

Dietary supplementation with Korean pine nut oil decreases body fat accumulation and dysregulation of the appetite-suppressing pathway in the hypothalamus of high-fat diet-induced obese mice.

BACKGROUND/OBJECTIVES: Korean pine nut oil (PNO) has been reported to suppress appetite by increasing satiety hormone release. However, previous studies have rendered inconsistent results and there is lack of information on whether dietary Korean PNO affects the expression of satiety hormone receptors and hypothalamic neuropeptides. Therefore, our study sought to evaluate the chronic effects of Korean PNO on the long-term regulation of energy balance. MATERIALS/METHODS: Five-week-old male C57BL/6 mice were fed with control diets containing 10% kcal fat from Korean PNO or soybean oil (SBO) (PC or SC) or high-fat diets (HFDs) containing 35% kcal fat from lard and 10% kcal fat from Korean PNO or SBO (PHFD or SHFD) for 12 weeks. The expression of gastrointestinal satiety hormone receptors, hypothalamic neuropeptides, and genes related to intestinal lipid absorption and adipose lipid metabolism was then measured. RESULTS: There was no difference in the daily food intake between PNO- and SBO-fed mice; however, the PC and PHFD groups accumulated 30% and 18% less fat compared to SC and SHFD, respectively. Korean PNO-fed mice exhibited higher messenger RNA (mRNA) expression of Ghsr (ghrelin receptor) and Agrp (agouti-related peptide) (P < 0.05), which are expressed when energy consumption is low to induce appetite as well as the appetite-suppressing neuropeptides Pomc and Cartpt (P = 0.079 and 0.056, respectively). Korean PNO downregulated jejunal Cd36 and epididymal Lpl mRNA expressions, which could suppress intestinal fatty acid absorption and fat storage in white adipose tissue. Consistent with these findings, Korean PNO-fed mice had higher levels of fecal non-esterified fatty acid excretion. Korean PNO also tended to downregulate jejunal Apoa4 and upregulate epididymal Adrb3 mRNA levels, suggesting that PNO may decrease chylomicron synthesis and induce lipolysis. CONCLUSIONS: In summary, Korean PNO attenuated body fat accumulation, and appeared to prevent HFD-induced dysregulation of the hypothalamic appetite-suppressing pathway.

Regulation of Adipose Tissue Biology by Long-Chain Fatty Acids: Metabolic Effects and Molecular Mechanisms.

Long-chain fatty acids (LCFA) modulate metabolic, oxidative, and inflammatory responses, and the physiological effects of LCFA are determined by chain length and the degree of saturation. Adipose tissues comprise multiple cell types, and play a significant role in energy storage and expenditure. Fatty acid uptake and oxidation are the pathways through which fatty acids participate in the regulation of energy homeostasis, and their dysregulation can lead to the development of obesity and chronic obesity-related disorders, including type 2 diabetes, cardiovascular diseases, and certain types of cancer. Numerous studies have reported that many aspects of adipose tissue biology are influenced by the number and position of double bonds in LCFA, and these effects are mediated by various signaling pathways, including those regulating adipocyte differentiation (adipogenesis), thermogenesis, and inflammation in adipose tissue. This review aims to describe the underlying molecular mechanisms by which different types of LCFA influence adipose tissue metabolism, and to further clarify their relevance to metabolic dysregulation associated with obesity. A better understanding of the effects of LCFA on adipose tissue metabolism may lead to improved nutraceutical strategies to address obesity and obesity-associated diseases.

Practical Application of Novel Test Methods to Evaluate the Potency of Botulinum Toxin: A Comparison Analysis among Widely Used Products in Korea.

The safe and effective dosing of botulinum neurotoxins (BoNTs) requires accurate and reliable methods to measure their potency. Several novel methods have been introduced over the past decade; however, only few studies have compared the potency of BoNT products with that of the LD50 and other alternative assays. Therefore, the objective of this study was to comparatively evaluate widely used BoNT products using various test methods. Four types of BoNTs (prabotulinumtoxin A, onabotulinumtoxin A, neubotulinumtoxin A, and letibotulinumtoxin A) were used in this study. The estimated potency was assessed using the LD50 assay, and the total BoNT type A protein levels were measured using the enzyme-linked immunosorbent assay (ELISA). The in vitro efficacy of the BoNTs was determined using fluorescence resonance energy transfer (FRET) and surface plasmon resonance (SPR) assays. The results showed differences in the total amount of BoNT protein and the cleavage activity of SNAP-25 within all types of BoNTs. The SPR study seemed to be useful for evaluating the potency by specifically measuring intact 19S neurotoxin, and these results provide new insights for assessing different BoNT products.

Distinct exhaustion features of T lymphocytes shape the tumor-immune microenvironment with therapeutic implication in patients with non-small-cell lung cancer.

BACKGROUND: Reinvigoration of T-cell exhaustion with antibodies has shown promising efficacy in patients with non-small-cell lung cancer (NSCLC). However, the characteristics of T-cell exhaustion with regard to tumor-infiltrating lymphocytes (TILs) are poorly elucidated in NSCLC. Here, we investigated the exhaustion status of TILs in NSCLC patients at the intraindividual and interindividual levels. METHODS: We obtained paired peripheral blood, normal adjacent tissues, peritumoral tissues, and tumor tissues from 96 NSCLC patients. Features of T-cell exhaustion were analyzed by flow cytometry. T cells were categorized according to their programmed cell death-1 (PD-1) expression (PD-1high, PD-1int, and PD-1neg cells). Patients were classified based on the presence or absence of discrete PD-1high CD8+ TILs. Production of effector cytokines by CD8+ TILs was measured after T-cell stimulation with or without antibodies against immune checkpoint receptors. RESULTS: Progressive T-cell exhaustion with marked expression of exhaustion-related markers and diminished production of effector cytokines was observed in PD-1high CD8+ TILs compared with PD-1int and PD-1neg CD8+ TILs. Patients with distinct PD-1high CD8+ TILs (PD-1high expressers) exhibited characteristics associated with a favorable anti-PD-1 response compared with those without these lymphocytes (non-PD-1high expressers). Combined inhibition of dual immune checkpoint receptors further restored effector cytokine production by CD8+ TILs following T-cell stimulation. PD-1high CD8+ T lymphocyte populations in the peripheral blood and tumors were significantly correlated. CONCLUSIONS: T-cell exhaustion was differentially regulated among individual patients and was prominent in a subgroup of NSCLC patients who may benefit from PD-1 blockade or combined blockade of other immune checkpoint receptors.

Dysregulation of TFH-B-TRM lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer.

Patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations exhibit an unfavorable response to PD-1 inhibitor through unclear mechanisms. Hypothesizing that EGFR mutations alter tumor-immune interactions, we compare tumor-infiltrating lymphocytes between EGFR mutant (EGFR-MT) and wild type (EGFR-WT) tumors through single-cell transcriptomic analysis. We find that B cells, CXCL13-producing follicular helper CD4+ T (TFH)-like cells, and tissue-resident memory CD8+ T (TRM)-like cells decreased in EGFR-MT tumors. The NOTCH-RBPJ regulatory network, which is vital for persistence of TRM state, is perturbed, and the interactions between TFH and B cells through the CXCL13-CXCR5 axis disappear in EGFR-MT tumors. Notably, the proportion of TRM-like cells is predictive for anti-PD-1 response in NSCLC. Our findings suggest that the impairment of TFH-B-TRM cooperation in tertiary lymphoid structure formation, accompanied by the dysregulation of TRM homeostasis and the loss of TFH-B crosstalk, underlies unfavorable anti-PD-1 response in EGFR-MT lung tumors.

Suppressing Pyroptosis Augments Post-Transplant Survival of Stem Cells and Cardiac Function Following Ischemic Injury.

The acute demise of stem cells following transplantation significantly compromises the efficacy of stem cell-based cell therapeutics for infarcted hearts. As the stem cells transplanted into the damaged heart are readily exposed to the hostile environment, it can be assumed that the acute death of the transplanted stem cells is also inflicted by the same environmental cues that caused massive death of the host cardiac cells. Pyroptosis, a highly inflammatory form of programmed cell death, has been added to the list of important cell death mechanisms in the damaged heart. However, unlike the well-established cell death mechanisms such as necrosis or apoptosis, the exact role and significance of pyroptosis in the acute death of transplanted stem cells have not been explored in depth. In the present study, we found that M1 macrophages mediate the pyroptosis in the ischemia/reperfusion (I/R) injured hearts and identified miRNA-762 as an important regulator of interleukin 1ß production and subsequent pyroptosis. Delivery of exogenous miRNA-762 prior to transplantation significantly increased the post-transplant survival of stem cells and also significantly ameliorated cardiac fibrosis and heart functions following I/R injury. Our data strongly suggest that suppressing pyroptosis can be an effective adjuvant strategy to enhance the efficacy of stem cell-based therapeutics for diseased hearts.

Effect of lipopolysaccharide on peripheral tissue and hypothalamic expression of metabolic and inflammatory markers in mice fed high-fat diets with distinct 18-carbon fatty acid composition.

Physiological and metabolic effects of fatty acids are determined by their degree of saturation and chain length. Effects of 18-carbon fatty acids with various degrees of saturation on inflammatory, oxidative, and neuropeptide gene transcription, especially in the hypothalamus, in response to LPS-induced acute inflammation have not been well studied. We conducted this study to test whether diets with distinct 18-carbon fatty acid differentially affect inflammatory and metabolic response to LPS exposure in the hypothalamus, liver, and muscle tissues. Four experimental diets were fed for 4 weeks to male C57BL/6J mice, and a terminal 4-h lipopolysaccharide (LPS) injection was administered. Diets included a control diet (CON) containing 5.6% kcal fat from lard and 4.4% kcal fat from soybean oil, and three high-fat diets (HFD) containing 25% kcal fat from lard and 20% kcal fat from either shea butter (SHB; saturated fatty acid-rich fat), olive oil (OLO; monounsaturated fatty acid-rich oil), or soybean oil (SBO; polyunsaturated fatty acid-rich fat). Compared to CON, HFD-fed mice had higher weight gain and body fat accumulation. The SBO group had lowest Cpt1b expression in the liver, and OLO group had the lowest Pomc and the highest Lepr expression in the hypothalamus. LPS challenge increased pro-inflammatory cytokine mRNA expression in the brain and peripheral tissues. However, the diets did not exert distinguishable effects on LPS-induced inflammatory responses. Therefore, saturation degree of 18-carbon fatty acids may not play a critical role in their effects on inflammatory and metabolic indicators in response to acute inflammation induced by LPS.

Therapeutic Effect of IL1ß Priming Tonsil Derived-Mesenchymal Stem Cells in Osteoporosis.

BACKGROUND: Stem cell therapies can be a new therapeutic strategy that may rebalance anabolic and anti-resorptive effects in osteoporosis patients. Tonsil-derived mesenchymal stem cells (TMSCs) can be an alternative therapeutic source for chronic degenerative diseases including osteoporosis. MSCs acquire immune regulatory function under the inflammatory cytokines. Since interleukin (IL) 1ß is known to be one of inflammatory cytokines involved in osteoporosis progression, treatment of IL1ß with TMSCs may enhance immunomodulatory function and therapeutic effects of TMSCs in osteoporosis. METHODS: For IL1ß priming, TMSCs were cultured in the presence of the medium containing IL1ß for 1 day. Characteristics of IL1ß priming TMSCs such as multipotent differentiation properties, anti-inflammatory potential, and suppression of osteoclast differentiation were assessed in vitro. For in vivo efficacy study, IL1ß priming TMSCs were intravenously infused twice with ovariectomized (OVX) osteoporosis mouse model, and blood serum and bone parameters from micro computed tomography images were analyzed. RESULTS: IL1ß priming TMSCs had an enhanced osteogenic differentiation and secreted factors that regulate both osteoclastogenesis and osteoblastogenesis. IL1ß priming TMSCs also suppressed proliferation of peripheral blood mononuclear cells (PBMCs) and decreased expression of Receptor activator of nuclear factor kappa-Β ligand (RANKL) in PHA-stimulated PBMCs. Furthermore, osteoclast specific genes such as Nuclear factor of activated T cells c1 (NFATc1) were effectively down regulated when co-cultured with IL1ß priming TMSCs in RANKL induced osteoclasts. In OVX mice, IL1ß priming TMSCs induced low level of serum RANKL/osteoprotegerin (OPG) ratio on the first day of the last administration. Four weeks after the last administration, bone mineral density and serum Gla-osteocalcin were increased in IL1ß priming TMSC-treated OVX mice. Furthermore, bone formation and bone resorption markers that had been decreased in OVX mice with low calcium diet were recovered by infusion of IL1ß priming TMSCs. CONCLUSION: IL1ß priming can endow constant therapeutic efficacy with TMSCs, which may contribute to improve bone density and maintain bone homeostasis in postmenopausal osteoporosis. Therefore, IL1ß priming TMSCs can be a new therapeutic option for treating postmenopausal osteoporosis.

Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells.

(1) Background: six mammalian ceramide synthases (CerS1-6) determine the acyl chain length of sphingolipids (SLs). Although ceramide levels are increased in murine allergic asthma models and in asthmatic patients, the precise role of SLs with specific chain lengths is still unclear. The role of CerS2, which mainly synthesizes C22-C24 ceramides, was investigated in immune responses elicited by airway inflammation using CerS2 null mice. (2) Methods: asthma was induced in wild type (WT) and CerS2 null mice with ovalbumin (OVA), and inflammatory cytokines and CD4 (cluster of differentiation 4)+ T helper (Th) cell profiles were analyzed. We also compared the functional capacity of CD4+ T cells isolated from WT and CerS2 null mice. (3) Results: CerS2 null mice exhibited milder symptoms and lower Th2 responses than WT mice after OVA exposure. CerS2 null CD4+ T cells showed impaired Th2 and increased Th17 responses with concomitant higher T cell receptor (TCR) signal strength after TCR stimulation. Notably, increased Th17 responses of CerS2 null CD4+ T cells appeared only in TCR-mediated, but not in TCR-independent, treatment. (4) Conclusions: altered Th2/Th17 immune response with higher TCR signal strength was observed in CerS2 null CD4+ T cells upon TCR stimulation. CerS2 and very-long chain SLs may be therapeutic targets for Th2-related diseases such as asthma.

Progenitor-like characteristics in a subgroup of UCP1+ cells within white adipose tissue.

Thermogenic beige fat found in white adipose tissue is a potential therapeutic target to curb the global obesity and diabetes epidemic. However, these inducible thermogenic beige adipocytes have been thought to be short-lived and to rapidly convert to "white-like" adipocytes after discontinuing stimuli. In this study, using effective labeling techniques and genetic mouse tools, we demonstrate that a subset of UCP1+ cells that exist within white adipose tissue are able to self-divide and contribute to new beige adipocyte recruitment in response to ß3 stimuli. When these cells are depleted or their adipogenic capability is blocked, ß3-induced beige adipocyte formation is impaired. We also identify a cell-cycle machinery of p21 and CDKN2A as a molecular basis of beige adipocyte regulation. Collectively, our findings provide new insights into the cellular and molecular mechanisms of beige adipocyte regulation and potential therapeutic opportunities to induce the beige phenotype and treat metabolic disease.

Ceramide synthases: Reflections on the impact of Dr. Lina M. Obeid.

Sphingolipids are a family of lipids that are critical to cell function and survival. Much of the recent work done on sphingolipids has been performed by a closely-knit family of sphingolipid researchers, which including our colleague, Dr. Lina Obeid, who recently passed away. We now briefly review where the sphingolipid field stands today, focusing in particular on areas of sphingolipid research to which Dr. Obeid made valued contributions. These include the 'many-worlds' view of ceramides and the role of a key enzyme in the sphingolipid biosynthetic pathway, namely the ceramide synthases (CerS). The CerS contain a number of functional domains and also interact with a number of other proteins in lipid metabolic pathways, fulfilling Dr. Obeid's prophecy that ceramides, and the enzymes that generate ceramides, form the critical hub of the sphingolipid metabolic pathway.