Metrics details. Plasma free fatty acids levels are increased in subjects with obesity and type 2 diabetes, playing detrimental roles in the pathogenesis of atherosclerosis and cardiovascular diseases. Increasing evidence showing that dysfunction of the vascular endothelium, the inner lining of the blood vessels, is the key player in the pathogenesis of atherosclerosis. In this review, we aimed to summarize the roles and the underlying mechanisms using the evidence collected from clinical and experimental studies about free fatty acid-mediated endothelial dysfunction. Because of the multifaceted roles of plasma free fatty acids in mediating endothelial dysfunction, elevated free fatty acid level is now considered as an important link in the onset of endothelial dysfunction due to metabolic syndromes such as diabetes and obesity.
Mol Cell Biol 21 4 — Volunteers from the region around Rochester, Minnesota who Private soccer lessons the inclusion criteria will be recruited. Obesity-associated focal segmental glomerulosclerosis: pathological features of the lesion and relationship with cardiomegaly and hyperlipidemia. Gluconeo- genesis. Role of nrf2 in oxidative stress and Free fatty acid causes. Availability of data and materials Not applicable. From here the three carbon atoms of the Free fatty acid causes glycerol can be oxidized via glycolysisor converted to glucose via gluconeogenesis. Olive oil polyphenols protect endothelial dysfunction induced by high glucose and free fatty acids by modulating nitric oxide and endothelin Genes Dev 18 24 —
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ScienceDaily, 16 August Not Entirely. Last October, the My model behavior with eva Heart Association revised its dietary recommendations to include advice to eat two meals of fatty fish — those highest in omega-3 fatty acids — per week. Specimen Handling Collection and Preparation. Leave a Reply Cancel reply Your email address will not be published. J Clin Invest ; The aftty is particularly important during the refining of oils and fats, for the assessment Free fatty acid causes the processing cycle and for the definition of product categories. Free fatty acids are one of the outcomes of the food digestion process. Serum free fatty acids are also increased in patients with uncontrolled type 2 diabetes mellitus and are an indicator of insulin resistance. Living Well. Solid fats : melted using bain-marie method before starting the test animal fats, palm oil, etc. Request a Free Quote Now! The free fatty acids released from acod tissue can be utilized anywhere there is Free fatty acid causes energy need within the body.
Metabolism, energetics, and lipid biology in the podocyte View all 4 Articles.
- Naturally occurring fatty acids usually contain carbon atoms, each with one or two hydrogen atoms attached, a methyl group CH 3 on one end and a carboxylic group COOH on the other one.
- Researchers have known that high levels of free fatty acids could trigger irregular heart rhythms in individuals with heart disease, but no one had studied whether they also can be dangerous for someone who is healthy, he says.
- Test type: End Point.
Metrics details. Plasma free fatty acids levels are increased in subjects with obesity and type 2 diabetes, playing detrimental roles in the pathogenesis of atherosclerosis and cardiovascular diseases. Increasing evidence showing that dysfunction of the vascular endothelium, the inner lining of the blood vessels, is the key player in the pathogenesis of atherosclerosis.
In this review, we aimed to summarize the roles and the underlying mechanisms using the evidence collected from clinical and experimental studies about free fatty acid-mediated endothelial dysfunction.
Because of the multifaceted roles of plasma free fatty acids in mediating endothelial dysfunction, elevated free fatty acid level is now considered as an important link in the onset of endothelial dysfunction due to metabolic syndromes such as diabetes and obesity. Free fatty acid-mediated endothelial dysfunction involves several mechanisms including impaired insulin signaling and nitric oxide production, oxidative stress, inflammation and the activation of the renin-angiotensin system and apoptosis in the endothelial cells.
Therefore, targeting the signaling pathways involved in free fatty acid-induced endothelial dysfunction could serve as a preventive approach to protect against the occurrence of endothelial dysfunction and the subsequent complications such as atherosclerosis. Cardiovascular diseases CVDs , particularly coronary heart disease CHD , account for the major causes of mortality worldwide [ 1 ]. The presence of atherosclerosis is a very common characteristic in patients with CHD [ 1 ], and that endothelial dysfunction ED is suggested as one of the early events in the pathogenesis of atherosclerotic progression.
The vascular endothelium is a tightly regulated organ that forms a vast interface between the blood and neighboring tissues, and is consisted of a monolayer of endothelial cells ECs.
However, various harmful stimuli such as oxidative stress and inflammation can alter the normal endothelium functioning and lead to the onset of ED.
Recent studies have shown that FFAs not only are the major causes of insulin resistance [ 4 , 5 ], but they are also responsible for inducing inflammatory events in the tissues targeted by insulin, such as ECs, liver and skeletal muscle [ 3 , 6 ]. The impairment of insulin-mediated glucose uptake is correlated to the circulating FFA levels, and such resistance to insulin might be due to FFA-mediated inactivation of phosphoinositide 3-kinase PI3K [ 7 ].
Interestingly, cancer-related up-regulation of FFAs was also reported in several types of cancer in many previous studies [ 8 , 9 , 10 , 11 ]. Specifically, insulin resistance, oxidative stress, and inflammatory burdens account for the substantial causes of FFA-induced ED [ 12 , 13 , 14 ]. Generally, diabetes and other metabolic states could give rise to elevated FFAs, which in turn impose a direct effect on transcription factors that trigger inflammation and oxidative stress in the endothelium [ 15 ].
The endothelium is a composition of a monolayer of ECs which lines on the inner surface of the vascular lumen between flowing blood and vascular smooth muscle cells VSMCs [ 20 ]. ECs are multifunctional; they are responsible for a wide range of vital functions, including the maintenance of vascular tone, blood fluidity and permeability [ 21 , 22 ]. Thus, impairment of the endothelial functions is suggested to play deleterious roles in the development of several diseases, including inflammatory angiitis syndrome, thrombotic embolism, disseminated intravascular coagulation DIC disorder, and neovascularization, tumor progression and diabetic retinopathy [ 23 ].
For example, endothelium-secreted molecules such as angiotensin II Ang II , endothelin-1 ET-1 , thromboxane A2 TXA2 , and prostacyclin H2 participate in vasoconstriction, whereas, molecules such as NO, bradykinin, and hyperpolarizing factor contribute to vasodilation that helps maintaining a balance between the vasoconstriction and vasodilation [ 20 ].
The fine balance between these secreted molecules is critical for a proper functioning of the endothelium, and an imbalance of these molecules may contribute to failure in vascular auto-regulation, and influence the structural and functional integrity of the circulation [ 24 ]. In the endothelium, NO is synthesized from L-arginine, a semi-essential amino acid, by the endothelial nitric oxide synthase eNOS , and L-citrulline is the by-product of this pathway [ 25 ].
Shear stress is a crucial factor for the activation of eNOS under physiological circumstances; other signaling molecules such as bradykinin, adenosine, vascular endothelial growth factor VEGF , and serotonin can also lead to the activation of eNOS [ 28 ]. It is an event that accounts for the risk of CVDs and precedes the development of atherosclerosis [ 20 , 29 ]. Among the relevant mechanisms of ED pathogenesis, proposed in previous studies, oxidative stress and inflammation account for the majority of them [ 12 , 13 , 29 , 30 , 31 ].
In addition, ED can also be induced by many factors such as dietary intake, drugs, and aging. Several classes of drugs, including anti-cancer drugs, immunosuppressive drugs, anti-retroviral drugs, and others, have been known to induce ED.
Notably, NO production is reduced in elderly people which has also been seen in aged animals through a downregulation of eNOS. On the other hand, ET-1 expression is also increased with aging; ET-1 inhibits acetylcholine ACh -dependent platelet inhibition in the endothelium and is a promoter of vWF expression.
Several compounds with therapeutic value against ED, in different diseased states, have been reported in the recent years. Rosuvastatin, a lipid-lowering statin, has been shown to improve endothelial function in patients with inflammatory joint diseases, systemic sclerosis and chronic heart failure CHF [ 51 , 52 , 53 ].
Particularly, in the CHF patients, the drug improved the flow-mediated dilation FMD by inducing antioxidant effects, neovascularization and Akt phosphorylation [ 53 ]. A synergistic protective effect of pioglitazone with quercetin, a naturally occurring plant polyphenol, on ED has also been shown on isolated rat aorta with the characteristics of T2DM [ 58 ]. A detailed meta-analysis on the effects of thiazolidinediones on the FMD has been reported elsewhere [ 59 ].
However, it should be noted that pioglitazone can induce heart failure in patients with underlying heart disease [ 61 ]. In addition, protective roles of many natural products, such as Traditional Chinese Medicines TCM , have been reported to improve endothelial function. Danshensu, another TCM, which is a water-extractable component of the medicinal herb Salvia miltiorrhiza , protects the endothelium in rats with hyperhomocysteinemia by modulating the abnormality in the parameters such as NO, ET-1, and other inflammatory markers induced by hyperhomocysteinemia [ 66 ]; homocysteine is a byproduct of numerous biological processes in the human body and, when elevated, it may be associated with severe atherosclerosis and thrombotic occlusions [ 67 ].
Some other types of TCM formulations with potential effects on the endothelium have been described elsewhere [ 68 ]. Other compounds having potential effects on endothelial function, which can be disturbed by FFAs, have been discussed in the later parts.
Fatty acids FAs are carboxylic acids with long aliphatic chains containing a methyl group at one end, while a carboxylic group at the other end. Depending on the presence of double bonds, they are classified into saturated fatty acids or SFAs with no double bonds, monounsaturated fatty acids or MUFAs with only one double bond and polyunsaturated fatty acids or PUFAs with at least two double bonds [ 69 ].
Detailed physiological and pathophysiological roles of these receptors have been described elsewhere [ 72 , 73 ]. Previous plasma metabolomic studies have confirmed PA as a strong contributing factor to the development of atherosclerosis [ 75 ]. Several recent in vivo and in vitro studies have revealed the mechanisms by which PA contributes the pathogenesis of CVDs. A very recent study has shown that PA is a promoter of inflammatory responses and cellular senescence in cardiac fibroblasts which it mediates via the activation of toll-like receptor 4 TLR4 and NLRP3 inflammasome, increasing mitochondrial ROS load and mitochondrial dysfunction, and functionality loss of the cardiac fibroblasts [ 76 ].
The specific roles and mechanisms of FFAs, in particular through mediation of ED, in the development of CVDs have been discussed in the later parts of this article Section 4. FAs possess different physiological roles - structurally they contribute to the constituents of the membrane lipids, including phospholipids and glycolipids, whereas, functionally they are important as fuel molecules [ 78 ].
Although they are important sources of energy, particularly during a fasting condition, abnormalities in FA metabolism may contribute to the pathogenesis of MetS [ 78 ], and may bear risks for developing atherosclerosis [ 79 ]. In turn, higher levels of FFAs inhibit the anti-lipolytic action of insulin, which further increases the rate of FFAs release into the circulation [ 81 ]. Clinical studies have shown that elevated level of FFAs leads to an insulin-resistant state, and that lowering of FFAs can be beneficial to insulin-stimulated glucose uptake [ 3 ].
FFAs are significant sources of reactive oxygen species ROS , which lead to the event of oxidative stress. All these inflammatory components play a role in chronic inflammation that might cause insulin resistance in the ECs [ 85 , 86 ].
Inflammasomes act as both innate immune system receptors and sensors, and regulate a number of activities such as the activation of caspase-1 and inducement of inflammation; NLRP3 is the best characterized inflammasome [ 87 ] that can correlate to a number of human diseases, including atherosclerosis, MetS and neurodegenerative diseases [ 88 ].
One study showed that increased level of FFAs in the bloodstream impairs endothelium-dependent vasodilation while the endothelium-independent vasodilation remains unaffected [ 94 ], suggesting FFAs have specific inhibitory roles on production of NO in the ECs. Another study reported that infusion of FFA in insulin-sensitive human subjects leads to a significant reduction in NO synthase flux and an impaired shear stress-induced production of NO [ 95 ].
Interestingly, even though PUFAs have a protective role against ED [ ], their free circulating form could also mediate a negative action on the endothelium by decreasing NO availability and increasing ET-1 [ ]. Decreases in NO synthesis and increase in the level of ET-1 can be reversed by treatment with the olive oil polyphenolic compounds [ ].
There are many clinical studies reporting the protective effects of EPA or olive oil constituents such as oleic acid OA on FMD and other endothelial markers [ , , ], which, however, did not focus on their effects on FFA-induced ED. Although the studies by Lee et al.
Calcium signaling plays a crucial role in endothelial function by facilitating the release of NO through activation of eNOS, which is a calcium-dependent enzyme [ ].
Intracellular calcium is important for mechanosensitivity responses of ECs [ ], and that shear stress-mediated release of NO largely depends on increases in cytosolic calcium levels [ , ]. Later on, another study confirmed the deleterious effects of FFAs on endothelial calcium signaling and subsequent eNOS activity that led to diminished NO production [ ] Fig. For example, FFAs can mediate oxidative stress and inflammation in the endothelium which can affect insulin signaling and contribute to dysregulated NO production.
Oxidative stress-related ED is not only a critical mechanism that leads to CVDs [ 30 ], but it is also a major contributor to the pathogenesis of MetS [ 3 ]. Interestingly, FFAs-induced increases in CV risk factors, characterized by elevated levels of endothelial markers, is seen in healthy subjects, a possible mechanism in the development of the CVDs [ ].
The study has shown that intralipid infusion in healthy subjects could lead to 4. FFAs may contribute to inflammatory states that lead to enhance endothelial permeability [ ]. In microvascular endothelial cells MVECs , using palmitate, the authors have showed that it could activate the NLRP3 inflammasome with a resulting reduction in endothelial tight junction proteins - zonula occludens-1 and -2 ZO-1 and ZO Further exploring of the mechanisms, it had been found that FFAs mediated such effects by triggering the production of HMGB1 which might explain the early onset of endothelial injury during obesity.
A role of Withaferin A WA , a steroidal lactone derived from Acnistus arborescens [ ], against PA-induced insulin resistance and dysfunction of the endothelium has been shown, mediated through its anti-oxidant and anti-inflammatory properties [ ]. The renin-angiotensin system RAS is a crucial regulator of the arterial blood pressure, and Ang II is known as a potent vasoconstrictor. While leukocytes activation is deleterious for endothelial health, FFAs can activate leukocytes and contribute to the adhesion properties of leukocytes in an Ang II-dependent manner, leading to the onset of ED [ ], and inhibition of the RAS is preventive against the FFA-induced ED in humans [ ] Fig.
EPCs participate in endothelial recovery following arterial injury, and factors such as oxidative stress contribute to dysfunction and apoptosis of the EPCs [ ].
MEG3 is required for human mesenchymal stem cells hMSCs differentiation into ECs [ ]; however, some studies showed that MEG3 may also interfere with the proliferation and angiogenesis in VECs and its expression may correlate with cardiovascular aging [ ]. These data raise a conflict of interest for which the pathophysiological roles of MEG3 needs to be studied with a deeper understanding in both EPCs and ECs.
However, patients with obesity or T2DM show higher levels of FFAs that lead to insulin resistance [ 4 ], which further contributes to ED, a pivotal step in the initiation and progression of atherosclerosis [ ]. Additionally, a study with direct infusion of insulin in the rats showed that hyperinsulinemia could mitigate FFA-induced ED in rat aortic rings [ ]; however, the direct effect of insulin infusion still remains questionable as the article is in a non-English language with unclear mechanisms.
Exendin-4, also having its synthetic counterpart known as exenatide, a glucagon-like protein-1 GLP-1 receptor agonist [ ], increases insulin sensitivity via a PI3K-dependent mechanism [ ]. Prevention of HFD-induced insulin resistance by Exendin-4 has been shown to be mediated through an increasing level of adiponectin [ ]. For a healthy endothelium, a balance in the relative pathways should be maintained.
Here, we highlight some targets that may serve as important therapeutic avenue against FFAs-induced ED. This pathway is an important regulator of oxidative stress, and its activation has been proved to be fruitful in many diseases through the modulation of oxidative stress, and inflammation [ , , , , ]. Nrf2, which belongs to the subfamily of basic region leucine zipper bZip transcription factors, is responsible for cellular defense mechanisms against oxidative stress and is also crucial for suppression of signaling cascades relative of inflammation [ ].
It plays a protective role on FFA-induced cardiotoxicity and ED [ , ], possibly due to its direct effects on mitochondrial FA oxidation [ , ]. On the other hand, HO-1, which also possesses anti-oxidative properties and is transcriptionally regulated by Nrf2 [ , ], is suppressed during oxidative stress-induced EC injury [ ], and inducing HO-1 in the mouse endothelium is favorable against T2DM-induced vascular injury, where HO-1 facilitates reendothelialization by increasing the number of EPCs through AMPK-mediated mechanism [ ].
An anti-apoptotic role of HO-1, as well as its isoform HO-2, is found in glutamate-induced toxicity and oxidative stress in the cerebrovascular endothelium [ ], where it plays a defensive role against disruption of the blood-brain barrier BBB and neurological deficits in stroke via the Nrf2 signaling [ ].
This study also showed that adiponectin, which is an anti-inflammatory protein, is induced by HO Interestingly, adiponectin, which mediates its protective role in cAMP-dependent alleviation of FFA-induced ED [ ], is endogenously regulated by HO-1 in obese and diabetic animal models [ , ], suggesting an important role of HO-1 in regulation of FFA-induced endothelial toxicity through multifaceted mechanisms. ED is an early event in atherosclerosis and other CVDs.
Therefore, it would require a better understanding of this field and identify some better, possible targets that could be used to develop better therapeutic approaches to intervene the early events of ED-related health conditions and pave the way for a better living.
Trans fatty acids and atherosclerosis-effects on inflammation and endothelial function. J Nutr Food Sci. Nonesterified fatty acids in blood pressure control and cardiovascular complications. Curr Hypertens Rep. Boden G. Obesity and free fatty acids. Endocrinol Metab Clin N Am. Capurso C, Capurso A. From excess adiposity to insulin resistance: the role of free fatty acids.
ScienceDaily shares links with scholarly publications in the TrendMD network and earns revenue from third-party advertisers, where indicated. The system is composed of both the analyzer based on photometric technology and a kit of low toxicity, pre-vialed reagents, developed by CDR. The mitochondria is the powerhouse of every cell. While this study shows an association between circulating levels of free fatty acids and a high risk of sudden cardiac death, an accompanying editorial says that not all fatty acids are equal in their propensity to cause arrhythmias. When the body is using one of its anaerobic energy systems, it cannot burn fat, but it will simply generate less energy and will sustain a greater glucose depletion. The information on this site is for educational purposes only and should not be considered diagnostic or medical advice.
Free fatty acid causes. Test Catalog
Abnormally high levels of free fatty acids are associated with uncontrolled diabetes mellitus and with conditions that involve excessive release of a lipoactive hormone such as epinephrine, norepinephrine, glucagon, thyrotropin, and adrenocorticotropin. Patient should fast for 12 to 14 hours; however, in prolonged fasting or starvation, free fatty acid levels rise as much as 3-fold.
In order to eliminate the generation of free fatty acids from triglycerides by serum lipases causing erroneous elevations , serum should be frozen soon after it is drawn and shipped frozen. Dole VP: A relation between non-esterified fatty acids in plasma and the metabolism of glucose.
J Clin Invest ; Biochim Biophys Acta, Mar; 3 Skip to main content. Register Sign In. Test Catalog Account. Test Catalog Go. Test Catalog Test Information. Utilization Management Publications and Tools. Clinical Specialties Clinical Specialties. Specimen Handling Collection and Preparation. It is for this reason that the body is equipped with special storage areas known as adipose tissue, each of which is a sophisticated series of cells equipped to both store and to release fat when signaled to do so.
Adipose tissues store fat in the same manner in which it naturally occurs in food. However, the fats are broken down on digestion within the body, and they are reformed into the storage form known as triglycerides, a term that describes a collection of three fatty acid molecules bound together with a glycerol molecule. Each fatty acid molecule is an extended chain of carbon and hydrogen atoms. The process of hydrolysis separates the stored fats into its two separate compounds, fatty acids and glycerol.
Glycerol has properties similar to alcohol and sugar; after the release by the adipose tissue, the glycerol is passed through the bloodstream for return to the liver for a conversion into a useful energy source, glucose.
The free fatty acids released from adipose tissue can be utilized anywhere there is an energy need within the body. The process of releasing these compounds begins with a signal from the pancreas, the organ responsible for the monitoring of glucose concentrations in the blood. When a low glucose level is detected, the glucagon hormone is released to stimulate glucose release from the stores of glycogen in the liver.
If the blood level of glucose is too high, the body releases the hormone insulin. In this circumstance, fatty acid production will be stimulated through the further trigger of the chemical lipase in the adipose tissue. The ultimate destination of the released fatty acids is the mitochondria of the subject cells that require energy. The mitochondria is the powerhouse of every cell. There is a well-known correlation between the consumption of caffeine and the metabolizing of free fatty acids.
Caffeine promotes the process of lipolysis, the breakdown of the triglycerides stored in the adipose cells. There is also a scientifically established linkage between the increased presence of fatty acids in the bloodstream and the onset of diabetes, the disease whereby the body produces insufficient amounts of insulin to properly regulate the level of blood sugars glucose.
Talk with your doctor and family members or friends about deciding to join a study. For general information, Learn About Clinical Studies. Criteria Inclusion Criteria:. Search for terms x. Save this study. Warning You have reached the maximum number of saved studies Production of Free Fatty Acids From Blood Triglycerides The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.
Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Last Update Posted : November 7, Study Description. The overall hypothesis of these studies is that circulating triglycerides, coming primarily from fat in the diet, are an important source of free fatty acids.
Free fatty acids are the major fat fuel in the body, and when they are elevated in the blood they are thought to raise the risk of cardiovascular disease by causing insulin resistance in some cases leading to diabetes , raising blood pressure, and other effects.
The investigator will use sophisticated methods for tracing triglycerides and free fatty acids in the blood. These methods involve the administration of low doses of radioactive and stable isotopes of naturally occurring fats.
The studies will determine the contribution of triglycerides to free fatty acids in normal people and also in people with diabetes. Lipid energy is transported in the blood in several forms, including chylomicrons and free fatty acids FFA. Chylomicrons are key elements in the absorption and storage of dietary fat, and also play a role in the pathogenesis of atherosclerosis via the production of remnant particles, but their role as a direct fuel source has not been explored.
FFA are the major lipid fuel in the body, and increases in their concentration have been shown to cause insulin resistance, endothelial dysfunction and increases in the production of very low density lipoproteins. FFA are released into the blood through the action of hormone sensitive lipase on triglyceride stores in fat cells. Very little is known about the role of chylomicrons in FFA metabolism, but the potential contribution of chylomicrons to FFA is considerable, especially in people who consume high fat diets.
Initial studies indicate that in addition to the role of chylomicrons in fat storage, a portion of chylomicron fatty acids are released as FFA in a process called "spillover". These studies indicate that the contribution of chylomicrons to FFA is increased in type 2 diabetes. A study of spillover in the splanchnic bed found very high rates of splanchnic spillover in overweight and obese individuals with hypertriglyceridemia. Extremely accurate and precise methods have been developed by the investigator for the measurement of the concentration and specific activity of FFA and chylomicron triglyceride fatty acids in plasma.
In addition, a tracer method for accurately determining the kinetics of chylomicrons has been developed. In the proposed studies, the tracer technique will be used to systematically investigate the contribution of chylomicrons to total FFA availability.
The technique will be applied to normal subjects at rest and after exercise, as well as subjects with type 2 diabetes mellitus and hypertriglyceridemia. Specifically, these studies will: 1 determine whether weight loss in people with type 2 diabetes reduces spillover from chylomicrons; 2 determine whether acute lowering of FFA with insulin infusion reduces spillover in nondiabetic individuals with dyslipidemia; 3 determine whether noninsulin-mediated lowering of FFA reduces spillover in diabetic individuals with dyslipidemia, and 4 determine whether obese, insulin-resistant individuals have increased spillover in the splanchnic bed.
Outcome Measures. Plasma samples obtained during the study are stored for lipid analysis. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Volunteers from the region around Rochester, Minnesota who meet the inclusion criteria will be recruited. Please refer to this study by its ClinicalTrials. Layout table for investigator information Principal Investigator: John M.
Miles, MD Mayo Clinic. Layout table for additonal information Responsible Party: John M. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Study Type :. Actual Enrollment :. Study Start Date :.
Actual Primary Completion Date :. Actual Study Completion Date :.