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Ascorbyl Palmitate as a Carrier of Ascorbate into Neural Tissues
Abstract
We have investigated the hypothesis that a lipid-soluble derivative of ascorbic acid, ascorbyl-6-palmitate (AP), could serve as a carrier of ascorbate into neural tissues. Ascorbate could then exert its physiological effects in the biomembranes that are the target sites of the cellular signaling pathways which are normally hardly accessible to this water-soluble compound. The potential role of AP would require that it penetrates into tissues. The major objective of the study was to determine whether ascorbate could be recovered from cerebral cortex and carotid body tissues, both sensitive to the hypoxic stimulus, after AP given by gavage. Biological samples were analyzed by HPLC for the determination of ascorbate. We found that ascorbate was recovered from the tissues studied. Its content was higher in both tissues, by nearly an order of magnitude, after ingestion of AP than after ingestion of ascorbic acid, and the ascorbate level was higher in the carotid body than in the cortex. Hypoxia decreased the ascorbate content which implies physiological activity of ascorbate carried alongside the AP molecule. The lipophilic AP was able to cross biological barriers and satisfied the tissue demand for ascorbate better than the hydrophilic form. AP should be considered as the preferred form of transport of ascorbate into neural tissues. The results of this study suggest wider pharmacological applications of ascorbyl palmitate.
... Fish oil (Omega 3), owing to its platelet-stabilizing and anti-vasospastic actions, is also used in managing migraines 10 . AP has anti-mutagenic, anti-neoplastic and antioxidant properties 11 . Overall, strong evidence exists that oral nutritional supplements have a good outcome in preventing and managing various pain conditions 12 . ...
... The hydrolysis of the ester was dependent on the type of compound which was examined [13]. According to Pokorski and colleagues (2003), ascorbyl palmitate-treated cats showed more recovery of ascorbate in their brain tissues compared to ascorbic acidtreated cats [14]. Therefore, it can be hypothesized that RES esters may exhibit beneficial effect even if hydrolyzed. ...
Resveratrol (RES) is gaining recognition as a natural bioactive compound. To expand the possible applications of RES with its enhanced bioactivity as well as to increase the health benefits of long-chain fatty acids, a lipophilization process of RES was performed using three fatty acids: palmitic acid (PA), oleic acid (OA), and conjugated linoleic acid (CLA). The obtained mono-, di-, and tri-esters of RES were evaluated for their anticancer and antioxidant properties against lung carcinoma (A549), colorectal adenocarcinoma (HT29), and pancreatic ductal adenocarcinoma (BxPC3) cell lines. Human fibroblast (BJ) cells were used as a control. Several parameters were investigated: cell viability and apoptosis, including the expression of major pro- and anti-apoptotic markers, as well as the expression of superoxide dismutase, a key enzyme of the body’s antioxidant barrier. Three of the obtained esters: mono-RES-OA, mono-RES-CLA, and tri-RES-PA, which significantly reduced the tumor cell viability up to 23%, at concentrations 25, 10, 50 μg/mL, respectively, turned out to be particularly interesting. The above-mentioned resveratrol derivatives similarly increased the tumor cells’ apoptosis by modifying their caspase activity of pro-apoptotic pathways (p21, p53, and Bax). Moreover, among the mentioned esters, mono-RES-OA induced apoptosis of the analyzed cell lines most strongly, reducing the number of viable cells up to 48% for HT29 cells versus 36% for pure RES. Furthermore, the selected esters exhibited antioxidant properties towards the normal BJ cell line by regulating the expression of major pro-antioxidant genes (superoxide dismutases—SOD1 and SOD2) without the effect on their expression in the tumor, and therefore reducing the defense of cancer cells against increased oxidative stress induced by high ROS accumulation. The obtained results indicate that the esters of RES and long-chain fatty acids allow enhancement of their biological activity. The RES derivatives have the potential for being applied in cancer prevention and treatment, as well as for oxidative stress suppression.
... Fish oil (Omega 3), owing to its platelet-stabilizing and anti-vasospastic actions, is also used in managing migraines 10 . AP has anti-mutagenic, anti-neoplastic and antioxidant properties 11 . Overall, strong evidence exists that oral nutritional supplements have a good outcome in preventing and managing various pain conditions 12 . ...
Objective:
Ascorbyl palmitate is a fat-soluble ester of vitamin C and is used as an antioxidant food additive. While literature reports that ascorbyl palmitate can prevent exacerbation of pain and improve the quality of life of patients suffering from pain, this is not yet supported by clinical trial data. Our study aimed to investigate the effectiveness of ascorbyl palmitate in managing trigeminal neuralgia.
Patients and methods:
This study was carried out in a single-centre clinical trial in which subjects suffering from trigeminal neuralgia (N=11) were included. All patients were on carbamazepine when first included and, after washout period, received Ascorbyl palmitate. Eligible patients had the most severe trigeminal neuralgia pain in the oral cavity or pain on touching trigger zones, aged 20 years or older, were capable of proper assessment of the severity of pain and their condition, and had experienced multiple episodes of intraoral pain for at least 3 months with a pain intensity of more than 4 points on the numerical rating scale. The Brief Pain Questionnaire was used to evaluate patient's quality of life.
Results:
A total of 11 patients were included with a mean age 55.36±10.67 years (7 males, 4 females). Most patients had compression by the superior cerebellar artery and vascular loops upon magnetic resonance examination. The mean numerical rating scale score for carbamazepine after one month was 7.9±0.56 (95% CI 7.49, 8.30). Similarly, for ascorbyl palmitate was 5.5±1.50 (95% CI 4.42, 6.57) (p<0.001).
Conclusions:
Ascorbyl palmitate can be used as an adjunct intervention in managing trigeminal neuralgia pain. According to the results, ascorbyl palmitate prevents frequent exacerbation of pain and improves patient quality of life.
... Among these, the fatty acid esters of ascorbic acid as ascorbyl palmitate (AP) has been recognized as a safe and excellent antioxidant compound [14]. AP has attracted considerable interest as an anticancer agent due to its lipophilicity, easy passage across cell membranes and satisfaction of the tissue demand for ascorbate better than the hydrophilic form [11,15,16]. Furthermore, AP has shown advantages in cancer treatment via antiproliferative activity in cancer cells [17,18]. AP is more stable than ascorbic acid, so it can be incorporated into nanocarriers to improve low bioavailability, poor water solubility and delivery efficacy of AP as well as reduce its administration dose without reducing its antitumor efficacy [16]. ...
The aim of the present study is to evaluate, for the first time, the anticancer activity of a stable nanoformulation of ascorbyl palmitate (APnp) and investigate its therapeutic action as well as its mechanism against Ehrlich ascites carcinoma (EAC)-bearing mice in comparison with native AP. AP was loaded into pluronic nanoparticles, fully characterized and then studied as an anticancer agent using EAC model. The APnp were spherical and attained a small size of 220 ± 9 nm and a zetapotential of −41.16 ± 2 mV. The release profile of the AP from the nanoparticles was around 72% within the first 2 h and the rest of the drug amount was released sustainably within 9 days. The results of the present study demonstrated that APnp treatment destroyed tumors with inhibition of proliferation by inhibiting signal transducer and activator of transcription 3 (STAT3) pathway leading to induction of apoptosis and cell cycle arrest at G2/M phase as well as preventing metastasis and invasion. Moreover, APnp significantly elevated antioxidant levels [superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH)], and significantly decreased the levels of oxidative stress biomarkers [malondialdehyde (MDA) and nitric oxide (NO)]. Besides, mitochondrial and nuclear degeneration in cancer cells was demonstrated by an electron microscope to be more severe in the case of using our newly-developed APnp. The present study revealed the superiority of APnp as a potent anticancer agent over free AP via increasing its bioavailability and specificity towards cancer cells.
... The alkyl esters of AA are of particular interest because they can penetrate cell membranes, however, they are poorly soluble in aqueous environments [2]. Ascorbyl palmitate ( Figure 1) is an alkyl ester already used in the cosmetics, dermatology, and food industries as a more stable lipophilic derivative of AA because it retains the antioxidant properties of ascorbate [3]. Therefore, it is important to develop formulations that could allow its administration under hydrophilic conditions. ...
Antitumor applications of ascorbic acid (AA) and its oxidized form dehydroascorbic acid (DHA) can be quite challenging due to their instability and sensitivity to degradation in aqueous media. To overcome this obstacle, we have synthesized solid lipid nanoparticles loaded with ascorbyl palmitate (SLN-AP) with variations in proportions of the polymer Pluronic F-68. SLNs were synthesized using the hot homogenization method, characterized by measuring the particle size, polydispersity, zeta potential and visualized by TEM. To investigate the cellular uptake of the SLN, we have incorporated coumarin-6 into the same SLN formulation and followed their successful uptake for 48 h. We have tested the cytotoxicity of the SLN formulations and free ascorbate forms, AA and DHA, on HEK 293 and U2OS cell lines by MTT assay. The SLN-AP in both formulations have a cytotoxic effect at lower concentrations when compared to ascorbate applied the form of AA or DHA. Better selectivity for targeting tumor cell line was observed with 3% Pluronic F-68. The antioxidative effect of the SLN-AP was observed as early as 1 h after the treatment with a small dose of ascorbate applied (5 µM). SLN-AP formulation with 3% Pluronic F-68 needs to be further optimized as an ascorbate carrier due to its intrinsic cytotoxicity.
... It is a lipid-soluble form of vitamin C. It maintains all the vitamin C activity without creating problems associated with ascorbic acids, such as less recycling capacity of αtocopherol in the lipid bilayer, reduced viability in-vivo, and others [122]. Additionally, it is reported that the demand for vitamin C can be better fulfilled with lipophilic form rather than hydrophilic form [131]. Ascorbyl palmitate can successfully cross the blood-brain barrier (BBB) [132] and is reported for its significant role in treating AD [133]. As ascorbyl palmitate resides in the cell membrane, it can accelerate the production of vitamin E. However, the protective role of vitamin C is still in debate as it is not yet clear whether vitamin C is acting alone or in combination for treating AD. ...
Alzheimer’s disease (AD) rate is accelerating with the increasing aging of the world’s population. The World Health Organization (WHO) stated AD as a global health priority. According to the WHO report, around 82 million people in 2030 and 152 million in 2050 will develop dementia (AD contributes 60% to 70% of cases), considering the current scenario. AD is the most common neurodegenerative disease, intensifying impairments in cognition, behavior, and memory. Histopathological AD variations include extracellular senile plaques’ formation, tangling of intracellular neurofibrils, and synaptic and neuronal loss in the brain. Multiple evidence directly indicates that oxidative stress participates in an early phase of AD before cytopathology. Moreover, oxidative stress is induced by almost all misfolded protein lumps like α-synuclein, amyloid-β, and others. Oxidative stress plays a crucial role in activating and causing various cell signaling pathways that result in lesion formations of toxic substances, which foster the development of the disease. Antioxidants are widely preferred to combat oxidative stress, and those derived from natural sources, which are often incorporated into dietary habits, can play an important role in delaying the onset as well as reducing the progression of AD. However, this approach has not been extensively explored yet. Moreover, there has been growing evidence that a combination of antioxidants in conjugation with a nutrient-rich diet might be more effective in tackling AD pathogenesis. Thus, considering the above-stated fact, this comprehensive review aims to elaborate on the basics of AD and antioxidants, including the vitality of antioxidants in AD. Moreover, this review may help researchers to develop effectively and potentially improved antioxidant therapeutic strategies for this disease as it also deals with the clinical trials in the stated field.
... Remarkably, hydrolysis of ethyl β-chlorooctanoate 5b promoted by HCl would provide an antibacterial compound 3 . Cetylates and stearates are privileged motifs encountered across the molecular sciences 23 , particularly in food chemistry 23 , medicinal chemistry 24 , flavor, and fragrance industry 25 . Reaction of 1-pentadecene or 1-heptadecene would afford the addition product of ethyl β-chlorocetylate 5d or ethyl β-chlorostearate 5e in moderate yields, respectively. ...
Aliphatic esters are essential constituents of biologically active compounds and versatile chemical intermediates for the synthesis of drugs. However, their preparation from readily available olefins remains challenging. Here, we report a strategy to access aliphatic esters from olefins through a photocatalyzed alkoxycarbonylation reaction. Alkyloxalyl chlorides, generated in situ from the corresponding alcohols and oxalyl chloride, are engaged as alkoxycarbonyl radical fragments under photoredox catalysis. This transformation tolerates a broad scope of electron-rich and electron-deficient olefins and provides the corresponding β-chloro esters in good yields. Additionally, a formal β-selective alkene alkoxycarbonylation is developed. Moreover, a variety of oxindole-3-acetates and furoindolines are prepared in good to excellent yields. A more concise formal synthesis of (±)-physovenine is accomplished as well. With these strategies, a wide range of natural-product-derived olefins and alkyloxalyl chlorides are also successfully employed.
... Remarkably, hydrolysis of ethyl β-chlorooctanoate 5b promoted by HCl would provide an antibacterial compound. 3 Cetylates and stearates are privileged motifs encountered across the molecular sciences, 20 particularly in food chemistry, 21 medicinal chemistry, 22 avor and fragrance industry. 23 Reaction of 1-pentadecene or 1-heptadecene would afford the addition product of ethyl β-chlorocetylate 5d or ethyl β-chlorostearate 5e in moderate yields, respectively. ...
Aliphatic esters are essential constituents of biologically active compounds and versatile chemical intermediates for the synthesis of drugs. However, their preparation from readily available olefins remains challenging. In this report, a new strategy to access aliphatic esters from olefins through a unique photocatalyzed alkoxycarbonylation reaction is described. Alkyloxalyl chlorides, generated in situ from the corresponding alcohols and oxalyl chloride, are engaged for the first time as alkoxycarbonyl radical fragments under photoredox catalysis. This transformation tolerates a broad scope of electron-rich and electron-deficient olefins and provides the corresponding β-chloro esters in good yields. Additionally, a formal β-selective alkene alkoxycarbonylation is developed. And, a variety of oxindole-3-acetates and furoindolines are prepared in good to excellent yields. A more concise formal synthesis of (±)-physovenine is accomplished as well. With these strategies, a wide range of natural-product-derived olefins and alkyloxalyl chlorides are also successfully employed.
Quercetin was esterified with fatty acids (FA) in order to expand its application in a wide range of food and biological systems. The antioxidant potential of the esters were examined using hydroxyl radical scavenging activity, antioxidation in oil-in-water emulsion and bulk oil, inhibition of low-density lipoprotein (LDL) oxidation and deoxyribonucleic acid (DNA) scission. Except for oil-in-water emulsion system, quercetin derivatives demonstrated similar and/or better antioxidant activity than quercetin itself in bulk oil (quercetin with C18:1 and C22:6), hydroxyl radical scavenging assay (quercetin with C3:0-C8:0), DNA scission (quercetin with C3:0-C8:0), and LDL oxidation (quercetin with C14:0-C22:6, except C18:0). These results suggest that esterification did not compromise the antioxidant activity of the parent compound and quercetin derivatives might be useful as possible antioxidants in food and biological systems.
Perineuronal nets (PNNs) are presumed to limit plasticity in adult animals. Ischemic stroke results in the massive breakdown of PNNs resulting in rejuvenating states of neuronal plasticity, but the mechanisms of this phenomenon are largely unknown. As hyaluronic acid (HA) is the structural backbone of PNNs, we hypothesized that these changes are a consequence of altered expression of HA metabolism enzymes. Additionally, we investigated whether early hyaluronidase inhibition interferes with poststroke PNN reduction and behavioural recovery.
We investigated the mRNA/protein expression of these enzymes in the perilesional, remote, and contralateral cortical regions in mice at different time points after photothrombosis, using quantitative real‐time polymerase chain reaction and immunofluorescence. Skilled reaching test was employed to test hyaluronidase inhibitor L‐ascorbic acid 6‐hexadecanoate influence on poststroke recovery. We found the simultaneous upregulation of mRNA of HA synthesizing and degrading enzymes in the perilesional area early after stroke, suggesting acceleration of HA turnover in ischemic animals. Immunostaining revealed differential cellular localization of enzymes, with hyaluronidase 1 in astrocytes and hyaluronan synthase 2 in astrocytes and neurons, and poststroke upregulation of both of them in astrocytes. β‐glucuronidase was observed in neurons but poststroke upregulation occurred in microglia. Inhibition of hyaluronidase activity early after stroke resulted in improved performance in skilled reaching test, without affecting the numbers of PNNs. These results suggest that after stroke, a substantial reorganization of polysaccharide content occurs, and interfering with this process at early time has a beneficial effect on recovery.
Simultaneous recordings of chemoreceptor discharge and redox state of cytochromes have been carried out on the rat carotid body in vitro under the influence of carbon monoxide (CO) in order to identify the primary oxygen sensor protein controlling transmitter release and electrical activity. CO excites in a photolabile manner chemoreceptor discharge under normoxic conditions and inhibits under hypoxic conditions probably by binding to heme proteins. We hypothesize that type I cells and adjacent nerve endings of the carotid body tissue have a different apparatus with oxygen sensing heme proteins to cooperate for the generation of peripheral chemoreceptor response. Transmitter release from type I cells might be established in a redox dependent manner whereas membrane potential of nerve endings might be controlled by a heme coupled to ion channels.
— The localization of an acid lipase-esterase which cleaves the fluorogenic substrate 4-methyl-umbelliferyl oleate at pH 5 was studied, because previous experiments has shown this activity to be reduced in the plaques of multiple sclerosis. In the human cerebellum, quantitative histochemical methods showed the activity to be relatively low in the molecular layer, compared to the granule cell layer; but the underlying white matter was the most active. In the human spinal cord, anterior horn cell bodies were richest in acid lipase, but white matter was, on a dry weight basis, as active as neuropil. Oligodendrocytes obtained in bulk from bovine white matter according to Poduslo & Norton (1972) had a specific activity up to 20 times greater than the crude myelin fraction. While it remains possible that in myelin the enzyme is in an inactive or inhibited state, the results indicate that the enzyme is localized in oligodendroglial cell bodies and suggest its use as a marker.
Previous studies have suggested that alterations in phospholipid composition of plasma membranes may underlie lethal cell injury due to hypoxic and ischemic injury. The present study was designed to determine if such alterations are due to the activation of a pH-dependent phospholipase A2. Loss of cell viability and phospholipase A2 activity measured by arachidonic acid release increased in parallel during metabolic inhibition with KCN and iodoacetate (chemical hypoxia). Acidosis (pH 6.5) and the phospholipase inhibitors, dibucaine and mepacrine, delayed loss of cell viability and release of arachidonic acid to a similar extent. These findings suggest that a pH-dependent phospholipase A2 causes alterations in plasma membrane phospholipid composition after ATP-depletion which contribute to lethal cell injury.
The effects of several antioxidants on the three major functions of human neutrophils--oxidative burst, secretion and leukotriene formation--were investigated with special emphasis on the lipophilicity. The most striking differences were obtained when ascorbate and the lipophilic ester ascorbyl palmitate were compared. As expected, the luminol- and lucigenin-dependent chemiluminescence was inhibited by all antioxidants to a different degree. Ascorbyl palmitate was able to block the biphasic luminol-dependent response completely with IC50 values of 10 and 25 microM for the first and second phase, respectively. In contrast, ascorbate only blocked efficiently the first phase of the response. The secretion of elastase was inhibited by ascorbyl palmitate dose-dependently with an IC50 value of around 200 microM, whereas ascorbate was completely inactive. Electron microscopy supported the assumption that inhibition was due to a block in degranulation and not to enzyme inactivation. This was further supported by a parallel, although somewhat lower, inhibition of other secretory enzymes like myeloperoxidase, beta-glucuronidase or lysozyme. Cells treated with the Ca2+-ionophore A23187 responded by LTB4-synthesis which was also inhibited by ascorbyl palmitate. A very efficient inhibition was observed in cell homogenates with an IC50 value of 1.5 microM. No inhibition by ascorbate was detected in both systems. Concomitant with the inhibition of 5-lipoxygenase the activity of 15-lipoxygenase increased. We conclude that cellular reductants may control neutrophil functions and that the inhibition by ascorbyl palmitate of the three processes relevant for inflammatory responses could be of therapeutic importance.
The antioxidants TBHQ, alpha-tocopherol, Prolong P (rosemary, thyme, marjoram mixture) or ascorbyl palmitate were not found able to replace the antioxidant BHA in potato flakes production if stored for up to 24 months. Ascorbyl palmitate gave good antioxidative protection up to 16 months of storage, and also protected against carotenoid degradation better than the other antioxidants. The ascorbyl palmitate lost its antioxidative effect after longer storage.
Groups of male Swiss-Webster mice were gavaged with acetaminophen (APAP), APAP + ascorbyl stearate (AS), or APAP + ascorbyl palmitate (AP) at a dose of 600 mg/kg for each chemical. APAP alone caused a significant increase in liver weight/body weight ratio and hepatic glutathione (GSH) depletion. Co-administration of the ascorbate esters AP or AS with APAP prevented an increase in liver weight/body weight ratios and hepatic glutathione depletion. APAP + AS treatments caused significantly greater reductions in rectal temperature at 15-30 min post-dosing periods when compared to APAP + AP or AS treatments. Blood levels of APAP had the same relationship. The study indicates a correlation between APAP blood levels and antipyretic effect of APAP + AS and APAP + AP coadministrations. While both ascorbate esters probably afford protection against APAP-induced hepatotoxicity in mice by reducing the reactive intermediate back to the parent compound, the APAP + AS combination provides better therapeutic efficacy as an antipyretic at the 15-30 min post-dosing periods.
The ability to synthesize ascorbic acid is absent in the insects, invertebrates, and fishes. The biosynthetic capacity started
in the kidney of amphibians, resided in the kidney of reptiles, became transferred to the liver of mammals, and finally disappeared
from the guinea pig, the flying mammals, monkey, and man. A similar transition in the biosynthetic ability was observed in
the branched evolution of the birds.
Hypoxia causes constriction in small pulmonary arteries and dilatation in systemic arteries. Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism by which pulmonary blood flow is controlled in the fetus and by which local lung perfusion is matched to ventilation in the adult. HPV reduces the flow of desaturated blood through underventilated areas of lung. Even though many vasoactive substances have been examined as possible mediators of HPV, these appear more likely to be modulators than mediators. Hypoxic contraction has been demonstrated in single pulmonary vascular smooth muscle cells (PVSMC). The ability to sense changes in oxygen tension is observed in PVSMC and type 1 cells of the carotid body. In both cells, hypoxia has been shown to inhibit an outward potassium current, thus causing membrane depolarization and calcium entry through the voltage-dependent calcium channels. In both cells there is evidence to suggest that changes in the redox status of the oxygen-sensitive potassium channel or channels may control current flow, so that the channel is open when oxidized and closed when reduced. The redox status may be determined by the effects of hypoxia on mitochondrial/peroxisomal function or on the activity of an oxidase similar to NAD(P)H oxidase. More studies are needed to precisely define the individual potassium channels responsive to hypoxia and to confirm the gating mechanism. In systemic arteries hypoxia causes an increased current through ATP-dependent potassium channels and vasodilatation, whereas in the pulmonary arteries hypoxia inhibits potassium current and causes vasoconstriction.