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INTRODUCING
INTERSTELLAR BLEND™
ceramide
blocker
lipotoxicity neutralizer
200:1 Concentration
scienTIFIC
EVIDENCE
Ceramides in insulin resistance and lipotoxicity
Ceramide has been shown to be toxic in a variety of different cell types (e.g. pancreatic β-cells, cardiomyocytes, etc.), and review of the literature reveals putative roles for the sphingolipid in the damage of cells and tissues which accompany diabetes, hypertension, cardiac failure, atherosclerosis, etc. In this review, I will evaluate the contribution of ceramides in the development of insulin resistance and the complications associated with metabolic diseases.
Ceramides–lipotoxic inducers of metabolic disorders
In obesity and dyslipidemia, the oversupply of fat to tissues not suited for lipid storage induces cellular dysfunction that underlies diabetes and cardiovascular disease (i.e., lipotoxicity). Of the myriad lipids that accrue under these conditions, sphingolipids such as ceramide or its metabolites are amongst the most deleterious because they disrupt insulin sensitivity, pancreatic β cell function, vascular reactivity, and mitochondrial metabolism. Remarkably, inhibiting ceramide biosynthesis or catalyzing ceramide degradation in rodents ameliorates many metabolic disorders including diabetes, cardiomyopathy, insulin resistance, atherosclerosis, and steatohepatitis.
Deleterious effects of lipid accumulation in non-adipose tissues are known as lipotoxicity. In fact, triglycerides may also serve a storage function for long-chain non-esterified fatty acids and their products such as ceramides and diacylglycerols (DAGs). Thus, excess DAG, ceramide and saturated fatty acids in obesity can induce chronic inflammation and have harmful effect on multiple organs and systems. In this context, chronic adipose tissue inflammation, mitochondrial dysfunction and IR have been discussed within the scope of lipotoxicity.
Insulin resistance, obesity and lipotoxicity
Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk and lipotoxicity seems to play a crucial role in the pathophysiology of these associations.
Ceramide dependent lipotoxicity in metabolic diseases
A panoply of recent studies has implicated ceramides in the development of the metabolic comorbidities of obesity such as diabetes and cardiovascular diseases. In particular, inhibition of ceramide biosynthesis in rodents ameliorates insulin resistance, diabetes, cardiomyopathy, atherosclerosis, and steatohepatitis. These data implicate ceramides as major contributors to the development of metabolic diseases.
Lipotoxicity contributes to endothelial dysfunction: a focus on the contribution from ceramide
This review will examine the contribution from elevated circulating fatty acids in these subjects that lead to lipotoxicity. Particular focus will be placed on the fatty acid metabolite ceramide.
Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance
Ceramides induce hypothalamic lipotoxicity and ER stress, leading to weight gain and the hypothalamus (VMH) abolishes ceramide action by reducing hypothalamic ER stress.
Manifestations and mechanisms of myocardial lipotoxicity in obesity
Obesity-associated perturbations in myocardial and systemic lipid metabolism are important contributors to cardiovascular complications of obesity. Accumulation of excess lipid in nonadipose cells of the cardiovascular system can cause cell dysfunction and cell death, a process known as lipotoxicity. These studies indicate that the molecular pathophysiology of lipid overload involves endoplasmic reticulum stress, alterations in autophagy, de novo ceramide synthesis, oxidative stress, inflammation and changes in gene expression.
Lipotoxic diseases of nonadipose tissues in obesity
It is proposed that an important function of leptin is to confine the storage of triglycerides (TG) to the adipocytes, while limiting TG storage in nonadipocytes. Excess TG deposition in nonadipocytes leads to impairment of functions, increased ceramide formation, which triggers nitric oxide-mediated lipotoxicity and lipoapoptosis.
Ceramides and Sphingosino-1-Phosphate in Obesity
Lipotoxicity in Obesity: This process leads to defective lipid oxidation, increased ceramide formation and accumulation of bioactive lipids in organs and tissues. Lipotoxicity has a substantial impact on pancreatic β-cells by impairing glucose-stimulated insulin secretion (32).
Roles of Ceramides in Non-Alcoholic Fatty Liver Disease
Liver fat accumulation induces the synthesis of specific lipid species and particularly ceramides, a sphingolipid. In turn, ceramides have deleterious effects on hepatic metabolism, a phenomenon called lipotoxicity.
Role of Ceramides in the Pathogenesis of Diabetes Mellitus and its Complications
Emerging evidence has implicated the accumulation of ceramide in metabolic tissues as contributing to impairment of insulin sensitivity and glucose homeostasis14, 26–29. Obesity is a strong risk factor for diabetes
Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome
These studies suggest that aberrant ceramide biosynthesis in response to a high fat diet contributes directly to the expression of the leptin resistance factor SOCS-3 in adipocytes and thereby contributes to leptin resistance associated with HFD induced obesity.
Plasma ceramides are associated with MRI-based liver fat content but not with noninvasive scores of liver fibrosis in patients with type 2 diabetes
There is growing evidence that ceramides play a significant role in the onset and progression of non-alcoholic fatty liver disease (NAFLD), a highly prevalent condition in patients with type 2 diabetes associated with hepatic and cardiovascular events.
People with High Ceramide Levels up to Four Times More Likely to Have Heart Attacks, Stroke
In particular, ceramide concentrations were higher in those who had had a previous heart attack or who had insulin resistance or type 2 diabetes. They also discovered that ceramides do not correlate strongly with triglycerides or other traditional measures of cardiovascular risk.
CERAMIDES: A BETTER WAY TO FIGHT HEART DISEASE
Elevated concentrations of circulating ceramides are linked to a higher incidence of ischemic heart disease, myocardial infarction, stroke, and type 2 diabetes mellitus. Three specific ceramides correlate with cardiovascular disease and insulin resistance: Cer16:0, Cer18:0, and Cer24:1.
Efficacy of nutritional interventions to lower circulating ceramides in young adults
We hypothesize that a dietary intervention focused on increasing the intake of fruit and vegetables, and reducing the consumption of refined carbohydrates or fat in free‐living subjects would lower serum ceramide concentrations in young adults.
ingredients
Abies nephrolepis
Methanol extracts of domestic plants of Korea were evaluated as a potential inhibitor of neutral pH optimum and membrane-associated 60 kDa sphingomyelinase (N-SMase) activity. In this study, we partially purified N-SMase from bovine brain membranes using ammonium sulfate. It was purified approximately 163-fold by the sequential use of DE52, Butyl-Toyopearl, DEAE-Cellulose, and Phenyl-5PW column chromatographies. The purified N-SMase activity was assayed in the presence of the plant extracts of three hundreds species.
Based on the in vitro assay, three plant extracts significantly inhibited the N-SMase activity in a time- and concentration-dependent manner. To further examine the inhibitory pattern, a Dixon plot was constructed for each of the plant extracts. The extracts of Abies nephrolepis, Acer tegmentosum, and Ginkgo biloba revealed a competitive inhibition with the inhibition constant (Ki) of 11.9 microg/ mL, 9.4 microg/mL, and 12.9 microg/mL, respectively. These extracts also inhibited in a dose-dependent manner the production of ceramide induced by serum deprivation in human neuroblastoma cell line SH-SY5Y.
Anthocyanins Blueberry
Blueberry anthocyanin-rich extract (BAE) was supplemented to high-fat diet (HFD)-fed mice to investigate sphingolipid metabolism modulating factors involved in the attenuated hyperinsulin emia and hyperlipidemia. A BAE-containing diet effectively controlled food intake and liver weight and significantly attenuated insulin resistance triggered by a HFD. Higher BAE (200 mg/kg of body weight) administration performed more efficiently in the improvement of hepatic steatosis and adipocyte hypertrophy, together with distinct suppressions in serum triacylglycerol and cholesterol in total and species. Serum lipid compositions revealed 200 mg/kg of BAE supplementation remarkably suppressed ceramide accumulation.
Consistently, genes encoding enzymes associated with sphingomyelin conversion and ceramide de novo synthesis were modulated toward a healthy direction for restrained sphingolipid accumulation. Further, the inhibited mRNA expressions of protein phosphatase 2A and protein kinase Cζ involved in blocking Akt phosphorylation connected the controlled ceramides with the restored insulin sensitivity.
The Impact of Phytochemicals in obesity-Related Metabolic diseases: Focus on Ceramide metabolism
The prevalence of obesity and related metabolic diseases has increased dramatically worldwide. As obesity progresses, various lipid species accumulate in ectopic tissues. Amongst them, ceramides—a deleterious sphingolipid species—accumulate and cause lipotoxicity and metabolic disturbances. Dysregulated ceramide metabolism appears to be a key feature in the pathogenesis of obesity-related metabolic diseases. Notably, dietary modification might have an impact on modulating ceramide metabolism.
Phytochemicals are plant-derived compounds with various physiological properties, which have been shown to protect against obesity-related metabolicdiseases. In this review, we aim to examine the impact of a myriad of phytochemicals and their dietary sources in altering ceramide deposition and ceramide-related metabolism from in vitro, in vivo, and human clinical/epidemiological studies. This review discusses how numerous phytochemicals are able to alleviate ceramide-induced metabolic defects and reduce the risk of obesity-related metabolic diseases via diverse mechanisms.
Anthocyanins Gooseberry
Background/aim: Obesity is the fifth largest risk factor of death in the world. The ceramide produced by obesity is closely related to insulin resistance (IR) caused by obesity. At present, the commercially available weight loss products have large side effects and limited therapeutic effects. Therefore, it is particularly important to find effective natural nontoxic products to treat obesity and explore its possible pathways and mechanisms.
Materials and methods: In this paper, a high-fat diet (HFD) mice model was established by intragastric administration of high-fat emulsion to investigate the intervention effect of Gooseberry anthocyanins (GA) on IR in HFD mice. We used molecular docking technology to find the binding sites and binding energy of anthocyanins on CerS6. Real-time PCR was used to detect the effect of GA on the expression of IL-6 and TNF-α mRNA in HFD mice. The expression of S1P/Cer signaling pathway in HFD mice with IR was detected by Western Blot.
Results: The results showed that GA could effectively inhibit visceral fat, liver index, the level of TC, TG and the level of LDL-C (p < 0.05), and improved HDL-C, GSH-Px and SOD (p < 0.05). GA decreased the level of insulin sensitivity index from −5.15 to −4.54 and improved insulin sensitivity and IR in HFD mice. The binding energy of anthocyanins on CerS6 was in the range of −8.2 to 5.2 kcal/mol, with low energy parameters and good binding positions. GA could reduce mRNA levels of inflammatory factors IL-6 and TNF-α (p < 0.05), inhibit the expression of CerS6, PKCζ, PPARγ, CD36 (p < 0.05), and enhance the expression of SphK2, Akt, p-Akt/Akt, ISR (p < 0.05).
Conclusion: This study investigated the effect and mechanism of GA on reducing ceramide content and reducing IR in mice, and provided an experimental basis for the prevention and treatment of obesity-related diseases.
Apigenin
Effects of Chamomilla recutita flavonoids on age-related liver sphingolipid turnover in rats
The increased sphingolipid turnover in the liver is associated with elevation of free radical production and state of chronic inflammation at old age. Plant polyphenols are reported to exhibit antioxidant and anti-inflammatory effects. In the present paper, the lipids contents and ceramide production in the liver and hepatocytes as well as the correction of sphingolipid metabolism at old age using the mixture of Chamomilla recutita flavonoids (chamiloflan) or apigenin-7-glucoside or luteolin-7-glucoside alone have been investigated.
To study the sphingolipids turnover, the [14C]serine-pre-labeled hepatocytes and [14C-methyl]- or [14C]palmitate-pre-labeled sphingomyelin (SM) and ceramide were used. The ceramide content was higher in the liver and hepatocytes of 24- and 27–28-month-old animals as compared to adult 3-month-old Wistar rats. An addition of flavonoids to the culture medium did not influence significantly on the lipids contents and metabolism in the isolated hepatocytes.
The administration of flavonoids to old rats decreased the elevated neutral and acid SMases activities and ceramide mass and did not affect both the lipid content in the liver of adult animals and ceramide conversion to the sphingosine or SM. These results suggest that the SMases play a key role in the flavonoid-induced decrease of ceramide levels in the liver of old rats.
Artemisia dracunculus L.
Ectopic lipids in peripheral tissues have been implicated in attenuating insulin action in vivo. The botanical extract of Artemisia dracunculus L. (PMI 5011) improves insulin action, yet the precise mechanism is not known. We sought to determine whether the mechanism by which PMI 5011 improves insulin signaling is through regulation of lipid metabolism. After differentiation, cells were separately preincubated with free fatty acids (FFAs) and ceramide C2, and the effects on glycogen content, insulin signaling, and ceramide profiles were determined. The effect of PMI 5011 on ceramide accumulation and ceramide-induced inhibition of insulin signaling was evaluated.
FFAs resulted in increased levels of total ceramides and ceramide species in L6 myotubes. Saturated FFAs and ceramide C2 inhibited insulin-stimulated phosphorylation of protein kinase B/Akt and reduced glycogen content. PMI 5011 had no effect on ceramide formation or accumulation but increased insulin sensitivity via restoration of Akt phosphorylation. PMI 5011 also attenuated the FFA-induced upregulation of a negative inhibitor of insulin signaling, i.e., protein tyrosine phosphatase 1B (PTP1B), and increased phosphorylation of PTP1B. PMI 5011 attenuates the reduction in insulin signaling induced by ceramide accumulation, but the mechanism of improved insulin signaling is independent of ceramide formation.
Averrhoacarambola (Oxalidaceae)
Aims: The aim of this study was to evaluate the hypoglycemic effect of the extract of Averrhoacarambola L. root (EACR) on the regulation of the toll-like receptor 4 (TLR4)–nuclear–factor kappa B (NF-κB) pathway in B) pathway in streptozotocin (STZ)-induced diabetic mice.
Methods: the mice were injected with STZ (120 mg/kg body weight) via a tail vein. After 72 h, the mice with FBG = 11.1 mmol/L were confirmed as having diabetes. Subsequently, the mice were treated intragastrically with EACR (300, 600, 1200 mg/kg body weight/d) and metformin (320 mg/kg body weight/d) for 14 days.
Results: As a result the serum fasting blood glucose (FBG), interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) levels were decreased following EACR administration. Immunohistochemical analysis revealed that the pancreatic tissue expression levels of TLR4 and NF-κB were downregulated after EACR administration. EACR suppressed pancreatic mRNA expression level of TLR4 and blocked the downstream NF-κB pathway in the pancreas. According to Western blot analysis EACR suppressed pancreatic TLR4 and NF-κB protein expression levels. Histopathological examination of the pancreas showed that STZ-induced pancreas lesions were alleviated by the EACR treatment.
Conclusion: These findings suggest that the modulation of the IL-6 and TNF-a inflammatory cytokines and the suppression of the TLR4–NF-κB pathway are most likely involved in the anti-hyperglycemic effect of EACR in STZ-induced diabetic mice.
Baicalin
In this study, Methionine and choline deficient diet (MCD)-induced NAFLD mice were treated with baicalin or baicalin-loaded nanoliposomes (BA-NL), then hepatic histopathological changes, biochemical parameters and inflammatory molecules were observed. We found that mice in MCD group showed significant increases in plasma transaminase, hepatocyte apoptosis, hepatic lipid accumulation, liver fibrosis, and infiltration of neutrophils and macrophages compared with control group, however, BA and BA-NL markedly attenuated MCD-induced the above changes.
Besides, further analysis indicated that BA and BA-NL also inhibited the up-regulation of toll-like receptor 4 (TLR4) signal and the production of inflammatory mediators in MCD mice. Importantly, BA-NL was found to be more effective than baicalin on MCD-induced NAFLD in mice.
These data suggested that BA and its nanoliposomes BA-NL could effectively protect mice against MCD-induced NAFLD, which might be mediated through Inhibiting TLR4 signaling cascade.
Berberine
Several studies have documented the effects of hypoxia and ceramides on lipid and glucose metabolism, resulting in insulin resistance. However, the roles of ceramide in hepatic hypoxia and hepatic insulin resistance remain to be clarified. This study aimed to explore the relationship between hypoxia, ceramide synthesis, and hepatic insulin resistance in high-fat diet (HFD)-fed mice.
Given the interaction of hypoxia-inducible factors 2α(HIF-2α) and berberine determined using molecular docking, this study also assessed the pharmacological effects of berberine on the HIF-2α-ceramide-insulin resistance pathway. In the preliminary phase of the study, gradually aggravated hepatic hypoxia and varying levels of ceramides were observed with the development of type 2 diabetes mellitus (T2DM) due to increasing HIF-2α accumulation.
Lipidomic analyses of animal and cell models revealed that berberine reduced hypoxia-induced ceramide production and attenuated ceramide-induced insulin resistance . This research provides timely and necessary evidence for the role of ceramide in hypoxia and insulin resistance in the liver. It also contributes to a better understanding of the pharmacological effects of berberine on ameliorating hypoxia and insulin resistance in T2DM therapy.
Betulinic acid (betulin)
Ethanol consumption leads to many kinds of liver injury and suppresses innate immunity, but the molecular mechanisms have not been fully delineated. The present study was conducted to determine whether betulinic acid (BA) or betulin (BT) would ameliorate acute ethanol-induced fatty liver in mice, and to characterize whether Toll like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) were involved in ethanol-stimulated hepatic stellate cells (HSCs). EtOH (5 mg/kg) and BA or BT (20 or 50 mg/kg) were applied in vivo, while EtOH (50 mM) and BA or BT (12.5 or 25 μM) were applied in vitro. Administration of BA or BT significantly prevented the increases of serum ALT and AST caused by ethanol, as well as serum TG.
Supplement of BA or BT prevented ethanol-induced acidophilic necrosis, increased hepatocyte nuclei and stromal inflammation infiltration as indicated by liver histopathological studies. Administration of BA or BT significantly decreased CYP2E1 activities and expression of SREBP-1 caused by ethanol, however, lower dosage of BA or BT showed slight effects on CYP2E1 activity or expression of SREBP-1c. BA or BT administration significantly decreased the expression of TLR4, and increased the phosphorylation of STAT3. In vitro, BA or BT treatment reduced the expressions of α-SMA and collagen-I in ethanol-stimulated HSCs via regulation of TLR4 and STAT3, coincided with in vivo.
All of these findings demonstrated that BA or BT might ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro, promising agents for ethanol-induced fatty liver therapies.
Bilberries (Vaccinium myrtillus)
Screening of herbal extracts for TLR2- and TLR4 -dependent anti-inflammatory effects
Herbal extracts represent an ample source of natural compounds, with potential to be used in improving human health. There is a growing interest in using natural extracts as possible new treatment strategies for inflammatory diseases. We therefore aimed at identifying herbal extracts that affect inflammatory signaling pathways through toll-like receptors (TLRs), TLR2 and TLR4.
Ninety-nine ethanolic extracts were screened in THP-1 monocytes and HeLa-TLR4 transfected reporter cells for their effects on stimulated TLR2 and TLR4 signaling pathways. The 28 identified anti-inflammatory extracts were tested in comparative assays of stimulated HEK-TLR2 and HEK-TLR4 transfected reporter cells to differentiate between direct TLR4 antagonistic effects and interference with downstream signaling cascades. Furthermore, the ten most effective anti-inflammatory extracts were tested on their ability to inhibit nuclear factor-κB (NF-κB) translocation in HeLa-TLR4 transfected reporter cell lines and for their ability to repolarize M1-type macrophages.
Ethanolic extracts which showed the highest anti-inflammatory potential, up to a complete inhibition of pro-inflammatory cytokine production were Castanea sativa leaves, Cinchona pubescens bark, Cinnamomum verum bark, Salix alba bark, Rheum palmatum root, Alchemilla vulgaris plant, Humulus lupulus cones, Vaccinium myrtillus berries, Curcuma longa root and Arctostaphylos uva-ursi leaves. Moreover, all tested extracts mitigated not only TLR4, but also TLR2 signaling pathways. Seven of them additionally inhibited translocation of NF-κB into the nucleus. Two of the extracts showed impact on repolarization of pro-inflammatory M1-type to anti-inflammatory M2-type macrophages.
Several promising anti-inflammatory herbal extracts were identified in this study, including extracts with previously unknown influence on key TLR signaling pathways and macrophage repolarization, serving as a basis for novel lead compound identification.
Caffeic acid
Interplay between ceramides and phytonutrients: New insights in Metabolic Syndrome
In this review, major role of ceramides in metabolic syndrome and the ability of certain phytonutrients to manage ceramides levels have been discussed. Ceramides act as an intracellular signaling molecules that affect the metabolism through different pathways such as adiposity linkage, insulin resistance and cardiometabolic syndrome. In addition, phytonutrients are novel therapeutic agents that may lower plasma ceramide levels involved in metabolic syndrome. Furthermore, relationship between ceramides and metabolic syndrome with regards to ceramide modulation and effect of bioactive phytonutrients in regulating the ceramides levels in relation to obesity-associated disorders is also elucidated.
One of the active compounds of propolis, caffeic acid phenethyl ester (CAPE, C9H8O4) has been shown to inhibit NF-κB. Certain mammalian trials have indicated that anti-inflammatory action of CAPE is due to inhibition in cell membrane that could be due to release of arachidonic acid, which suppresses cyclooxygen ase-1 and -2 (COX-1 and COX-2) and inhibits the expression of the gene COX-2 activation (Bezerra et al., 2012).
The inhibition of intestine FXR signaling by administration of CAPE has been known to improve the glucose metabolism dysfunction through intestinal FXR-ceramide pathway, leading to decrease the he-patic mitochondrial acetyl-CoA levels and plasma cell membrane glycoprotein-1 activities without affecting hepatic insulin signaling.
Background: Propolis and its major constituent – caffeic acid phenethyl ester (CAPE) have good abilities on antitumor and anti-inflammation. However, little is known about the actions of propolis and CAPE on tumor in inflammatory microenvironment, and inflammatory responses play decisive roles at different stages of tumor development. To understand the effects and mechanisms of ethanol-extracted Chinese propolis (EECP) and its major constituent – CAPE in inflammation -stimulated tumor, we investigated their effects on toll-like receptor 4 (TLR4) signaling pathway which plays a crucial role in breast cancer MDA-MB-231 cell line.
Methods: 80% confluent breast cancer MDA-MB-231 cells were stimulated with 1 μg/mL lipopolysaccaride (LPS). Then the cells were divided for treatment by CAPE (25 μg/mL) and EECP (25, 50 and 100 μg/mL), respectively. Cell viability, nitric oxide (NO) production and cell migration were measured by sulforhodamine B assay, chemical method and scratch assay. The levels of TLR4, MyD88, IRAK4, TRIF, caspase 3, PARP, LC3B and p62 were investigated through western blotting. The expression of TLR4, LC3B and nuclear factor-κB p65 (NF-κB p65) were tested by immunofluorescence microscopy assay.
Results: Treatment of different concentrations of EECP (25, 50 and 100 μg/mL) and CAPE (25 μg/mL) significantly inhibited LPS-stimulated MDA-MB-231 cell line proliferation, migration and NO production. Furthermore, EECP and CAPE activated caspase3 and PARP to induce cell apoptosis , and also upregulated LC3-II and decreased p62 level to induce autophagy during the process. TLR4 signaling pathway molecules such as TLR4, MyD88, IRAK4, TRIF and NF-κB p65 were all down-regulated after EECP and CAPE treatment in LPS-stimulated MDA-MB-231 cells.
Conclusions: These findings indicated that EECP and its major constituent – CAPE inhibited breast cancer MDA-MB-231 cells proliferation in inflammatory microenvironment through activating apoptosis, autophagy and Inhibiting TLR4 signaling pathway. EECP and CAPE may hold promising prospects in treating inflammation-induced tumor.
Carotenoids
Interplay between ceramides and phytonutrients: New insights in Metabolic Syndrome
Crocetin glycosides (C20H24O4) such as crocin, dicrocin and tri- crocin, are present in carotenoid pigments of saffron. Crocin can sup-press death of PC12 cells (pheochromocytoma cell line) caused due to serum deprivation by increasing the synthesis of glutathione (GSH) and thus Inhibiting ceramide production and neutral sphingomyelinase (nSMase) activity. The carotenoid pigments of saffron consist of croce- tin-di-(β-D-gentiobiosyl)-ester (crocin), crocetin di-(β-D-glucosyl)-ester (dicrocin) and crocetin-(β-D-gentiobiosyl)-(β-D-glucosyl)-ester (tricro- cin) that prevent the activation of the JNK pathway, which has a role in the ceramide signaling downstream cascade (Ochiai et al., 2007).
Moreover, saturated fatty acids can stimulate TLR4, which raises the expression of ceramide synthase and serine palmoyl transfer in skeletal muscles, and also triggers hepatic sphingomyelinase. In some interven-tional pilot studies, several ceramides have been effectively linked with pro-inflammatory cytokines in various studies. The ability of β-carot-enoids to inhibit and reduce inflammation is noticeable as the con-sumption of β-carotenoids is inversely proportional to pro-inflammatory markers (Mathews et al., 2017).
Chamiloflan
Interplay between ceramides and phytonutrients: New insights in Metabolic Syndrome
The flavonoids of chamomile such as chamiloflan plays an essential role in ceramide modulation. In a study regarding toxin-damaged liver and cultured hepatocytes, the flavonoids of chamomile influenced the sphingomyelinases and ceramide metabolism. Both in-vitro and in-vivo effects of the flavonoids of the plants have been determined. Increased ceramide content in the affected hepatocytes or liver (likely by neutral sphingomyelinases inhibition and activation of inflammatory) was normalized through the addition of flavonoid to the culture media or administration to the rats.
The improvement in sphingolipid turnover caused by flavonoids associated with the stability of the toxin-treated hepatocyte membranes prevented the death of cells (Babenko & Sha-khova, 2008).
The Impact of Phytochemicals in obesity -Related Metabolic disease s: Focus on Ceramide metabolism
The prevalence of obesity and related metabolic diseases has increased dramatically worldwide. As obesity progresses, various lipid species accumulate in ectopic tissues. Amongst them, ceramides—a deleterious sphingolipid species—accumulate and cause lipotoxicity and metabolic disturbances. Dysregulated ceramide metabolism appears to be a key feature in the pathogenesis of obesity-related metabolic diseases. Notably, dietary modification might have an impact on modulating ceramide metabolism.
Phytochemicals are plant-derived compounds with various physiological properties, which have been shown to protect against obesity-related metabolic diseases. In this review, we aim to examine the impact of a myriad of phytochemicals and their dietary sources in altering ceramide deposition and ceramide-related metabolism from in vitro, in vivo, and human clinical/epidemiological studies. This review discusses how numerous phytochemicals are able to alleviate ceramide-induced metabolic defects and reduce the risk of obesity-related metabolic diseases via diverse mechanisms.
Chlorogenic acid
Chlorogenic Acid inhibits Ceramide accumulation to Restrain hepatic Glucagon response
The elevated levels of endogenous glucose production induced by infusion of glucagon or pyruvate were lowered in mice administered with Chlorogenic acid (CGA). Furthermore, chronic CGA treatment ameliorated the accumulation of glucose and ceramide in high-fat diet (HFD)-fed mice. CGA also attenuated HFD-fed-induced inflammation response. The protective effect of CGA on glucose production was further confirmed in primary mouse hepatocytes by Inhibiting accumulation of ceramide and expression of p38 MAPK. Moreover, CGA administration in HFD-fed mice preserved the decreased phosphorylation of Akt in the liver, resulting in the inhibition of FoxO1 activation and, ultimately, hepatic gluconeogenesis.
However, these protective effects were significantly attenuated by the addition of C2 ceramide. These results suggest that CGA inhibits ceramide accumulation to restrain hepatic glucagon response.
Choline
Before detecting increased apoptosis in choline-deficient cells, we measured a significant increase in ceramide (218% control) and diacyglycerol (155% control) concentrations. The addition of a cell-permeable ceramide to cells in control medium induced apoptosis; however, adding a cell-permeable diacyglycerol did not induce apoptosis. Caspase is a common mediator of apoptosis, and choline deficiency-induced apoptosis was prevented completely by replacing choline or adding a caspase inhibitor into the medium within 48 h of initial choline deprivation. In those cells rescued by replacing choline at 36 h, the concentrations of phosphatidylcholine, sphingomyelin, ceramide, and diacyglycerol returned to levels of control cells.
In those cells rescued by adding a caspase inhibitor at 36 h, the concentrations of sphingomyelin and ceramide returned to control levels, but the concentrations of phosphatidylcholine and diacyglycerol did not return to normal. We propose that availability of dietary factors (choline in this model) can modulate apoptosis. Mechanisms that we identify using this model may help us to explain why dietary choline influences brain development.
Chrysanthemum morifolium
In our analysis, the ND, HFD, CLE, and LU groups were clearly differentiated by partial least-squares discriminant analysis (PLS-DA) score plots. The major metabolites contributing to this differentiation were cholesteryl esters (CEs), lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), ceramides (CERs), and sphingomyelins (SMs). The levels of plasma CEs, LPCs, PCs, SMs, and CERs were significantly increased in the HFD group compared to those in the ND group, and levels of these lipids recovered to normal after administration of CLE or LU.
Furthermore, changes in hepatic mRNA expression levels involved in the Kennedy pathway and sphingolipid biosynthesis were also suppressed by treatment with CLE or LU. In conclusion, this study examined the beneficial effects of CLE and LU on obesity and dyslipidemia, which were demonstrated as reduced synthesis of lipotoxic intermediates.
These results may provide valuable insights towards evaluating the therapeutic effects of CLE and LU and understanding obesity-related diseases.
Cimifugin
Results: Cim significantly reversed palmitate-induced hepatocellular injury in a dose-dependent manner, accompanied by improvements in oxidative stress and mitochondrial damage. Cim pretreatment reversed palmitate-stimulated TLR4/p38 MAPK activation and SIRT1 reduction without affecting JNK, ERK1/2, and AMPK pathways. The hepatoprotective effects of Cim were abolished either through activating TLR4/p38 by their pharmacological agonists or genetical silencing SIRT1 via special siRNA, indicating a mechanistic involvement. Moreover, Cim treatment improved oleate-induced hepatocellular lipid accumulation, which could be blocked by either TLR4 stimulation or SIRT1 knockdown. We observed that SIRT1 was a potential target of TLR4 in palmitate-treated hepatocytes, since TLR4 agonist LPS aggravated, whereas TLR4 antagonist CLI-095 alleviated palmitate-decreased SIRT1 expression. SIRT1 knockdown did not affect palmitate-induced TLR4. In addition, TLR4 activation by LPS significantly abolished Cim-protected SIRT1 reduction induced by palmitate. These results collaboratively indicated that TLR4-regulated SIRT1 pathways was mechanistically involved in the protective effects of Cim against lipotoxicity.
Conclusion: In brief, we demonstrate the protective effects of Cim against lipotoxicity-induced cell death and steatosis in hepatocytes. TLR4-regulated p38 MAPK and SIRT1 pathways are involved in Cim-protected hepatic lipotoxicity. Cim is a potential candidate for improving hepatic metabolic disorders mediated by lipotoxicity.
Cinchona (Cinchona pubescens)
Screening of herbal extracts for TLR2- and TLR4 -dependent anti-inflammatory effects
Herbal extracts represent an ample source of natural compounds, with potential to be used in improving human health. There is a growing interest in using natural extracts as possible new treatment strategies for inflammatory diseases. We therefore aimed at identifying herbal extracts that affect inflammatory signaling pathways through toll-like receptors (TLRs), TLR2 and TLR4 . Ninety-nine ethanolic extracts were screened in THP-1 monocytes and HeLa-TLR4 transfected reporter cells for their effects on stimulated TLR2 and TLR4 signaling pathways. The 28 identified anti-inflammatory extracts were tested in comparative assays of stimulated HEK-TLR2 and HEK-TLR4 transfected reporter cells to differentiate between direct TLR4 antagonistic effects and interference with downstream signaling cascades.
Furthermore, the ten most effective anti-inflammatory extracts were tested on their ability to inhibit nuclear factor-κB (NF-κB) translocation in HeLa-TLR4 transfected reporter cell lines and for their ability to repolarize M1-type macrophages. Ethanolic extracts which showed the highest anti-inflammatory potential, up to a complete inhibition of pro-inflammatory cytokine production were Castanea sativa leaves, Cinchona pubescens bark, Cinnamomum verum bark, Salix alba bark, Rheum palmatum root, Alchemilla vulgaris plant, Humulus lupulus cones, Vaccinium myrtillus berries, Curcuma longa root and Arctostaphylos uva-ursi leaves.
Moreover, all tested extracts mitigated not only TLR4, but also TLR2 signaling pathways. Seven of them additionally inhibited translocation of NF-κB into the nucleus. Two of the extracts showed impact on repolarization of pro-inflammatory M1-type to anti-inflammatory M2-type macrophages.
Citrus aurantium extract
Results: Citrus flavonoid extract (CFE) significantly lowered serum concentrations of lipopolysaccharide (LPS) pro-inflammatory cytokines (TNF-α and IL-6), acute phase proteins (LPS-binding protein and haptoglobin) in dairy cows fed a high-starch diet. Dietary CFE supplementation increased fecal butyrate production and decreased fecal LPS. In addition, dietary CFE influenced the overall hindgut microbiota’s structure and composition. Notably, potentially beneficial bacteria, including Bacteroides, Bifidobacterium, Alistipes, and Akkermansia, were enriched in CFE and were found to be positively correlated with fecal metabolites and host metabolites. Fecal and serum untargeted metabolomics indicated that CFE supplementation mainly emphasized the metabolic feature “sphingolipid metabolism.” Metabolites associated with the sphingolipid metabolism pathway were positively associated with increased microorganisms in dairy cows fed CFE, particularly Bacteroides. Serum lipidomics analysis showed that the total contents of ceramide and sphingomyelin were decreased by CFE addition. Some differentially abundant sphingolipid species were markedly associated with serum IL-6, TNF-α, LPS, and fecal Bacteroides. Metaproteomics revealed that dietary supplementation with CFE strongly impacted the overall fecal bacterial protein profile and function. In CFE cows, enzymes involved in carbon metabolism, sphingolipid metabolism, and valine, leucine, and isoleucine biosynthesis were upregulated.
Conclusions: Our research indicates the importance of bacterial sphingolipid s in maintaining hindgut symbiosis and homeostasis. Dietary supplementation with CFE can decrease systemic inflammation by maintaining hindgut microbiota homeostasis and regulating sphingolipid metabolism in dairy cows fed a high-starch diet.
Citrus reticulata Blanco extract
Results: Citrus flavonoid extract (CFE) significantly lowered serum concentrations of lipopolysaccharide (LPS) pro-inflammatory cytokines (TNF-α and IL-6), acute phase proteins (LPS-binding protein and haptoglobin) in dairy cows fed a high-starch diet. Dietary CFE supplementation increased fecal butyrate production and decreased fecal LPS. In addition, dietary CFE influenced the overall hindgut microbiota’s structure and composition. Notably, potentially beneficial bacteria, including Bacteroides, Bifidobacterium, Alistipes, and Akkermansia, were enriched in CFE and were found to be positively correlated with fecal metabolites and host metabolites. Fecal and serum untargeted metabolomics indicated that CFE supplementation mainly emphasized the Metabolic feature “sphingolipid metabolism.”
Metabolites associated with the sphingolipid metabolism pathway were positively associated with increased microorganisms in dairy cows fed CFE, particularly Bacteroides. Serum lipidomics analysis showed that the total contents of ceramide and sphingomyelin were decreased by CFE addition. Some differentially abundant sphingolipid species were markedly associated with serum IL-6, TNF-α, LPS, and fecal Bacteroides. Metaproteomics revealed that dietary supplementation with CFE strongly impacted the overall fecal bacterial protein profile and function. In CFE cows, enzymes involved in carbon metabolism, sphingolipid metabolism , and valine, leucine, and isoleucine biosynthesis were upregulated.
Conclusions: Our research indicates the importance of bacterial sphingolipids in maintaining hindgut symbiosis and homeostasis. Dietary supplementation with CFE can decrease systemic inflammation by maintaining hindgut microbiota homeostasis and regulating sphingolipid metabolism in dairy cows fed a high-starch diet.
Coumestrol
The sphingolipid concentrations were assessed by HPLC whereas the expression of all the proteins was evaluated by Western blot. Coumestrol markedly reduced the accumulation of sphingolipis, namely, ceramide and sphinganine through noticeable inhibition of the ceramide de novo synthesis pathway in insulin-resistant hepatocytes. Moreover, coumestrol augmented the expression of fatty acid transport proteins, especially FATP5 and FAT/CD36, which also were responsible for excessive sphingolipid accumulation.
Furthermore, coumestrol altered the sphingolipid salvage pathway, which was observed as the excessive deposition of the sphingosine-1-phosphate and sphingosine. Our study clearly showed that coumestrol ameliorated hepatic insulin resistance in primary rat hepatocytes. Thus, we believe that our study may contribute to the discovery of novel preventive and therapeutic methods for metabolic disorders.
Danhe granule (DHG)
Inhibition of sphingolipid synthesis by Cycloserine In Vitro and In Vivo
Abstract: d- and l-cycloserine were shown to be irreversible inhibitors of the first enzyme of the sphingolipid pathway, 3-ketodihydrosphingosine synthetase, in a study using bacterial and brain microsomal enzymes, l-Cycloserine was shown to be 100 times more inhibitory than the d-isomer for the brain microsomal enzyme in vitro.
In vivo, l-cycloserine caused a 70% inhibition of brain microsomal enzyme. Following one injection, enzyme activity recovered 80% of normal after 16 hours. Daily dosages of l-cycloserine on a regimen of intraper-itoneal injection for 7 days caused a significant reduction in total brain ganglioside and cerebroside plus sulfatide levels.
Dendrobii Caulis extract
The plasma and liver ceramide levels were analyzed using HPLC-QQQ-MS/MS. The expression of serine palmitoyl-CoA transferase (Spt), ceramide synthase 6 (Cers6), dihydroceramide desaturase 1 (Des1), glucosylceramide synthase (Gcs), and ceramide kinase (Cerk) mRNA was assayed by RT-qPCR, while the protein expression of CerS6, DES1, GCS, CerK, and casein kinase 2α (CK2α) was tested by western blotting (WB). CerS6 degradation was evaluated using a cycloheximide (CHX) assay in vitro.
The ceramide (Cer 16:0), and hexosylceramide (Hex Cer 16:0, Hex Cer 18:0, Hex Cer 22:0, Hex Cer 24:0 and Hex Cer 24:1) levels decreased by approximately 17–56% in the plasma of the DHG-M and H rats. The Cer 16:0 content in the liver decreased by 20%, 50%, and 70% with the DHG-L, M, and H treatments; additionally, the dh Cer 16:0, Cer 18:0, Hex Cer 18:0, Hex Cer 20:0 Cer 22:0–1P, Cer 24:0–1p, Cer 24:1–1p, and Cer 26:1–1p levels decreased in the DHG groups. The mRNA and protein expression levels of DES1, GCS, Cerk, CerS6, and CHX assay indicated that DHG decreased the mRNA and protein expression levels of CerK and reduced CerS6 protein expression by promoting its degradation. Additionally, DHG attenuated the protein expression of CK2α which could increase CerS6 enzymatic activity by phosphorylating its C-terminal region.
Dendrobium catenatum
DOP treatment alleviates the extent of disturbances in the metabolism of fatty acids, glycerolipids (diacylglycerol and triacylglycerol), and glycerophospholipids (phosphatidylcholine and phosphatidylethanolamine) in diabetic rats. The levels of fatty acids (FAs) and glycerophospholipids are typically lower in the DOP-treated group compared to the diabetic model rats. SFAs can act as substrates for ceramide biosynthesis (77), and ceramides, in turn, reduce AKT activity by acting on Protein Phosphatase 2A (PP2A) or PKCζ or through activation of inflammatory mediators (e.g., TNF-α) thus leading to insulin resistance (78).
Furthermore, the SFA-TLR4 signaling pathway also mediates the development of insulin resistance by upregulating the transcription of ceramide biosynthetic enzymes (79). DOP treatment significantly alleviates the accumulation of saturated fatty acids (SFA’s) and unsaturated fatty acids (UFAS) in the liver. UFAs are deemed as activators of the innate immune component Toll-like receptor 4 (TLR4) and this modulatory effect may be associated with the function of Dop in alleviating insulin resistance.
Descurainiae Semen extract
Sphingolipids are a class of essential lipids found in cell membranes. They can regulate the immunity, proliferation, inflammation signaling, migration, adhesion, and cytoskeletal rearrangement of cells (Hannun and Obeid, 2018). Ceramide and sphingosine-1-phosphate (S1P) are major mediators involved in acute lung injury (Brinkmann and Baumruker, 2006; Ebenezer et al., 2016). Ceramide can be converted from sphingomyelin by sphingomyelinase (aSMase), whereas S1P is produced from ceramide via sphingosine-kinases (Lin et al., 2011). Serum S1P plays a key part in maintaining vascular homeostasis, which is crucial for the pathophysiologic processes of pulmonary diseases (Thuy et al., 2014).
S1P enhances the barrier function of the lung capillary endothelium through S1P receptor1-mediated rearrangement of action microfilaments and maintains vascular integrity by tightening intercellular adhesion, thereby decreasing vascular permeability and alveolar edema in lung inflammation (Obinata and Hla, 2019). ceramide exerts opposite effects: it increases vascular leakage and the apoptosis of endothelial cells to induce lung edema. Besides, the rate-limiting enzyme aSMase can be activated by proinflammatory factors and platelet-activating factor to increase ceramide synthesis in response to lung injury (Yagci et al., 2019).
In the present study, ceramide might increase in model group due to the down-regulation of its downstream products including SM(d18:1/23:0) and 3-O-Sulfogalactosylceramide (d18:1/20:0). The S1P level was also increased in the model group. Therefore, levels of ceramide and S1P were increased in the serum of PE-model rats (Supplementary Material S4). The reason for the increase in concentration of ceramide and S1P might be that S1P protects against ceramide-caused tissue injury under inflammatory stimuli, which represents self-defense in vivo (von Bismarck et al., 2012). The S1P content in the DS-Oli group and DS-FG group tended to be normal, and levels of the relevant metabolites in this pathway tended to return to normal in the DS group. Also, the dynamic equilibrium between ceramide and S1P is crucial to maintain homeostasis of alveolar functions (Petrache and Berdyshev, 2016).
Hence, treatment with DS, DS-Oli, or DS-FG could improve vascular leakage and lung-tissue damage, and maintain the integrity of the alveolar capillary membrane by altering the dynamic balance of ceramide and S1P in sphingolipid metabolism.
Didymin
The present study aimed to investigate the protective effects and mechanisms of Didymin from Mentha spicata on non-alcoholic fatty liver disease (NAFLD) induced by dexamethasone and high-fat diet (DEX/HFD) in C57BL/6J mice. Briefly, mice were acclimated for 5 days and then subjected to DEX/HFD from days 5 to 28; meanwhile, the animals were treated with Didymin or Silibinin from days 12 to 28. Key indicators of NAFLD were then detected, including the pathological changes of liver tissues, serum biochemical indicators, inflammation, oxidative stress, apoptosis and lipid metabolism. Besides, the expressions of pivotal genes and proteins of the TLR4 /NF-κB and PI3K/Akt pathways were examined to further elucidate the mechanisms of Didymin.
The results demonstrated that Didymin significantly extenuated hepatocyte damage and lipid disorder. Moreover, Didymin markedly decreased hepatocyte apoptosis by regulating the expressions of B-cell lymphoma-2 (Bcl-2) family and the expressions of the caspase family. Further study elucidated that Didymin decreased the expressions of toll-like receptor 4 (TLR4), as well as the phosphorylation of inhibitor of nuclear factor kappa-B (IκB) and nuclear factor kappa-B p65 (NF-κB p65), suggesting the inhibition of Didymin on the TLR4/NF-κB pathway.
Similarly, the PI3K/Akt pathway was also inhibited by Didymin, as evidenced by the decrease in the phosphorylation levels of PI3K and Akt. In summary, this study indicates that Didymin mitigates NAFLD by alleviating lipidosis and suppressing the TLR4/NF-κB and PI3K/Akt pathways, which may be a potential natural medicine for the treatment of NAFLD.
Emodin
The present study aimed to investigate the relationship between the protective effects of exendin‑4 (EX‑4) on lipotoxicity‑induced oxidative stress and meta‑inflammation in β‑cells and the toll‑like receptor 4 (TLR4 )/NF‑κB signaling pathway. Lipotoxicity, hydrogen peroxide (H2O2)‑induced oxidative stress in β cells, obese Sprague Dawley rats and TLR4 truncation rats were utilized in the present study.
The expression levels were detected by western blotting; cell apoptosis was detected by TUNEL assay; and the intra-cellular reactive oxygen species (ROS) levels were analyzed using a ROS assay kit. The findings of the present study showed that EX‑4 inhibited the expression of TLR4, NF‑κB p65 subunit and p47phox in a concentration‑dependent manner, and decreased the intracellular level of ROS. Additionally, silencing of TLR4 expression enhanced the protective effects of EX‑4, while overexpression of TLR4 attenuated these protective influences. Simultaneously, it was demonstrated that TLR4 was involved in the process of EX‑4 intervention to inhibit H2O2‑induced oxidative stress in islet β‑cells.
Moreover, it was found that EX‑4 also inhibited TLR4 or NF‑κB agonist‑induced oxidative stress. These results were also confirmed in an animal model of obese rats, in which EX‑4 was able to improve the function of β‑cells, attenuate oxidative stress, and inhibit the expression levels of TLR4 and NF‑κB p65 subunit in the pancreas of the diet‑induced obese rats. Furthermore, truncation of the TLR4 gene in SD rats delayed the aforementioned damage. In summary, EX‑4 may inhibit lipotoxicity‑induced oxidative stress in β‑cells by Inhibiting the activation of the TLR4 /NF‑κB signaling pathway.
Epigallocatechin gallate (EGCG)
The Impact of Phytochemicals in obesity -Related Metabolic diseases: Focus on Ceramide metabolism
The prevalence of obesity and related metabolic disease s has increased dramatically worldwide. As obesity progresses, various lipid species accumulate in ectopic tissues. Amongst them, ceramides a deleterious sphingolipid species accumulate and cause lipotoxicity and metabolic disturbances. Dysregulated ceramide metabolism appears to be a key feature in the pathogenesis of obesity-related Metabolic disease s. Notably, dietary modification might have an impact on modulating ceramide metabolism . Phytochemicals are plant-derived compounds with various physiological properties, which have been shown to protect against obesity-related metabolic diseases.
In this review, we aim to examine the impact of a myriad of phytochemicals and their dietary sources in altering ceramide deposition and ceramide-related metabolism from in vitro, in vivo, and human clinical/epidemiological studies. This review discusses how numerous phytochemicals are able to alleviate ceramide-induced metabolic defects and reduce the risk of obesity-related metabolic diseases via diverse mechanisms.
Obesity-related insulin resistance is associated with chronic systemic low-grade inflammation, and toll-like receptor 4 (TLR4 ) regulates inflammation. We investigated the pathways involved in epigallocatechin gallate (EGCG) modulation of insulin and TLR4 signaling in adipocytes. Inflammation was induced in adipocytes by lipopolysaccharide (LPS).
An antibody against the 67 kDa laminin receptor (67LR, to which EGCG exclusively binds) was used to examine the effect of EGCG on TLR4 signaling, and a TLR4/MD-2 antibody was used to inhibit TLR4 activity and to determine the insulin sensitivity of differentiated 3T3-L1 adipocytes. We found that EGCG dose-dependently inhibited LPS stimulation of adipocyte inflammation by reducing inflammatory mediator and cytokine levels (IKKβ, p-NF-κB, TNF-α, and IL-6). Pretreatment with the 67LR antibody prevented EGCG inhibition of inflammatory cytokines, decreased glucose transporter isoform 4 (GLUT4) expression, and inhibited insulin-stimulated glucose uptake.
TLR4 inhibition attenuated inflammatory cytokine levels and increased glucose uptake by reversing GLUT4 levels. These data suggest that EGCG suppresses TLR4 signaling in LPS-stimulated adipocytes via 67LR and attenuates insulin-stimulated glucose uptake associated with decreased GLUT4 expression.
Evening Primrose extract
Furthermore, several studies have reported that phytosterol and, in particular, β-sitosterol supplementation replaces cholesterol and reduces growth and survival signals routed through caveolar rafts in membranes of several cancer cell lines (Hac-Wydro, 2013, López et al, 2014). Among the many mechanisms by which phytosterols exhibit anti-cancer activity in vitro are the modulation of ceramide metabolism, liver X receptor activation, cell cycle progression, and apoptosis (Bradford & Awad, 2010).
Exendin-4
Context: Increased apoptosis of cardiomyocytes and cardiac progenitor cells (CPCs) in response to saturated fatty acids (SFAs) can lead to myocardial damage and dysfunction. ceramides mediate lipotoxicity-induced apoptosis. Glucagonlike peptide-1 receptor (GLP1R) agonists exert beneficial effects on cardiac cells in experimental models.
Objective: To investigate the protective effects of GLP1R activation on SFA-mediated apoptotic death of human CPCs.
Design: Human CPCs were isolated from cardiac appendages of nondiabetic donors and then exposed to palmitate with or without pretreatment with the GLP1R agonist exendin-4. Ceramide accumulation was evaluated by immunofluorescence. Expression of key enzymes in de novo ceramide biosynthesis was studied by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Apoptosis was evaluated by measuring release of oligonucleosomes, caspase-3 cleavage, caspase activity, and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling.
Results: Exposure of the CPCs to palmitate resulted in 2.3- and 1.9-fold higher expression of ceramide synthase 5 (CERS5) and ceramide desaturase-1, respectively (P < 0.05). This was associated with intra-cellular accumulation of ceramide and activation of c-Jun NH2-terminal protein kinase (JNK) signaling and apoptosis (P < 0.05). Both coincubation with fumonisin B1, a specific ceramide synthase inhibitor, and CERS5 knockdown prevented ceramide accumulation, JNK activation, and apoptosis in response to palmitate (P < 0.05). Exendin-4 also prevented the activation of the ceramide biosynthesis and JNK in response to palmitate, Inhibiting apoptosis (P < 0.05).
Conclusions: Excess palmitate results in activation of ceramide biosynthesis, JNK signaling, and apoptosis in human CPCs. GLP1R activation counteracts this lipotoxic damage via inhibition of ceramide generation, and this may represent a cardioprotective mechanism.
Fucoxanthin
Results indicate that Fx attenuated alcohol-induced oxidative lesions and inflammatory response s by activating the nuclear factor erythrocyte-2-related factor 2 (Nrf2)-mediated signaling pathway and down-regulating the expression of the toll-like receptor 4 (TLR4)-mediated nuclear factor–kappa B (NF-κB) signaling pathway, respectively. Our findings suggest that Fx can be developed as a potential nutraceutical for preventing alcohol-induced liver injury in the future.
Ganoderma lucidum
Activated AMPK can then relay signals to induce catabolism and suppress anabolism, thereby ameliorating obesity and insulin resistance [8,44]. The role of AMPK in metabolic regulation is mediated by various downstream effectors, including ACC, FAS, and GLUT4. ACC converts acetyl-CoA to malonyl-CoA, a fatty acid precursor that downregulates fatty acid oxidation by inhibiting CPT1 [45], thus increasing the availability of FFAs to synthesize other metabolites such as diacylglycerol (DAG) and ceramide [46].
DAG activates PKC which phosphorylates and inhibits insulin receptor kinase (IRK), leading to insulin resistance, while ceramide can inhibit glucose uptake by downregulating GLUT4 at the transcriptional level and inhibiting its localization to the membrane [15,35,47]. Therefore, ACC phosphorylation and inhibition by AMPK may improve GLUT4 localization and insulin sensitivity. A previous study reported that the F31 polysaccharide of G. lucidummight activate AMPK to suppress enzymes that regulate glucose metabolism and inhibit glucose production in the liver, thereby increasing GLUT4 expression and improving insulin resistance [20].
Gedunin
Biological Activities of Gedunin—A Limonoid from the Meliaceae Family
Geniposide
Background: Depression is a severe mental disorder. Unfortunately, more than half of patients with major depression disorder cannot achieve remission after initial treatment with an antidepressant. Geniposide, a bioactive iridoid glycoside isolated from Gardenia jasminoides Ellis, can ameliorate depressive-like behaviors in mice. However, the underlying mechanism is still not very clear.
Methods: The pharmacological methods including ELISA, immunofluorescence, and Western blot were used to investigate the role of geniposide on chronic unpredictable mild stress (CUMS)-induced depression mice.
Results: In this study, we found that geniposide could inhibit CUMS-induced depressive-like behaviors in mice. Geniposide is able to reduce the levels of ceramide and lower the activity of acid sphingomyelinase (ASM) in hippocampus; besides, ASM inhibitor (amitriptyline) can decrease the concentration of ceramide and ameliorate depressive-like behaviors of mice. Moreover, geniposide can also alleviate CUMS-induced hippocampal neuronal apoptosis and increase the phosphorylated form of PI3K, Akt, and GSK3β. Additionally, PI3K inhibitor (LY294002) can also abolish the neuroprotective effect of geniposide on hippocampal neurons in vitro.
Conclusions: These results indicate that geniposide exert a potential antidepressant-like effect on CUMS mice, and its effect might be associated with activated PI3K/Akt/GSK3β signaling, reduced the level of ceramide and hippocampal neuron apoptosis.
German chamomile
Effects of flavonoids on sphingolipid turnover in the toxin-damaged liver and liver cells
Background: The ceramide generation is an early event in the apoptotic response to numerous stimuli including the oxidative stress and ceramide analogs mimic the stress effect and induce apoptosis. Flavonoids of German chamomile are reported to exhibit the hepatoprotective effect. Flavonoids affect sphingolipid metabolism and reduce the elevated ceramide level in the aged liver. In the present paper, the ceramide content and production in the CCl4- and ethanol-treated liver and hepatocytes as well as the correction of sphingolipid metabolism in the damaged liver using the mixture of German chamomile flavonoids (chamiloflan) or apigenin-7-glucoside (AP7Glu) have been investigated.
Results: The experiments were performed in either the rat liver or hepatocytesof normal, CCl4- and ethanol-treated or flavonoid- and toxin plus flavonoid-treated animals. [14C]palmitic acid and [methyl-14C-phosphorylcholine]sphingomyelin were used to investigate the sphingolipid turnover. Addition of the CCl4 or ethanol to isolated hepatocyte suspensions caused loss of cell viability and increased the lactate dehydrogenase release from the cells into supernatant and ceramide level in the cells. CCl4 administration to the rats enlarged ceramide mass as well as neutral sphingomyelinase (SMase) activity and reduced ceramide degradation by the neutral ceramidase. Pretreatment of isolated hepatocytes with flavonoids abrogated the CCl4 effects on the cell membrane integrity and normalized the ceramide content. Flavonoid administration to the rats normalized the elevated ceramide content in the damaged liver via neutral SMase inhibition and ceramidase activation.
Conclusion: The data obtained have demonstrated that flavonoids affect sphingolipid metabolism in the CCl4- and ethanol-damaged liver and liver cells. Flavonoids normalized activities of key enzymes of sphingolipid turnover (neutral SMase and ceramidase) and ceramide contents in the damaged liver and liver cells, and stabilized the hepatocyte membranes.
Ginkgo biloba extract
Apoptosis was demonstrated to be a major mode of intestinal epithelial cell death caused by intestinal ischemia/reperfusion (II/R). Ceramide has been proposed as a messenger for apoptosis. The present study was aimed to investigate the effect of Ginkgo biloba extract 761 (EGb 761) pretreatment on II/R-induced intestinal mucosal epithelial apoptosis in rats and the mechanism related to ceramide. The rat model of II/R injury was produced by clamping superior mesenteric artery for 60 min followed by reperfusion for 180 min. Twenty four rats were randomly allocated into Sham, II/R and EGb + II/R groups. In EGb + II/R group, EGb 761 (100 mg/kg per day) was administered intragastrically for 7 days before the surgery. Animals in II/R and sham groups were treated with equal volume of normal saline solution. Intestinal mucosal epithelial apoptosis was detected via electron microscopy and TUNEL method.
Lipid peroxidation in intestinal mucosa was determined by detecting the malondialdehyde level and the activities of superoxide dismutase and peroxidase glutathione. The ceramide generation and sphingomyelinase (SMase) mRNA expression in intestinal mucosa were determined by high performance, thin layer chromatography, and RT-PCR, respectively. II/R caused intestinal mucosal epithelial apoptosis and over-production of the ceramide accompanied by up-regulation of SMase mRNA expression and increases of lipid peroxidation. EGb 761 pretreatment significantly decreased apoptosis index, and concurrently reduced the ceramide generation accompanied by down-regulation of SMase expression and inhibition of lipid peroxidation. The findings indicate that EGb 761 pretreatment attenuates II/R-induced intestinal epithelial apoptosis, which might be attributable to its antioxidant action of mediating ceramide pathway.
Ginseng extract Ginsenoside
Cardiovascular disease (CVD) is a crucial cause of death in postmenopausal women. Plasma ceramide concentrations are correlated with the development of atherosclerosis and are significant predictors of CVD. Here, we conducted a 4-week, double-blinded, placebo-controlled clinical pilot study to investigate the effect of Korean red ginseng (KRG) on serum ceramide concentrations in 68 postmenopausal women with hypercholesterolemia.
Patients were randomly assigned to two groups: the experimental group (n = 36) received KRG and the control (n = 32) group received placebo, 2 g each, once daily. Serum ceramides were measured using liquid chromatography–tandem mass spectrometry at baseline and study completion, with changes in serum ceramide levels as the primary end point.
We detected significantly greater mean changes in C16 ceramide levels (d18:1/16:0: −6.4 ± 6.3 pmol/mL vs. 14.6 ± 6.8 pmol/mL, respectively, p = 0.040; d18:1/22:0: −20.8 ± 24.4 pmol/mL vs. 71.1 ± 26.2 pmol/mL, respectively, p = 0.020). Additionally, changes in the median C16 (d18:1/16:0) and C22 (d18:1/22:0) ceramide levels were significantly greater in KRG-group subjects with metabolic syndrome than those without. Therefore, we found that KRG decreases the serum levels of several ceramides in postmenopausal women with hypercholesterolemia, suggesting it may be beneficial for preventing CVD in these individuals.
Glutathione
Reduced glutathione and N-acetylcysteine can inhibit both apoptosis and necrosis of several cell types, suggesting a critical role for reactive oxygen species (ROS) in cell death. However, how the cellular defense against oxidative stress is connected with other cell death mediators remains unclear. We selectively investigated the interaction of seleno-glutathione peroxidase-1 (GPx-1), the major enzyme responsible for peroxide detoxification in mammalian cells, with the cytotoxic response of T47D human breast cancer cells to doxorubicin, an anticancer drug known to promote production of ROS and apoptotic mediator ceramide.
Interestingly, in addition to a decrease in ROS production, the activation of neutral sphingomyelinase, sphingomyelin hydrolysis, and ceramide generation in response to doxorubicin was impaired in T47D/GPx2 cells compared with control cells. In contrast, GPx overexpression did not protect breast cancer cells from cell death induced by exogenous cell-permeant ceramide. Moreover, the basal activity of neutral sphingomyelinase was considerably lower in T47D/GPx2. Taken together, these results indicate that GPx-1 can regulate doxorubicin-induced cell death signaling at least in part by interfering with the activation of the sphingomyelin-ceramide pathway.
Grape Seed Proanthocyanidin
The Impact of Phytochemicals in obesity -Related Metabolic diseases: Focus on Ceramide metabolism
Green Tea Polyphenols
The Impact of Phytochemicals in obesity -Related Metabolic diseases: Focus on Ceramide metabolism
The prevalence of obesity and related Metabolic diseases has increased dramatically worldwide. As obesity progresses, various lipid species accumulate in ectopic tissues. Amongst them, ceramides — a deleterious sphingolipid species — accumulate and cause lipotoxicity and metabolic disturbances.
Dysregulated ceramide metabolism appears to be a key feature in the pathogenesis of obesity-related metabolic diseases. Notably, dietary modification might have an impact on modulating ceramide metabolism. Phytochemicals are plant-derived compounds with various physiological properties, which have been shown to protect against obesity-related metabolic diseases.
In this review, we aim to examine the impact of a myriad of phytochemicals and their dietary sources in altering ceramide deposition and ceramide-related metabolism from in vitro, in vivo, and human clinical/epidemiological studies. This review discusses how numerous phytochemicals are able to alleviate ceramide-induced metabolic defects and reduce the risk of obesity-related Metabolic diseases via diverse mechanisms.
Grifola frondosa
Obesity is characterized by massive fat deposition and is related to a series of metabolic complications, such as insulin resistance (IR) and steatohepatitis. Grifola frondosa (GF) is a basidiomycete fungus and a source of various nutritional ingredients related to human health. In this study, after a systematic analysis of its nutritional ingredients, GF was administered to mice fed a high-fat diet (HFD) to investigate its effects on lipid metabolism . In HFD-fed mice, GF significantly controlled the body weight, blood glucose and related organ indices, and effectively counteracted hyperlipidemia and IR triggered by the HFD. GF administration efficiently alleviated hepatic steatosis and adipocyte hypertrophy, and regulated alanine aminotransferase and aspartate aminotransferase in the liver.
An analysis of the intestinal microflora showed that GF reversed obesity-induced dysbiosis by affecting the relative abundance of certain bacteria, reducing lipopolysaccharide production and regulating the superpathway of heme biosynthesis associated with inflammation. According to the results of lipidomics, ceramide, a metabolite related to inflammation and IR, was found to be dysregulated in HFD-fed mice.
However, GF regulated the ceramide levels and restored lipid metabolism via the suppression of toll-like receptor 4/nuclear factor kappa-B signaling, which is involved in inflammation and IR. This study provides the experimental basis for the application of GF as an agent for obesity.
Hesperidin
Interplay between ceramides and phytonutrients: New insights in Metabolic Syndrome
Lipidomic analysis by Lee et al. (2020) revealed that 0.22 mg/g hesperidin (C28H34O15) was present in Yijin (Erchen)-Tang extracts (a Chinese herbal medicine) and after six weeks of its treatment, it resulted in action of adiponectin, an insulin-sensitizing, antidiabetic, and car- dioprotective adipokine, to activate ceramidase, which deacylated ceramides in obese mice. Triglycerides and ceramides with mono- unsaturated and saturated fatty acids were improved significantly with the effect of Chinese herbal treatment, which had been significantly correlated with adipocytokine signaling pathway in pathway enrich- ment analysis and insulin resistance and advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) in diabetic complications.
Inulin
Elevated circulating levels of ceramides (Cers) are associated with increased risk of cardio metabolic diseases, and Cers may play a causative role in metabolic dysfunction that precedes cardiac events , such as mortality as a result of coronary artery disease. Although the mechanisms involved are likely complex, these associations suggest that lowering circulating Cer levels could be protective against cardiovascular diseases. Conversely, dietary fibers, such as inulin, have been reported to promote cardiovascular and metabolic health. However, the mechanisms involved in these protective processes also are not well understood. We studied the effects of inulin on lipid metabolism with a model of atherosclerosis in LDL receptor-deficient mice using lipidomics and transcriptomics. Plasma and tissues were collected at 10 days and/or 12 weeks after feeding mice an atherogenic diet supplemented with inulin or cellulose (control).
Compared with controls, inulin-fed mice displayed a decreased C16:0/C24:0 plasma Cer ratio and lower levels of circulating Cers associated with VLDL and LDL. liver transcriptomic analysis revealed that Smpd3, a gene that encodes neutral SMase (NSMase), was downregulated by 2-fold in inulin-fed mice. hepatic NSMase activity was 3-fold lower in inulin-fed mice than in controls. Furthermore, liver redox status and compositions of phosphatidylserine and FFA species , the major factors that determine NSMase activity, were also modified by inulin. Taken together, these results showed that, in mice, inulin can decrease plasma Cer levels through reductions in NSMase expression and activity, suggesting a mechanism by which fiber could reduce cardio Metabolic disease risk.
Isorhamnetin
Effects of Chamomilla recutita flavonoids on age-related liver sphingolipid turnover in rats
The increased sphingolipid turnover in the liver is associated with elevation of free radical production and state of chronic inflammation at old age. Plant polyphenols are reported to exhibit antioxidant and anti-inflammatory effects. In the present paper, the lipids contents and ceramide production in the liver and hepatocytes as well as the correction of sphingolipid metabolism at old age using the mixture of Chamomilla recutita flavonoids (chamiloflan) or apigenin-7-glucoside or luteolin-7-glucoside alone have been investigated. To study the sphingolipids turnover, the [14C]serine-pre-labeled hepatocytes and [14C-methyl]- or [14C]palmitate-pre-labeled sphingomyelin (SM) and ceramide were used.
The ceramide content was higher in the liver and hepatocyte s of 24- and 27–28-month-old animals as compared to adult 3-month-old Wistar rats. An addition of flavonoids to the culture medium did not influence significantly on the lipids contents and metabolism in the isolated hepatocytes. The administration of flavonoids to old rats decreased the elevated neutral and acid SMases activities and ceramide mass and did not affect both the lipid content in the liver of adult animals and ceramide conversion to the sphingosine or SM. These results suggest that the SMases play a key role in the flavonoid-induced decrease of ceramide levels in the liver of old rats.
L-carnitine
Besides the well-documented effect of the chemotherapeutic drug doxorubicin on free radical generation, the exact signaling mechanisms by which it causes cardiac damage remain largely unknown and are of fundamental importance in understanding anthracycline cardiotoxicity. In this study, we describe that a 1 h treatment of isolated adult rat cardiac myocytes with doxorubicin (0.5 microM) induced DNA fragmentation associated with the classical morphological features of apoptosis observed after 7 days of culture. The doxorubicin toxicity was preceded by an increase in intracellular ceramide levels with a concurrent decrease in sphingomyelin.
Anthracycline-induced ceramide accumulation resulted from the activation of a sphingomyelinase assayed under acidic conditions, an effect related to an increase in V(max). Pretreatment of cardiac myocytes with L-carnitine (200 microgram/ml), a compound known for its protective effect on cardiac metabolic injuries, was found to dose-dependently inhibit the doxorubicin-induced sphingomyelin hydrolysis and ceramide generation as well as subsequent cell death. However, L-carnitine did not protect cardiac myocytes from apoptosis induced by exogenous cell-permeant ceramide. L-carnitine pretreatment did not affect the sphingomyelinase basal activity but abolished the doxorubicin-induced increase in V(max).
Moreover, in vitro studies conducted on cell extracts or with purified acid sphingomyelinase demonstrated that L-carnitine exerted a dose-dependent, sphingomyelinase inhibitory effect (through V(max) reduction). Taken together, these findings show that by Inhibiting a (perhaps novel) drug-activated acid sphingomyelinase and ceramide generation, L-carnitine can prevent doxorubicin-induced apoptosis of cardiac myocytes.
Lactoferrin
Lactoferrin inhibits neutrophil apoptosis via blockade of proximal apoptotic signalingevents
Neutrophils are the most abundant leukocyte and have a short lifespan, dying by apoptosis approximately five days after leaving the bone marrow. Their apoptosis can be delayed at sites of inflammation to extend their functional lifespan, but inappropriate inhibition of apoptosis contributes to chronic inflammatory disease. Levels of the physiological iron chelator lactoferrin are raised at sites of inflammation and we have shown previously that iron-unsaturated lactoferrin inhibited human neutrophil apoptosis, but the mechanisms involved were not determined. Here we report that the anti-apoptotic effect of lactoferrin is dependent upon its iron saturation status as iron-saturated lactoferrin did not affect neutrophil apoptosis.
We also show that the effect of lactoferrin is mediated at an early stage in apoptosis as it inhibited activation of sphingomyelinase, generation of ceramide, activation of caspase 8 and Bax and cleavage of Bid. Lactoferrin did not inhibit apoptosis induced by exogenous ceramide, supporting the proposal that it acts upstream of ceramide generation. We therefore conclude that raised lactoferrin levels are likely to contribute to chronic inflammation by delaying neutrophil apoptosis and that this is achieved by Inhibiting proximal apoptotic signaling events.
Luteolin
Effects of Chamomilla recutita flavonoids on age-related liver sphingolipid turnover in rats
The increased sphingolipid turnover in the liver is associated with elevation of free radical production and state of chronic inflammation at old age. Plant polyphenols are reported to exhibit antioxidant and anti-inflammatory effects. In the present paper, the lipids contents and ceramide production in the liver and hepatocyte s as well as the correction of sphingolipid metabolism at old age using the mixture of Chamomilla recutita flavonoids (chamiloflan) or apigenin-7-glucoside or luteolin-7-glucoside alone have been investigated. To study the sphingolipids turnover, the [14C]serine-pre-labeled hepatocyte s and [14C-methyl]- or [14C]palmitate-pre-labeled sphingomyelin (SM) and ceramide were used. The ceramide content was higher in the liver and hepatocyte s of 24- and 27–28-month-old animals as compared to adult 3-month-old Wistar rats.
An addition of flavonoids to the culture medium did not influence significantly on the lipids contents and metabolism in the isolated hepatocyte s. The administration of flavonoids to old rats decreased the elevated neutral and acid SMases activities and ceramide mass and did not affect both the lipid content in the liver of adult animals and ceramide conversion to the sphingosine or SM. These results suggest that the SMases play a key role in the flavonoid-induced decrease of ceramide levels in the liver of old rats.
luteolin-7-glucoside (LU7Glu)
Effects of Chamomilla recutita flavonoids on age-related liver sphingolipid turnover in rats
The increased sphingolipid turnover in the liver is associated with elevation of free radical production and state of chronic inflammation at old age. Plant polyphenols are reported to exhibit antioxidant and anti-inflammatory effects. In the present paper, the lipids contents and ceramide production in the liver and hepatocyte s as well as the correction of sphingolipid metabolism at old age using the mixture of Chamomilla recutita flavonoids (chamiloflan) or apigenin-7-glucoside or luteolin-7-glucoside alone have been investigated. To study the sphingolipid s turnover, the [14C]serine-pre-labeled hepatocyte s and [14C-methyl]- or [14C]palmitate-pre-labeled sphingomyelin (SM) and ceramide were used.
The ceramide content was higher in the liver and hepatocyte s of 24- and 27–28-month-old animals as compared to adult 3-month-old Wistar rats. An addition of flavonoids to the culture medium did not influence significantly on the lipids contents and metabolism in the isolated hepatocytes. The administration of flavonoids to old rats decreased the elevated neutral and acid SMases activities and ceramide mass and did not affect both the lipid content in the liver of adult animals and ceramide conversion to the sphingosine or SM. These results suggest that the SMases play a key role in the flavonoid-induced decrease of ceramide levels in the liver of old rats.
Mangifera indica L (induces Adiponectin increase)
Mangifera indica L. Leaf Extract Induces Adiponectin and Regulates Adipogenesis
Natural bioactive compounds may be used in obese patients because of their ability to impact on various key mechanisms involved in the complex pathophysiological mechanisms of such condition. The aim of this study was to investigate the effect of a Mangifera indica L. leaf extract (MLE) on adipogenic differentiation of murine preadipocyte cells. 3T3-L1 cells were treated during their differentiation with various concentrations of (Mangifera indica L.) leaves extract (MLE) (750, 380, 150, 75 and 35 μg) in order to assess their lipid content, adiponectin production, expression profile of genes involved in lipid metabolism, oxidative stress and inflammation.
Our results showed that MLE was particularly enriched in polyphenols (46.30 ± 0.083 mg/g) and that pharmacological treatment of cells resulted in a significant increase of adiponectin levels and reduction of intra-cellular lipid content. Consistently with these results, MLE resulted in a significant decrease of the expression of genes involved in lipid metabolism (FAS, PPARG, DGAT1, DGAT2, and SCD-1). In conclusion, our results suggest that MLE may represent a possible pharmacological tool for obese or metabolic syndrome patients.
Mulberry Fruit Extract Anthocyanin
Interplay between ceramides and phytonutrients: New insights in Metabolic Syndrome
Anthocyanins (C15H11O+) are sugar-based anthocyanidins, a sub- group of flavonoids that exhibits high bioactivity as well as antioxidant effects. Berries, currants, grapes and some tropical fruits have high an- thocyanins content. There have been some mammalian studies on berry- derived anthocyanins in reducing metabolic syndromes. As ceramides inhibit insulin activity through two primary ways (by either direct activation of protein kinase C (phosphorylates and inhibits the trans- location of Akt/PKB) or by stimulation of protein phosphatase 2A that in turn dephosphorylate Akt/PKB), high dose of anthocyanins has been observed to inhibit the insulin resistance and normalize insulin signaling as well as reduce body weight and correct abnormal liver functions by suppressing the serum ceramides and DAGs in specific body tissues (Si et al., 2020).
Mulberry Leaf extract
Interplay between ceramides and phytonutrients: New insights in Metabolic Syndrome
Anthocyanins (C15H11O+) are sugar-based anthocyanidins, a sub- group of flavonoids that exhibits high bioactivity as well as antioxidant effects. Berries, currants, grapes and some tropical fruits have high an- thocyanins content. There have been some mammalian studies on berry- derived anthocyanins in reducing Metabolic Syndromes. As ceramides inhibit insulin activity through two primary ways (by either direct activation of protein kinase C (phosphorylates and inhibits the trans- location of Akt/PKB) or by stimulation of protein phosphatase 2A that in turn dephosphorylate Akt/PKB), high dose of anthocyanins has been observed to inhibit the insulin resistance and normalize insulin signaling as well as reduce body weight and correct abnormal liver functions by suppressing the serum ceramides and DAGs in specific body tissues (Si et al., 2020).
n-acetylcysteine (NAC)
obesity-related disruption in lipid metabolism contributes to cardiovascular dysfunction. Despite numerous studies on lipid metabolism in the left ventricle, there is no data describing the influence of n-acetylcysteine (NAC) and α-lipoic acid (ALA), as glutathione precursors, on sphingolipid metabolism , and insulin resistance (IR) occurrence. The aim of our experiment was to evaluate the influence of chronic antioxidants administration on myocardial sphingolipid state and intracellular insulin signaling as a potential therapeutic strategy for obesity-related cardiovascular IR. The experiment was conducted on male Wistar rats fed a standard rodent chow or a high-fat diet with intragastric administration of NAC or ALA for eight weeks.
Cardiac and plasma sphingolipid species were assessed by high-performance liquid chromatography (HPLC). The proteins expressed from sphingolipid and insulin signaling pathways were determined by Western blot. Antioxidant supplementation markedly reduced ceramide accumulation by lowering the expression of selected proteins from the sphingolipid pathway and simultaneously increased the myocardial sphingosine-1-phosphate level. Moreover, NAC and ALA augmented the expression of GLUT4 and the phosphorylation state of Akt (Ser473) and GSK3β (Ser9), which improved the intracellular insulin transduction pathway. Based on our results, we may postulate that NAC and ALA have a beneficial influence on the cardiac ceramidose under IR conditions.
Naringin
Interplay between ceramides and phytonutrients: New insights in Metabolic Syndrome
From literature, lipidomic analysis revealed that nutritional intervention (consuming plant-based foods as a source of phytonutrients) can help in lowering the circulating ceramides especially C16:0 and C24:0 ceramides, a potential known inhibitor of insulin signaling.
Naringin (C27H32O14) is a glycoside component of naringenin found in citrus and grapefruit. It is hydrolyzed to flavanone naringenin by the microflora present inside intestine. This class of flavonoids con- tains tangeretin and polymethoxylated polyphenol nobiletin, which are abundantly present in oranges and tangerines and are readily accessible even with a lower proportion of overall intake. Naringin has also been reported to enhance hepatic AMP activated protein kinase and M.A. Shabbir et al. eventually regulate lipid metabolism and fatty oxidation in Wistar rats model (Mi˜n´on-Hern´andez et al., 2020).
In a related study, administration of orange juice or grapefruit to hypercholesterolemic casein fed rabbits decreased hepatic lipid accumulation and low-density lipoprotein cholesterol (LDL-C), indicating that citrus components may have lipid lowering characteristics. In rats with streptozotocin-induced dia- betes, administration of naringenin improved dyslipidemia with a decline in blood glucose levels. These preliminary results indicated that citrus-derived flavonoids can promote metabolic health in patients with insulin resistance and may help in preventing diabetes and cardiovascular disease (Mulvihill & Huff, 2012).
Omega-3 fatty acids
Interplay between ceramides and phytonutrients: New insights in Metabolic Syndrome
Walnuts (Juglans regia) are particularly rich in polyunsaturated fatty acids, predominantly alpha-linolenic acid (ALA) and omega-3 fatty acids (C60H92O6), and the majority of nuts contain high amounts of mono- unsaturated fatty acids. Serum concentrations of dihydroceramide (de novo synthesis markers), sphingomyelins (sphingomyelin hydrolysis markers), hexosylceramides (salvage pathway markers) and sphingosine (ceramide degradation markers) have been observed in various studies. These studies indicate that without changes in dihydroceramide con- centration, walnut intake reduces overall ceramides, sphingomyelins and hexosylceramides and increases sphingosines. The overall decrease in the levels of various groups of ceramides may suggest either a decline in the development of ceramides and/or an increase in the deterioration of ceramides.
In particular, decline in sphingomyelins and hexosylcer-amides may signify a decrease in the activation of sphingomyelin hy- drolysis pathway and salvage pathway, respectively. While an increase in sphingosines may suggest that intake of walnuts may have decreased ceramide levels by enhancing the levels of ceramidase, with corre- sponding increases in sphingosine. Walnuts are high in ALA content and significant increase has been observed in plasma ALAs from walnut intake. In randomized and placebo-controlled clinical trials, consump- tion of ALAs is known to change concentrations of adipokine, especially adiponectin, and may also decrease concentration of ceramides by transforming ceramides into sphingosine (Tuccinardi et al., 2019).
Panacis Quinquefolii Radix extract
Cardiovascular disease (CVD) is a crucial cause of death in postmenopausal women. Plasma ceramide concentrations are correlated with the development of atherosclerosis and are significant predictors of CVD. Here, we conducted a 4-week, double-blinded, placebo-controlled clinical pilot study to investigate the effect of Korean red ginseng (KRG) on serum ceramide concentrations in 68 postmenopausal women with hypercholesterolemia. Patients were randomly assigned to two groups: the experimental group (n = 36) received KRG and the control (n = 32) group received placebo, 2 g each, once daily. Serum ceramides were measured using liquid chromatography–tandem mass spectrometry at baseline and study completion, with changes in serum ceramide levels as the primary end point.
We detected significantly greater mean changes in C16 ceramide levels (d18:1/16:0: −6.4 ± 6.3 pmol/mL vs. 14.6 ± 6.8 pmol/mL, respectively, p = 0.040; d18:1/22:0: −20.8 ± 24.4 pmol/mL vs. 71.1 ± 26.2 pmol/mL, respectively, p = 0.020). Additionally, changes in the median C16 (d18:1/16:0) and C22 (d18:1/22:0) ceramide levels were significantly greater in KRG-group subjects with Metabolic Syndrome than those without. Therefore, we found that KRG decreases the serum levels of several ceramides in postmenopausal women with hypercholesterolemia, suggesting it may be beneficial for preventing CVD in these individuals.
Procyanidins
Interplay between ceramides and phytonutrients: New insights in Metabolic Syndrome
Chocolate and cocoa contain different proportions of flavonoids. In reality, flavanol-rich and plant-derived foods and beverages include tea, wine, various berries and fruits, as well as chocolate and cocoa products. Flavanols are found both as catechin and epicatechin monomers or oligomers (procyanidins, C30H26O13). Flavan-3-ols along with their oligomeric counterparts, procyanidins, are the major flavonoids involved in cocoa. These compounds are host to many beneficial effects, such as regulation of vascular homeostasis and antioxidant defense. Numerous molecular markers, such as endothelial nitric oxide synthase, NF-κB and angiotensin-converting enzyme, have been reported to pro- vide possible beneficial cardiovascular effects of cocoa flavonoids by suppressing the ceramide synthesis pathway. In addition, certain types of cocoa and chocolate high in flavanols may have the ability to improve insulin resistance.
Cocoa consumption can avoid high fat, diet induced obesity by decreasing the synthesis of fatty acids and transportation. Long term dietary intake of cocoa flavanol oligomers is the most effec- tive method for reducing obesity, elevated body mass, insulin resistance and impaired glucose tolerance. Studies revealed that as compared to cocoa with low flavanol concentrations, high concentration of flavanol in cocoa rapidly improved endothelial function and also reduced insulin tolerance over a period of 12 weeks in Wistar rats. In comparison, sugar- free cocoa intake increases endothelial activity more efficiently as opposed to sugar-sweetened cocoa.
Quercetin
Effects of Chamomilla recutita flavonoids on age-related liver sphingolipid turnover in rats
The increased sphingolipid turnover in the liver is associated with elevation of free radical production and state of chronic inflammation at old age. Plant polyphenols are reported to exhibit antioxidant and anti-inflammatory effects. In the present paper, the lipids contents and ceramide production in the liver and hepatocytes as well as the correction of sphingolipid metabolism at old age using the mixture of Chamomilla recutita flavonoids (chamiloflan) or apigenin-7-glucoside or luteolin-7-glucoside alone have been investigated. To study the sphingolipid s turnover, the [14C]serine-pre-labeled hepatocytes and [14C-methyl]- or [14C]palmitate-pre-labeled sphingomyelin (SM) and ceramide were used. The ceramide content was higher in the liver and hepatocyte s of 24- and 27–28-month-old animals as compared to adult 3-month-old Wistar rats.
An addition of flavonoids to the culture medium did not influence significantly on the lipids contents and metabolism in the isolated hepatocyte s. The administration of flavonoids to old rats decreased the elevated neutral and acid SMases activities and ceramide mass and did not affect both the lipid content in the liver of adult animals and ceramide conversion to the sphingosine or SM. These results suggest that the SMases play a key role in the flavonoid-induced decrease of ceramide levels in the liver of old rats.
Radix Puerariae extract
The incidence of type 2 diabetes and Metabolic disease is rapidly increasing, but effective therapies for their prevention and treatment have been poorly tolerated or minimally effective. In this study, chronic administration of kudzu root extract (8 months, 0.2%, w/w, in diet) decreased baseline fasting plasma glucose (183 ± 14 vs. 148 ± 11 mg/dl) and improved glucose and insulin tolerance in C57BL/6J ob/ob mice (1.67 ± 0.17 ng/ml [kudzu treated] vs. 2.35 ± 0.63 ng/ml [control]), but such treatment did not alter these parameters in lean control mice.
Among the mice on the kudzu supplementation, plasma levels of isoflavone metabolites were significantly higher in ob/ob versus lean control mice, and unmetabolized puerarin (11.50 ± 5.63 ng/g) was found in adipose tissue only in the treated mice. Together, these data demonstrate that a puerarin containing kudzu diet improves glucose and insulin responsiveness in ob/ob mice, suggesting that puerarin may be a beneficial adjuvant for treating metabolic disease.
Resveratrol
Interplay between ceramides and phytonutrients: New insights in Metabolic Syndrome
There are many known anti-hyperglycemic effects of resveratrol (C14H12O3), a natural polyphenol found in grapes, including activation of glucose upsurge and prevention of harmful alterations that may cause skeletal muscle insulin resistance . Various researches at cellular level have shown that blockade of Forkhead box protein O1 transcription factor (Foxo1) increases insulin sensitivity at both expression and activity levels, which is an effect primarily attributable to regulation of glucose upsurge and its utilization in the skeletal muscle and decreased liver gluconeogenesis. In addition to facilitating mitochondrial meta- bolism via the silent information regulator 1-peroxisome proliferator- activated receptor-gamma coactivator-1alpha (SirT1-PGC1) alpha axis, resveratrol actually functions as an anti-diabetic intervention, limiting glucose uptake due to Foxo1-induced repression as a result of SirT1 deacetylase activation, which is considered a novel anti-hyperglycemic mechanism of resveratrol (Sin, Yung, & Siu, 2015).
In another study, resveratrol was observed to protect against the hepatic insulin resistance in a rat’s model of non-alcoholic fatty liver disease by down-regulation of glycerol-3-phosphate acyltransferase (GPAT-1) and diacylglycerol O-Acyltransferase 2 (DGAT2) expression and inhibition of PKC membranous translocation. Moreover, this study showed that resveratrol could protect from early hyperlipidemia induced hepatic IR and enhance insulin action in a high fat diet fed rat model of non-alcoholic fatty liver disease (NAFLD ) through mediating transcriptional down-regulation of two key enzymes in the glyceralde- hyde 3-phosphate (G3P) pathway and Inhibiting PKC/JNK signaling (Badi, Mostafa, Khaleel, & Satti, 2019). Recent cell culture study suggested that resveratrol also has insulin – sensitizing properties, which renders a direct DES1 inhibitor. Resvera- trol has also been studied to restore the insulin signaling and inhibit palmitate (PA)-induced ceramide accumulation, partially inducing dihydroceramides (Bikman et al., 2012).
Resveratrol (RSV) is a natural compound exhibiting anti-inflammatory effect, but the anti-inflammatory mechanism has not been fully understood. This study is aimed to evaluate the anti-inflammatory activity and mechanism of RSV in lipopolysaccharides-induced rats’ model. The visceral wet/dry weight ratios and the changes of hematologic and biochemical indices indicated that LPS- stimulation mainly caused damages to liver and lung, while pretreatment with RSV could alleviate the lesions.
The cytokine assays showed that RSV could markedly decrease the production of proinflammatory mediators and cytokines (IL-1, IL-1β, IL-6, NO, iNOS and COX-2), and increase the expression of anti-inflammatory mediator (IL-10). RSV could inhibit TLR4 signaling pathway by down-regulating the mRNA levels of MyD88 and TRAF6, and suppressing the TLR4 protein. RSV could inhibit the signaling cascades of NF-κB p65 and MAPKs through down-regulating the mRNA levels of IκBα, p38MAPK, JNK, ERK1, ERK2 and ERK5 in liver and lung, and suppressing the dynamic changes of proteins and phosphorylated proteins including IκBα, NF-κB p65, p38MAPK, JNK, ERK1/2 and ERK5 from tissue’s cytoplasm to nucleus. In conclusion, RSV possessed a therapeutic effect on LPS-induced inflammation in rats and the mechanism mainly attributed to suppressing the signaling cascades of NF-κB p65 and MAPKs by Inhibiting the TLR4 signaling pathway.
Rhubarb (Rheum palmatum)
Screening of herbal extracts for TLR2- and TLR4 -dependent anti-inflammatory effects
Herbal extracts represent an ample source of natural compounds, with potential to be used in improving human health. There is a growing interest in using natural extracts as possible new treatment strategies for inflammatory disease s. We therefore aimed at identifying herbal extracts that affect inflammatory signaling pathways through toll-like receptor s (TLRs), TLR2 and TLR4.
Ninety-nine ethanolic extracts were screened in THP-1 monocytes and HeLa-TLR4 transfected reporter cells for their effects on stimulated TLR2 and TLR4 signaling pathways. The 28 identified anti-inflammatory extracts were tested in comparative assays of stimulated HEK-TLR2 and HEK-TLR4 transfected reporter cells to differentiate between direct TLR4 antagonistic effects and interference with downstream signaling cascades. Furthermore, the ten most effective anti-inflammatory extracts were tested on their ability to inhibit nuclear factor -κB (NF-κB ) translocation in HeLa-TLR4 transfected reporter cell lines and for their ability to repolarize M1-type macrophages.
Ethanolic extracts which showed the highest anti-inflammatory potential, up to a complete inhibition of pro-inflammatory cytokine production were Castanea sativa leaves, Cinchona pubescens bark, Cinnamomum verum bark, Salix alba bark, Rheum palmatum root, Alchemilla vulgaris plant, Humulus lupulus cones, Vaccinium myrtillus berries, Curcuma longa root and Arctostaphylos uva-ursi leaves. Moreover, all tested extracts mitigated not only TLR4, but also TLR2 signaling pathways. Seven of them additionally inhibited translocation of NF-κB into the nucleus.
Two of the extracts showed impact on repolarization of pro-inflammatory M1-type to anti-inflammatory M2-type macrophages. Several promising anti-inflammatory herbal extracts were identified in this study, including extracts with previously unknown influence on key TLR signaling pathways and macrophage repolarization, serving as a basis for novel lead compound identification.
Rutin
Rutin, a natural flavonoid, possess beneficial health effects. However, its renoprotective effect against carbon tetrachloride (CCl4) induced injury and the underlying mechanism is not clarified. The current study aims is to identify the therapeutic effects of rutin on oxidative stress, inflammation and apoptosis in mouse kidney exposed to CCl4. ICR mice received CCl4 with or without rutin co-administration for one week. Compared with the control group, mice receiving CCl4 alone showed kidney injury as evidenced by elevation in serum biochemical markers, inflammation, caspase-3 activity and apoptosis in kidney, while rutin administration significantly attenuated these pathophysiological changes. Exploration of the underlying mechanisms of its action demonstrated that rutin reduced the ROS, calpain and ceramide levels in mouse kidneys.
Rutin significantly decreased the p53, TNF-α, IL-1β activities and mitogen-activated protein kinase (MAPK) phosphorylation in the kidneys. In addition, rutin increased the levels of Bcl-2 protein and reduced levels protein of Bax. Rutin also inhibited the release of cytochrome C from mitochondria in kidneys of the CCl4-treated mice. Taken together, rutin ameliorates CCl4-induced oxidative stress, inflammation and apoptosis through regulating the ceramide, MAPK, p53 and calpain activities and thereby suppressing apoptosis by the mitochondrial pathway.
Salidroside
Lipotoxicity plays a detrimental role in the pathogenesis of non-alcoholic fatty liver disease s (NAFLD ). Salidroside (Sal), a phenylpropanoid glycoside extracted from Rhodiola rosea L, conferred resistance to high-fat diet-induced liver injury. However, the underlying mechanisms are still unclear. This study aimed at investigating Sal-inhibited lipotoxicity and clarify its potential mechanisms. Our study indicated that Sal significantly reversed palmitic acids-induced injury in dose-dependent manner in AML-12 mouse hepatocyte s, accompanied with improvement of oxidative stress and mitochondrial damage.
Mechanistic analysis revealed that Sal protected hepatic lipotoxicity via reversing TLR4 /MAPKs (including JNK, p38, and ERk1/2) and p53 activation, independent from autophagy, AMPK, and Akt pathways. Moreover, TLR4 inhibition also contributed to salidroside-reduced lipids deposition. In sum, this research clearly demonstrated the protective effects of Sal against lipotoxicity-induced hepatic cell death, which was mediated by downregulation of TLR4 /MAPKs pathways in hepatocyte s. We conclude that Sal is a potential candidate for the treatment of NAFLD.
Salvianolic acid A (SAA)
The occurrence of lipotoxicity during obesity-associated cardiomyopathy is detrimental to health. Salvianolic acid A (SAA), a natural polyphenol extract of Salvia miltiorrhiza Bunge (Danshen in China), is known to be cardioprotective. However, its clinical benefits against obesity -associated cardiomyocyte injuries are unclear. This study aimed at evaluating the protective effects of SAA against lipotoxicity-induced myocardial injury and its underlying mechanisms in high fat diet (HFD)-fed mice and in palmitate-treated cardiomyocyte cells (H9c2). Our analysis of aspartate aminotransferase and creatine kinase isoenzyme-MB (CM-KB) levels revealed that SAA significantly reversed HFD-induced myocardium morphological changes and improved myocardial damage.
Salvianolic acid A pretreatment ameliorated palmitic acid-induced myocardial cell death and was accompanied by mitochondrial membrane potential and intracellular reactive oxygen species improvement. Analysis of the underlying mechanisms showed that SAA reversed myocardial TLR4 induction in HFD-fed mice and H9c2 cells. Palmitic acid-induced cell death was significantly reversed by CLI-95, a specific TLR4 inhibitor. TLR4 activation by LPS significantly suppressed SAA-mediated lipotoxicity protection. Additionally, SAA inhibited lipotoxicity-mediated expression of TLR4 target genes, including MyD88 and p-JNK/MAPK in HFD-fed mice and H9c2 cells.
However, SAA did not exert any effect on palmitic acid-induced SIRT1 suppression and p-AMPK induction. In conclusion, our data shows that SAA protects against lipotoxicity-induced myocardial damage through a TLR4 /MAPKs mediated mechanism.
Sargassum fusiforme fucoidan
Sargassum fusiforme fucoidan (SFF) is a highly sulfated heteropolysaccharide with various biological activities. As one of the causative factor s of type 2 diabetes mellitus (T2DM), insulin resistance has become a global health issue. In this study, we investigated the potential pharmacological mechanisms by which SFF ameliorates insulin resistance in high-fat diet (HFD)-fed mice. SFF significantly enhanced tauroursodeoxycholic acid (TUDCA, a conjugated bile acid) levels and inhibited the farnesoid X receptor (FXR) signaling in the colon. SFF administration reduced ceramide levels in both serum and colonic tissue of HFD-fed mice, as well as reduced expression of SPT and CerS genes, which encode enzymes crucial to the biosynthesis of ceramides regulated by FXR signaling.
Pearson’s analysis showed that the TUDCA level was positively correlated with the gut bacteria Clostridium, and this was further validated in pseudo-germfree mice. Taken together, the results suggested that SFF increased TUDCA levels by remodeling gut microbiota, and TUDCA, a natural FXR antagonist, inhibited the FXR/SHP signaling pathway to reduce colon-derived biosynthesis of ceramide, thereby improving insulin resistance in the diet-induced obese (DIO) mice. This study has provided new insights into the therapeutic potential of S. fusiforme fucoidan in Metabolic diseases.
Schizonepeta tenuifolia
Inflammatory disease s remain the leading cause of mortality worldwide in both men and women. Schizonepeta tenuifolia (ST) exerts a wide range of physiological activities and has been found to possess beneficial efficacies against inflammation -related disease s; however, the molecular mechanisms underlying this anti-inflammatory activity remain to be elucidated. We investigated the molecular basis for the downregulation of toll-like receptor 4 (TLR4) signal transduction by ST ethanol extract in lipopolysaccharide (LPS)-stimulated macrophages. In this study, ST ethanol extract (100 μg/mL) did not induce cell cytotoxicity and was used in all the following experiments.
Treatment of LPS-stimulated macrophages with ST ethanol extract resulted in a significant decrease in cyclooxygen ase-2 and prostaglandin E2 levels, and inducible nitric oxide synthase-mediated NO production . LPS-induced expression of cell surface molecules (CD80 and CD86) and production of pro-inflammatory cytokines (tumor necrosis factor -α, interleukin [IL]-1β, and IL-6) were inhibited by ST ethanol extract. Further, we also found that the anti-inflammatory activities of ST ethanol extract was caused by inhibition of LPS-induced activation of mitogen-activated protein kinases, such as extracellular signal-regulated kinase 1/2 and p38, and the translocation of nuclear factor κB through TLR4 in macrophages. Thus, ST ethanol extract may possess novel and potent therapeutic efficacy for the treatment of inflammatory disease.
Shenling Baizhu
Objective: High-fat diet (HFD) and inflammation are two key contributors to nonalcoholic fatty liver disease (NAFLD). Shenling Baizhu powder (SLBZP), a classical herbal compound, has been successfully used to alleviate NAFLD. However, its specific mechanisms are not fully understood. In this study, we assessed the anti-NAFLD effect of SLBZP in vivo.
Methods: Rats were fed an HFD with or without SLBZP or with probiotics. At the end of week 16, an echo magnetic resonance imaging (EchoMRI) body composition analyser was used to quantitatively analyse body composition; a micro-computed tomography (micro-CT) imaging system was used to evaluate whole body and liver fat; and the Moor full-field laser perfusion imager 2 was used to assess liver microcirculation, after which, all rats were sacrificed. Then, biochemical indicators in the blood and the ultrastructure of rat livers were evaluated. Protein expression related to the liver toll-like receptor 4 (TLR4)/Nod-like receptor family pyrin domain-containing 3 (NLRP3) signalling pathway was assessed using Western blot analysis. Further, high-throughput screening of 29 related inflammatory factors in liver tissue was performed using a cytokine array.
Results: SLBZP supplementation reduced body weight, serum free fatty acid, and insulin resistance index (P < 0.05). It also ameliorated liver microcirculation and ultrastructural abnormalities. EchoMRI and micro-CT quantitative analyses showed that treatment with SLBZP reduced fat mass and visceral fat (P < 0.05 and P < 0.01, respectively). In addition, SLBZP decreased the expression of lipopolysaccharide (LPS)-activated TLR4 /NLRP3 signalling pathway-related proteins and altered the expression levels of some inflammatory cytokines in liver tissues.
Conclusion: SLBZP can inhibit NLRP3 inflammasome activation and interleukin-1β release by suppressing LPS-induced TLR4 expression in rats with HFD-induced NAFLD. Thus, SLBZP may be beneficial for the prevention and treatment of inflammatory damage and associated diseases.
Stinging Nettle
Objective: Excess dietary lipids result in the accumulation of lipid metabolites including ceramides that can attenuate insulin signaling. There is evidence that a botanical extract of Urtica dioica L. (stinging nettle) improves insulin action, yet the precise mechanism(s) are not known. Hence, we examined the effects of Urtica dioica L. (UT) on adipocytes.
Research Design: We investigated the effects of an ethanolic extract of UT on free fatty acid (palmitic acid) induced inhibition of insulin -stimulated Akt serine phosphorylation and modulation of ceramidase expression in 3T3-L1 adipocytes. Adipocytes were exposed to excess FFAs in the presence or absence of UT. Effects on adiponectin expression, ceramidase expression, ceramidase activity, ceramide accumulation and insulin signaling were determined.
Results: As expected, FFAs reduced adiponectin expression and increased the expression of ceramidase enzymes but not their activity. FFA also induced the accumulation of ceramides and reduced insulin-stimulated phosphorylation of Akt in adipocytes. The effects of FFA were partially reversed by UT. UT enhanced adiponectin expression and ceramidase activity in the presence of excess FFAs. UT abated ceramide accumulation and increased insulin sensitivity via enhanced Akt phosphorylation. A siRNA knockdown of adiponectin expression prevented UT from exerting positive effects on ceramidase activity but not Akt phosphorylation.
Conclusions: In adipocytes, the ability of UT to antagonize the negative effects of FFA by modulating ceramidase activity and ceramide accumulation is dependent on the presence of adiponectin. However, the ability of UT to enhance Akt phosphorylation is independent of adiponectin expression. These studies demonstrate direct effects of UT on adipocytes and suggest this botanical extract is metabolic ally beneficial.
Sulforaphane
Cruciferous vegetables like cabbage and broccoli usually contain a naturally occurring isothiocyanate compound named sulforaphane (C6H11NOS2). This phytonutrient has been studied in relation to its anticancer effect in cell culture studies. However, it has been found to improve hepatic glucose homeostasis and insulin sensitivity by reducing ceramide formation. Sulforaphane has been observed to suppress cer- amide synthesis in obese subjects through downregulation of serine palmitoyl transferase long chain base subunit 3 expression. This pro- vides the framework for improving ceramide scores for treating obesity-associated T2D (Teng et al., 2019).
Turmeric (Curcuma longa)
Screening of herbal extracts for TLR2- and TLR4 -dependent anti-inflammatory effects
Herbal extracts represent an ample source of natural compounds, with potential to be used in improving human health. There is a growing interest in using natural extracts as possible new treatment strategies for inflammatory disease s. We therefore aimed at identifying herbal extracts that affect inflammatory signaling pathways through toll-like receptor s (TLRs), TLR2 and TLR4 . Ninety-nine ethanolic extracts were screened in THP-1 monocytes and HeLa-TLR4 transfected reporter cells for their effects on stimulated TLR2 and TLR4 signaling pathways. The 28 identified anti-inflammatory extracts were tested in comparative assays of stimulated HEK-TLR2 and HEK-TLR4 transfected reporter cells to differentiate between direct TLR4 antagonistic effects and interference with downstream signaling cascades.
Furthermore, the ten most effective anti-inflammatory extracts were tested on their ability to inhibit nuclear factor-κB (NF-κB ) translocation in HeLa-TLR4 transfected reporter cell lines and for their ability to repolarize M1-type macrophages. Ethanolic extracts which showed the highest anti-inflammatory potential, up to a complete inhibition of pro-inflammatory cytokine production were Castanea sativa leaves, Cinchona pubescens bark, Cinnamomum verum bark, Salix alba bark, Rheum palmatum root, Alchemilla vulgaris plant, Humulus lupulus cones, Vaccinium myrtillus berries, Curcuma longa root and Arctostaphylos uva-ursi leaves. Moreover, all tested extracts mitigated not only TLR4, but also TLR2 signaling pathways. Seven of them additionally inhibited translocation of NF-κB into the nucleus.
Two of the extracts showed impact on repolarization of pro-inflammatory M1-type to anti-inflammatory M2-type macrophages. Several promising anti-inflammatory herbal extracts were identified in this study, including extracts with previously unknown influence on key TLR signaling pathways and macrophage repolarization, serving as a basis for novel lead compound identification.
Vitamin D
Interplay between Vitamin D and sphingolipid s in CardioMetabolic disease s
Sphingolipids (SLs) are structural, bioactive molecules with several key cellular roles, whereas 1,25-dihydroxyvitamin D (1,25(OH)D), the active form of vitamin D, is considered the major regulator of calcium homeostasis, although it also exerts other extraskeletal effects. Many studies reported the physiological connection between vitamin D and SLs, highlighting not only the effects of vitamin D on SL metabolism and signaling but also the influence of SLs on vitamin D levels and function, thus strongly suggesting a crosstalk between these molecules. After a brief description of 1,25(OH)D and SL metabolism, this review aims to discuss the preclinical and clinical evidence on the crosstalk between SLs and 1,25(OH)D, with a special focus on cardio metabolic diseases.
Vitamin D reduces myocellular insulin resistance , but the effects of vitamin D on intramyocellular lipid (IMCL) partitioning are unknown. The purpose of this study was to understand how calcitriol, the active vitamin D metabolite, affects insulin sensitivity and lipid partitioning in skeletal muscle cells. C2C12 myotubes were treated with calcitriol (100 nM) or vehicle control for 96 h. insulin -stimulated Akt phosphorylation (Thr 308) was determined by western blot. Intramyocellular triacylglycerol (IMTG), diacylglycerol (DAG), and ceramide content were measured by LC/MS. IMTG partitioning and lipid droplet accumulation were assessed by oil red O. Expression of genes involved in lipid droplet packaging and lipolysis were measured by RT-PCR.
Compared to vehicle-treated myotubes, calcitriol augmented insulin-stimulated pAkt. Calcitriol increased total ceramides and DAG in a subspecies -specific manner. Specifically, calcitriol preferentially increased ceramide 24:1 (1.78 fold) and di-18:0 DAG (46.89 fold). Calcitriol increased total IMTG area as assessed by oil red O, but decreased the proportion of lipid within myotubes. Calcitriol increased mRNA content of genes involved in lipid droplet packaging (perilipin 2; PLIN 2, 2.07 fold) and lipolysis (comparative gene identification-58; CGI-58 and adipose triglyceride lipase; ATGL, ~ 1.80 fold). Calcitriol alters myocellular lipid partitioning and lipid droplet packaging which may favor lipid turnover and partially explain improvements in insulin sensitivity.
Xanthohumol
The Impact of Phytochemicals in obesity -Related Metabolic disease s: Focus on Ceramide metabolism
The prevalence of obesity and related Metabolic disease s has increased dramatically worldwide. As obesity progresses, various lipid species accumulate in ectopic tissues. Amongst them, ceramides —a deleterious sphingolipid species —accumulate and cause lipotoxicity and Metabolic disturbances. Dysregulated ceramide metabolism appears to be a key feature in the pathogenesis of obesity -related Metabolic diseases. Notably, dietary modification might have an impact on modulating ceramide metabolism.
Phytochemicals are plant-derived compounds with various physiological properties, which have been shown to protect against obesity -related Metabolic disease s. In this review, we aim to examine the impact of a myriad of phytochemicals and their dietary sources in altering ceramide deposition and ceramide-related metabolism from in vitro, in vivo, and human clinical/epidemiological studies. This review discusses how numerous phytochemicals are able to alleviate ceramide-induced metabolic defects and reduce the risk of obesity -related Metabolic diseases via diverse mechanisms.
Interplay between ceramides and phytonutrients: New insights in Metabolic Syndrome
Hops-derived flavonoids (xanthohumol, C21H22O5) regulate the liver -brain system with prevalent prenylated flavonoids in hops (Humulus lupulus) and its hydrogenated derivatives i.e., α, β-dihydrox- anthohumol and tetrahydroxanthohumol. In a study relating to effect of xanthohumol and its derivatives in mice, increase in peripheral and core Metabolic impairments was consistent but with a reduction in ceramides in both liver and hippocampus.
These data suggested that bile acid- mediated regulation of farnesoid X receptor (FXR) activity could contribute to improving Metabolic dysfunction by modulating the signaling axis of bile acid FXR-ceramide in mice fed with these flavo- noids. These results are significant because experimental treatments targeted at ceramide aggregation in the brain and peripheral organs are an effective way to reduce Metabolic impairments associated with obesity (Paraiso et al., 2020).
α-lipoic acid (ALA)
obesity-related disruption in lipid metabolism contributes to cardiovascular dysfunction. Despite numerous studies on lipid metabolism in the left ventricle, there is no data describing the influence of n-acetylcysteine (NAC) and α-lipoic acid (ALA), as glutathione precursors, on sphingolipid metabolism , and insulin resistance (IR) occurrence. The aim of our experiment was to evaluate the influence of chronic antioxidants administration on myocardial sphingolipid state and intracellular insulin signaling as a potential therapeutic strategy for obesity -related cardiovascular IR. The experiment was conducted on male Wistar rats fed a standard rodent chow or a high-fat diet with intragastric administration of NAC or ALA for eight weeks. Cardiac and plasma sphingolipid species were assessed by high-performance liquid chromatography (HPLC). The proteins expressed from sphingolipid and insulin signaling pathways were determined by Western blot.
Antioxidant supplementation markedly reduced ceramide accumulation by lowering the expression of selected proteins from the sphingolipid pathway and simultaneously increased the myocardial sphingosine-1-phosphate level. Moreover, NAC and ALA augmented the expression of GLUT4 and the phosphorylation state of Akt (Ser473) and GSK3β (Ser9), which improved the intracellular insulin transduction pathway. Based on our results, we may postulate that NAC and ALA have a beneficial influence on the cardiac ceramidose under IR conditions.
α-Mangostin
This study investigated the potential protective effects of alpha-mangostin (α-MG) on ultraviolet B (UVB)-induced damage in HaCaT cells. The results showed that α-MG less than 10 μM had no significant cytotoxicity and exposure to UVB (50 mJ/cm2) reduced cell viability by approximately 50% compared with the control. The 2 μM α-MG upregulated cell viability and downregulated the expression of metal matrix proteases (MMPs). The results of flow cytometry, real-time quantitative PCR (RT-qPCR), and immunoblotting manifested that α-MG relieved the extent of apoptosis and reduced the levels of apoptosis -associated mRNAs and proteins, respectively.
The results of RT-qPCR and ELISA indicated that α-MG suppressed the generation of IL-6 and TNF-α. Furthermore, α-MG effectively downregulated activation of the UVB-induced nuclear factor κB (NF-κB ) and mitogen-activated protein kinase (MAPK) signaling pathways. Finally, lipidomics profiling demonstrated that α-MG significantly reduced UVB radiation-increased ceramide. Overall, these results demonstrated that α-MG has beneficial effects against photoaging by reducing the ceramide content and Inhibiting MAPK and NF-κB signaling pathways.
| Size | 100g |
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4 reviews for CERAMIDE BLOCKER 200:1 – Lipotoxicity Neutralizer – WORLD WIDE LAUNCH DATE APRIL 15th!
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Marissa Cervantes –
Just when you thought it couldn’t get better….BOOM Ceramide Blocker is here!
At 51 obese, lazy , and stressed this blend helped me in so many ways. Trying to lose weight with diet and exercise I hit the inevitable plateau. I started taking Ceramide Blocker on is own just to see what would happen. Within 2 days the scale started moving in the right direction and my confidence came back immediately. I was down 10lbs in about a week. No more high blood pressure, no risk of diabetes and no dependence on prescription medications. Ceramide Blocker is a game changer for sure.
Heidi –
Ceramide! This is an incredible blend! I started taking it a little over a month ago and it immediately moved to my top favorites! I have been working on improving my numbers from blood work panels. Triglycerides, cholesterol, Gluclose, weight loss, etc. This blend has been a huge part of my success! The inches are melting off and the weight has continued dropping weekly! I lost 10 pounds in my first week alone on this blend! I could feel my body feeling supported, energized, and functioning at a better level! And I described it as a good clean energy boost!
Ceramide has helped me reduce my triglyceride numbers from the 200’s (which is high) and has moved it below 100. Generally sitting consistently in the 60-70 range sometimes even lower! This is just after a couple short weeks of use! It sure didn’t take long to see dramatically improved blood panels! This has been the same for cholesterol, dramatically decreasing it quite quickly!
Another huge benefit from this amazing blend is the weight loss effects! I have consistently lost multiple lbs weekly with 22/2 fasting and this impressive blend! This blend helps provide energy, mental clarity, a functioning mind, and a drive to propel forward! I have made this blend a part of my daily protocol! I love the way it makes me feel with a boosted energy!
If you’re looking to improve your daily stamina, loose weight, get the clock ticking correctly in overall function, fix your blood panel readings, lower cholesterol, lower triglycerides, feel better quickly, drop inches, and much more…then I highly suggest moving this blend to the forefront of your reach! I love this blend! It’s a “FEEL REAL GOOD” blend for me and I won’t be letting my CERAMIDE jar run low! Thank you Gavin! This is a big FAVORITE for me and I hope many more people with give it a try to feel and benefit for themselves! IMPRESSIVE!
Katherine Flaherty –
This blend is a game changer for anyone who needs help assisting in supporting cardiovascular health. With the aid or the ceramide blocker I have lost 40 lbs and counting so far since starting it in Feb2024. I have seen a 200% improvement in 2 months time of my blood pressure, cholesterol and blood triglycerides. Ceramide Blocker being at an arms length 24/7 is a must. Will have your heart pumping at optimal peak for a very long time. This blend really helps cut through the issue I have with losing weight bc of my hypothyroidism. I can only imagine how many other issues it would reduce to a minimum or fully eradicate when taken. It’s super easy to-take as well and not much is needed to get these results. The doctors wanted me buying all the high priced prescription medications with negative side effects. I took matters into my own hands and chose blends, intermittent fasting and cardio. Only positive benefits to that direction. Please if you want to lose weight the Ceramide Blocker is one of the key factors. You got this 💪💯🔥
Kate Flaherty –
This blend is a game changer for anyone who needs help assisting in supporting cardiovascular health. With the aid or the ceramide blocker I have lost 40 lbs and counting so far since starting it in Feb2024. I have seen a 200% improvement in 2 months time of my blood pressure, cholesterol and blood triglycerides. Ceramide Blocker being at an arms length 24/7 is a must. Will have your heart pumping at optimal peak for a very long time. This blend really helps cut through the issue I have with losing weight bc of my hypothyroidism. I can only imagine how many other issues it would reduce to a minimum or fully eradicate when taken. It’s super easy to-take as well and not much is needed to get these results. The doctors wanted me buying all the high priced prescription medications with negative side effects. I took matters into my own hands and chose blends, intermittent fasting and cardio. Only positive benefits to that direction. Please if you want to lose weight the Ceramide Blocker is one of the key factors. You got this 💪💯🔥