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Acetic Acid Bacterial Lipids Improve Cognitive Function in Dementia Model Rats
Abstract
Acetic acid bacteria, fermentative microorganisms of traditional foods, have unique alkali-stable lipids (ASL), such as dihydroceramide which is a precursor of sphingolipids. Sphingolipids are important components of the brain tissue. We examined the effect of oral administration of ASL in a rat model of dementia (7-week-old, male) with a basal forebrain lesion. In a water maze test, the dementia model rats demonstrated poor spatial orientation. The administration of ASL (165 or 1650 mg/kg of body weight per day, for 14 days) produced a significant improvement in learning ability in the dementia model rats. In vitro experiments showed ASL had the ability to promote neurite outgrowth in pheochromocytoma (PC12) cells. Among the ASL components, dihydroceramide has the most potent effect on the differentiation of PC12 cells. It is highly possible that oral administration of dihydroceramide-containing ASL reverses the decline in cognitive function in dementia.
... Sphingolipid is basic as well as important component of constructive block of brain tissues. Fukami et al. (2010) reported that AAB is having stability to produce originator of sphingolipid named as alkali stable lipids (ASL). AAB have potential to produce ASL therefore, dihydroceramide is part of AAB. ...
... After that, signposted that due to ASL pheochromocytoma (PC12) in nurite is enhances also, dihydroceramide is having compelling impact. Fukami et al. (2009) and Fukami et al. (2010) reported that ingestion of vinegar is might be results to enhances mental 594 Copyright ⓒ 2019Authors ability of human brain as well as potent working ability of brain. As per other studies it is also hypothesized combination of sialic acid and oligosaccharides gangliosides were produced. ...
Vinegar having near about 5% acetic acid incorporated in water. Traditionally
vinegar implemented in food preservations applications. Vinegar production mechanizations
assortments implementation of wooden carks, traditional process (Orleans), Generator
process for operation of submerged fermentation. Incorporation of Acetobacter species for
transformation of ethyl alcohol into acetic acid. Vinegar has numerous medicinal as well as
theoretic potentials. It has great influence on brain. Physical as well as chemical attributes of
vinegar are analyzed. The aim of this article are to study historical aspects, chemical
formulation during fermentation, production methods and mechanizations, varieties,
functional parameters, safety, quality control and electrochemistry application.
Keywords: Vinegar, Acetic acid, Functional properties, Mechanization, AAB
... Acetic acid has also been reported to enhance lipid homeostasis and help lower the cholesterol level in vivo. Fukami et al. (2010) reported that acetic acid bacteria produce alkali-stable lipids (ASL), which have a significant effect in improving cognitive ability because they contain highly pure free dihydroceramide, a precursor to various sphingolipids such as gangliosides (Fukami et al., 2010). Gangliosides are composed of sialic acid-and ceramide-conjugated oligosaccharides, which have been shown to be effective in improving the symptoms of Alzheimer's disease (Svennerholm, 1994). ...
... Acetic acid has also been reported to enhance lipid homeostasis and help lower the cholesterol level in vivo. Fukami et al. (2010) reported that acetic acid bacteria produce alkali-stable lipids (ASL), which have a significant effect in improving cognitive ability because they contain highly pure free dihydroceramide, a precursor to various sphingolipids such as gangliosides (Fukami et al., 2010). Gangliosides are composed of sialic acid-and ceramide-conjugated oligosaccharides, which have been shown to be effective in improving the symptoms of Alzheimer's disease (Svennerholm, 1994). ...
... Acetic acid has also been reported to enhance lipid homeostasis and helps to lower cholesterol level in vivo. A study by Fukami, Tachimoto, Kishi, Kaga, and Tanaka (2010) indicates that acetic acid bacteria produce alkalistable lipids (ASL). ASL have a significant effect in improving cognitive ability, as they contain highly pure free dihydroceramide, a precursor to various sphingolipids such as gangliosides (Fukami et al., 2010), which are composed of sialic acid-and ceramideconjugated oligosaccharides (Svennerholm, 1994). ...
... A study by Fukami, Tachimoto, Kishi, Kaga, and Tanaka (2010) indicates that acetic acid bacteria produce alkalistable lipids (ASL). ASL have a significant effect in improving cognitive ability, as they contain highly pure free dihydroceramide, a precursor to various sphingolipids such as gangliosides (Fukami et al., 2010), which are composed of sialic acid-and ceramideconjugated oligosaccharides (Svennerholm, 1994). These sialic acid-and ceramide-conjugated oligosaccharides have been shown to be effective in improving the symptoms of Alzheimer patients (Svennerholm, 1994). ...
Vinegars are liquid products produced from the alcoholic and subsequent acetous fermentation of carbohydrate sources. They have been used as remedies in many cultures and have been reported to provide beneficial health effects when consumed regularly. Such benefits are due to various types of polyphenols, micronutrients and other bioactive compounds found in vinegars that contribute to their pharmacological effects, among them, antimicrobial, antidiabetic, antioxidative, antiobesity and antihypertensive effects. There are many types of vinegars worldwide, including black vinegar, rice vinegar, balsamic vinegar and white wine vinegar. All these vinegars are produced using different raw materials, yeast strains and fermentation procedures, thus giving them their own unique tastes and flavours. The main volatile compound in vinegar is acetic acid, which gives vinegar its strong, sour aroma and flavour. Other volatile compounds present in vinegars are mainly alcohols, acids, esters, aldehydes and ketones. The diversity of vinegars allows extensive applications in food.
... It is known that acetate, the main metabolic product of AAB, is the most powerful activator of intestinal receptors for shortchain fatty acids. New evidence of AAB antitumour activity (Bedada et al., 2020;Wan Mohd Kamaluddin et al., 2020), possible impact on cognitive improvement (Fukami, Tachimoto, Kishi, Kaga, & Tanaka, 2010), and mycotoxin adsorption and biodetoxification (Adebiyi, Kayitesi, Adebo, Changwa, & Njobeh, 2019;Afshar, Shokrzadeh, Raeis, Saraei, & Nasiraii, 2020;Taheur et al., 2017) have appeared. It has been also shown that AAB of the genus Acetobacter produce a significant part of secondary metabolites in fermented milk products of natural fermentation and are a good source of bioactive compounds, including fundamentally new ones (You et al., 2022). ...
... Prevención de enfermedades cardiovasculares.[26] Mejora de la homeostasis de lípidos y reducción del nivel de colesterol in vivo.[27] I.B. ...
... Alternatively, the acetic acid in PJ may have an effect on cognition. The vinegar component in PJ is made from acetic acid bacteria, and studies have shown that acetic acid bac-teria enhances cognitive function in both mice and elderly persons (Fukami, 2009;Fukami et al., 2010). ...
Pickle juice is widely used by athletes for muscle cramps and recovery. The purpose of this study was to evaluate the effects of pickle juice on core temperature (CT), heart rate (HR), movement economy, RPE, thermal sensation, and cognition during an exercise session simulating a soccer game in a hot and humid environment. 14 female soccer players (age=22.3+4.27y, body fat percentage= 25.2+6.38%, VO2 max=43.7+5.78 ml/kg/min) completed two counterbalanced sessions on a treadmill in a heat chamber (WBGT=31.2oC, & humidity=80-85%) during which they consumed water only versus pickle juice and water. HR and movement economy (oxygen consumption) were similar during sessions while core temperature was lower during the water-only trial. During the pickle juice trial, RPE was significantly lower and cognitive function was higher. Data indicates that pickle juice supplementation may reduce perception of exercise intensity and enhance cognitive function in hot environments but may cause a relatively small rise in core
temperature.
... Further investigations demonstrated that ASL enhanced the growth of neurites in dihydroceramide and pheochromocytoma (PC12) cells, leading to a powerful eff ect. Fukami and others postulated that vinegar utilization may amend cognitive function in humans [90,91]. Diff erent studies revealed that gangliosides along with ceramide were useful for amelio- of the diabetes eff ects, prevention of cardiovascular diseases, and antibacterial and antioxidant activities. ...
While the use of vinegar to fi ght against infections and other crucial conditions dates back to Hippocrates, recent research has foundthat vinegar consumption has a positive effect on biomarkers for diabetes, cancer, and heart diseases. Different types of vinegar have been
used in the world during different time periods. Vinegar is produced by a fermentation process. Foods with a high content of carbohydrates area good source of vinegar. Review of the results of different studies performed on vinegar components reveals that the daily use of these components has a healthy impact on the physiological and chemical structure of the human body. During the era of Hippocrates, people used vinegar as a medicine to treat wounds, which means that vinegar is one of the ancient foods used as folk medicine. The purpose of the current reviewpaper is to provide a detailed summary of the outcome of previous studies emphasizing the role of vinegar in treatment of different diseasesboth in acute and chronic conditions, its in vivo mechanism and the active role of different bacteria.
... One of the metabolites (alkali-stable lipid) of acetic acid bacteria have demonstrated improvement of cognitive functions in rats that had brain injury. It was extracted the metabolite of acetic bacteria and administered in mice in the ratio of 165 or 1650 mg/kg per day for 14 days (Fukami et al., 2010). ...
Resumo
Vinegar is a widely used condiment, consumed by all social classes and has great potential for health benefits, which justifies the concern for their beneficial activity. The country is still a beginner in vinegar research, concerning the verification of its health benefits, as the raw materials used and the production process. The article aims to gather and discuss studies that show the vinegar beneficial effects for human health. In studies conducted in Europe and Asia, it was observed that consumption of vinegar can be beneficial, as it showed antitumor effect, reduced the blood glucose level, effects on the immune system, anti-hypertensive effect, among others. Those responsible for the medicinal effects are acetic acid (at least 4% in vinegars, under Brazilian law), but also other compounds resulting from the metabolism of microorganisms during the stages of fermentation and/or aging. Despite these results, “in vivo” research as are still deficient concerning the recommended daily doses that prove the medicinal efficacy of vinegar are unknown. However, in view of the favorable results, the functional potential of these vinegars should not be ignored, then, more studies are necessary in order to demonstrate their functional properties.
Additional keywords: antioxidant action; human health benefits; vinegar consumption.
... [31] Kefir has fractions and compounds that can activate NMDA receptors in the brain and alter some ions such as calcium and sodium that result in better learning and memory. [31][32][33] Tryptophan is an important amino acid involved in the production of melatonin and serotonin. This amino acid and its byproducts play an important role in regulating mood (anxiety and depression), sleep cycles and the perception of pain. ...
Nicotine as one of the potent psychostimulant drugs is characterized by its parasympathomimetic activity. Upon the abrupt discontinuation of nicotine intake, a number of symptoms such as anxiety, depression and cognition impairment develop. Kefir as a food supplement is rich in tryptophan. In this study, we have evaluated the effects of Kefir on nicotine cessation-induced anxiety, depression and cognition impairment.
Forty adult male rats were divided into four groups. All the groups received 6 mg/kg/day of nicotine for 17 days and then the negative control groups got 5 mg/kg/day of normal saline. The positive control groups were given 40 mg/kg/day of Sertraline HCl for 7 days. The group treated with Cow Milk Kefir (CMK) and Soy Milk Kefir (SMK) received 5 mg/kg/day for 7 days. On the 25(th) day, Elevated Plus Maze (EPM), Open Field Test (OFT) and Forced Swim Test (FST) were used to investigate anxiety and depression. In addition, Moris Water Maze was applied to evaluate learning and memory in the animals between the 20(th) and 25(th) days.
The results showed that administration of CMK, SMK and Sertraline had higher anti-depression and anxiolytic effects on nicotine withdrawal-induced depression and anxiety in rats (P < 0.05). Moreover, CMK and SMK improved learning and memory impairment results in the nicotine withdrawal period (P < 0.05).
This study revealed that Kefir had a potential effect on the treatment of nicotine cessation-induced depression, anxiety and cognition impairment in the animal model. Kefir may be useful for adjunct therapy for nicotine abandonment treatment protocols.
... On the contrary, sphingolipids have gained attention in terms of their moisture-holding abilities. Moreover, sphingolipids are generating increasing interest because of their effect in the formation of lamella phases in the skin and in maintaining the skin barrier function 4,5 , Moreover, sphingolipids have roles in cell signaling and apoptosis 6,7 , improving the cognitive function 8 , suppressing tumorigenesis by reducing the number of aberrant colonic crypt foci by dietary intake 9 13 , adiponectin signaling 14 , and type 2 diabetes through mediating the loss of insulin sensitivity 15,16 . However, the content or molecular structures of the sphingolipids contained in sake lees have not been investigated to date. ...
Sake lees are solid parts filtered from the mash of sake, the traditional rice wine of Japan, which is brewed with Aspergillus oryzae and Saccharomyces cerevisiae. The moisture-holding activity of sake lees has long been recognized in Japan. However, the constituent responsible for this activity has not been elucidated. In this study, we first determined the structure of the glucosylceramides contained in sake lees. The glucosylceramides contained in sake lees were N-2'-hydroxyoctadecanoyl-l-O-β-D-glucopyranosyl-9-methyl-4,8-sphingadienine (d19:2/C18:0h), N-2'-hydroxyoctadecanoyl-l-O-β-D-glucopyranosyl-4,8-sphingadienine (d18:2/C18:0h), N-2'-hydroxyicosanoyl-l-O-β-D-glucopyranosyl-4,8-sphingadienine (d18:2/C20:0h) and N-2'-hydroxyicosanoyl-l-O-β-D-glucopyranosyl-4,8-sphingadienine (d18:2/C22:0h), which corresponded to those of A. oryzae and rice. The glucosylceramide produced by A. oryzae constituted the most abundant species (43% of the total glucosylceramide) in the sake lees. These results will be of value in the utilization of sake lees for cosmetics and functional foods.
... Sphingolipids reportedly improve cognitive function in dementia model rats. 17 Thus, the potential utility of sphingolipids as cosmetics, functional foods, and anticancer medicines is likely to expand. Commercial sphingolipids are extracted from bovine brain. ...
Shochu is traditional Japanese liquor produced from various crops and fungi Aspergillus kawachi or A. awamorii . The amount of unutilized shochu distillation remnants is increasing because of the recent prohibition of ocean dumping of these remnants. In this Article, we first describe the structures of glucosylceramides contained in shochu distillation remnants by fragment ion analysis using ESI-tandem mass spectrometry. Shochu distillation remnant produced from barley contained glucosylceramides d18:2/C16:0h, d18:2/C20:0h, d19:2/C18:1h, and d18:2/C18:0h. Koji (barley fermented with A. kawachii ) contained the same glucosylceramides. Shochu distillation remnants produced from rice contained glucosylceramides d18:2/C18:0h and d19:2/C18:1h. The culture broth of A. kawachii contained glucosylceramides d19:2/C18:1h and d19:2/C18:0h. These results indicate that the glucosylceramides contained in crops and those produced by A. kawachii transfer through the processes of fermentation with yeast and distillation to the shochu distillation remnant. This information will enable utilization of shochu distillation remnants and koji as novel sources of sphingolipids.
Exposure to ionizing radiation (IR) tends to cause serious health concerns. Thus, radioprotective agents are vital for the population exposed to radiation. As microorganisms have the advantages of fast reproduction and no geographical restrictions, direct microbe-based and environmental induction compounds are thriving radioprotectants resources. Oxidative system and oxidase in Acetobacter pasteurianus are unique and intriguing, the radioprotective effect of the cell-free extract from A. pasteurianus (APE) and ⁶⁰Coγ-treated extract (IRE) were comparatively investigated in the present study. The survival rate of A. pasteurianus with IRE addition was 149.1% in H2O2 damage test, while that with APE was only 10.4%. The viability of ⁶⁰Coγ-treated AML-12 cells was increased by 18.8% with IRE addition, yet APE showed no significant radioprotective effect. Moreover, in ⁶⁰Coγ-treated mice, IRE could significantly protect the white blood cell, improve the liver index, and attenuate the injuries of immune organs in mice. Administration of IRE significantly raised the activities of superoxide dismutase (SOD) and reduced the products of lipid peroxidation. These results clarified that gavage with APE and IRE presented notable antioxidant and radioprotective efficacy. A. pasteurianus showed appealing potential to be novel radioprotective bioagents and ⁶⁰Coγ treatment on microbe could be a new method for the development of better radioprotectant.
Key points
• ⁶⁰Coγ induction could improve the radioprotective effect of APE.
• IRE protected white blood cell in mice under IR.
• IRE products have broad application prospects in radioprotection based on microbes.
Graphical abstract
The acetic acid–water binary system is a classical hydroxy–carboxy mixed system, while new and interesting phenomena appear under stimulated Raman scattering (SRS). Compared with the weaker signal of the acetic acid–water binary system obtained in spontaneous Raman scattering, SRS provides a finer band and a relatively distinct structural transition point. The structural transformation points are respectively at 30% and 80% by volume ratio under the condition of spontaneous Raman spectroscopy, while they are respectively at 15% and 25% under the condition of SRS. This phenomenon is attributed to the generation of laser induced plasma and shockwave induced dynamic high pressure environment during SRS.
Aim:
The aim of present study is to investigate the relationship between gut microbiota and Alzheimer's disease (AD) using Drosophila model.
Materials & methods:
The microbiota was characterized by Illumina sequencing of 16S rRNA gene. Gas chromatography-mass spectrometer was performed to measure the level of short-chain fatty acids (SCFAs), metabolites of the commensal microbiota.
Results:
The diversity of the gut microbiota increased in AD Drosophila. As the most enriched bacteria at genus level, the proportions of Acetobacter and Lactobacillus decreased dramatically. Acetate was the most abundant SCFA derived from the dysregulated microbiota and markedly downregulated in AD Drosophila.
Conclusion:
Our study on Drosophila model suggests that dysregulation of gut microbiota may participate in AD pathogenesis by influencing SCFA level.
Licorice, an edible and officinal plant, has attracted considerable attention for its wide range of pharmacological activities. The present study focused on the protective effect of licorice on aging rats and on exploring its potential mechanisms. Aging in rats was induced by D-gal (300 mg kg⁻¹) for 5 weeks continuously with intraperitoneal injection, while control rats received physiological saline, and other groups received different concentrations of licorice extract (1, 5 and 10 g of herb per kg) by oral gavage after being D-gal induced. Their spatial and learning memory abilities were evaluated by the Morris water maze test and an object-place recognition test. Some related biochemical indices were also determined by assay kits. Neuronal cell injury in the hippocampal region was observed by hematoxylin and eosin (HE) staining. The expression levels of Bax, Bcl-2, caspase-3 and Cyt-C in the hippocampus were detected by western blot. The results showed that licorice extract could significantly ameliorate the learning and memory abilities impaired by D-gal. The licorice extract significantly increased the SOD, GSH-Px and CAT activity and synchronously decreased the content of MDA in the hippocampus. It also ameliorated the dysfunction of the cholinergic system induced by D-gal. Furthermore, the licorice extract also protected the hippocampal neurons against damage and could significantly reduce the expression of the Bax/Bcl-2 protein ratio, caspase-3 and Cyt-C protein in the hippocampus. These findings indicate that the licorice extract effectively attenuated cognitive damage, improved oxidative stress and apoptosis in aging rats induced by D-gal, and played a significant role in antioxidation and anti-neuronal apoptosis.
A variety of natural vinegar products are found in civilizations around the world. A review of research on these fermented products indicates numerous reports of health benefits derived by consumption of vinegar components. Therapeutic effects of vinegar arising from consuming the inherent bioactive components including acetic acid, gallic acid, catechin, ephicatechin, chlorogenic acid, caffeic acid, p-coumaric acid, and ferulic acid cause antioxidative, antidiabetic, antimicrobial, antitumor, antiobesity, antihypertensive, and cholesterol-lowering responses. The aims of this article are to discuss vinegar history, production, varieties, acetic acid bacteria, and functional properties of vinegars.
Fourteen-week-old db/db mice showed significant higher blood glucose levels than 7 week-old mice. The mRNA levels of IL-1beta and S100a4/a6/a9 in peripheral leukocytes were higher in 14 week-old mice than in 7 week-old mice. Together, inflammatory cytokine/cytokine-like factor mRNA levels in peripheral leukocytes were associated with progression of diabetes in db/db mice.
We administered Acetobacter malorum NCI1683 (S24), containing a high concentration of dihydroceramide (7.2 mg/g of dry cell weight), consecutively to aged rats (male Crlj:Wistar rats, 22 months old). The ingestion of Acetobacter malorum for 89 d significantly extended the memory retention in passive avoidance tests, increased the release of acetylcholine with depolarization of brain synaptosomes and decreased the causative agents of neurodegenerative diseases in the cerebral cortices.
We have identified a Saccharomyces cerevisiae gene necessary for the step in sphingolipid synthesis in which inositol phosphate is added to ceramide to form inositol-P-ceramide,
a reaction catalyzed by phosphatidylinositol:ceramide phosphoinositol transferase (IPC synthase). This step should be an effective
target for antifungal drugs. A key element in our experiments was the development of a procedure for isolating mutants defective
in steps in sphingolipid synthesis downstream from the first step including a mutant defective in IPC synthase. An IPC synthase
defect is supported by data showing a failure of the mutant strain to incorporate radioactive inositol or N-acetylsphinganine into sphingolipids and, by using an improved assay, a demonstration that the mutant strain lacks enzyme
activity. Furthermore, the mutant accumulates ceramide when fed exogenous phytosphingosine as expected for a strain lacking
IPC synthase activity. Ceramide accumulation is accompanied by cell death, suggesting the presence of a ceramide-activated
death response in yeast. A gene, AUR1 (YKL004w), that complements the IPC synthase defect and restores enzyme activity and sphingolipid synthesis was isolated.
Mutations in AUR1 had been shown previously to give resistance to the antifungal drug aureobasidin A, leading us to predict that the drug should
inhibit IPC synthase activity. Our data show that the drug is a potent inhibitor of IPC synthase with an IC50 of about 0.2 nM. Fungal pathogens are an increasing threat to human health. Now that IPC synthase has been shown to be the target for aureobasidin
A, it should be possible to develop high throughput screens to identify new inhibitors of IPC synthase to combat fungal diseases.
We report here that a microbial extracellular glycolipid,mannosylerythritol lipid (MEL), induces the outgrowth ofneurites from and enhances the activity of acetylcholinesterase(AChE) in PC12 pheochromocytoma cells. Furthermore, treatment ofPC12 cells with MEL increased levels of galactosylceramide(Galbeta1-1'Cer; GalCer). Exposure of PC12 cells to exogenous GalCer caused the dose-dependent outgrowth ofneurites. By contrast, treatment of PC12 cells with nerve growthfactor (NGF) did not increase the level of GalCer in the cells. The neurite-related morphological changes induced by GalCerdifferend from those induced by NGF, indicating differencesbetween the signal transduction pathways triggered by NGF and by GalCer.
Several lines of evidence have suggested that ganglioside GM1 stimulates neuronal sprouting and enhances the action of nerve growth factor (NGF), but its precise mechanism is yet to be elucidated. We report here that GM1 directly and tightly associates with Trk, the high-affinity tyrosine kinase-type receptor for NGF, and strongly enhances neurite outgrowth and neurofilament expression in rat PC12 cells elicited by a low dose of NGF that alone is insufficient to induce neuronal differentiation. The potentiation of NGF activity by GM1 appears to involve tyrosine-autophosphorylation of Trk, which contains intrinsic tyrosine kinase activity that has been localized to the cytoplasmic domain. In the presence of GM1 in culture medium, there is a > 3-fold increase in NGF-induced autophosphorylation of Trk as compared with NGF alone. We also found that GM1 could directly enhance NGF-activated autophosphorylation of immunoprecipitated Trk in vitro. Monosialoganglioside GM1, but not polysialogangliosides, is tightly associated with immunoprecipitated Trk. Furthermore, such tight association of GM1 with Trk appears to be specific, since a similar association was not observed with other growth factor receptors, such as low-affinity NGF receptor (p75NGR) and epidermal growth factor receptor (EGFR). Thus, these results strongly suggest that GM1 functions as a specific endogenous activator of NGF receptor function, and these enhanced effects appear to be due, at least in part, to tight association of GM1 with Trk.
Neuronal growth is regulated by both extracellular and cellular determinants and is believed to proceed by the addition of new membrane material at the growth cone. To determine whether lipid synthesis is necessary to maintain neuronal growth, we have examined the effect of Fumonisin B1, an inhibitor of ceramide synthesis, on the development of cultured hippocampal neurons. Fumonisin B1 inhibits ceramide synthesis in hippocampal neurons both in vivo and in vitro. Ganglioside synthesis and content was reduced after Fumonisin B1 treatment, and ganglioside GD1b was not detectable at the cell surface by immunofluorescence. Inhibition of sphingolipid synthesis by Fumonisin B1 had a significant effect on axonal growth. Between days 2-3 in culture, mean axon length increased from 170 to 240 microns, but in Fumonisin-treated cells, no increase in axon length was observed. Addition of a fluorescent derivative of ceramide together with Fumonisin B1 reversed this effect, confirming that Fumonisin B1 acts via inhibition of ceramide synthase. Further, ceramide by itself caused a significant increase in axon length. We discuss three possible mechanisms by which inhibition of sphingolipid synthesis could disrupt axonal growth, among them the possibility that ongoing sphingolipid synthesis is necessary to provide new membrane material to the growing axon.
Effects of lithium and tetrahydroaminoacridine (THA), either alone or in combination, were tested in an animal model of excitotoxic cholinergic deafferentation of the cerebral cortex. Rats received ibotenic acid lesions of cholinergic basal forebrain nuclei resulting in a 30% to 40% depletion of both cortical choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity. Lithium as well as THA, given separately either prior or subsequently to the development of the lesion, had small but significant effects on the recovery of cortical ChAT and AChE activity. Applied in combination, these drugs clearly showed synergistic effects. These potentiating actions might be due to neuroprotective/ neurotrophic mechanisms as well as to effects on acetylcholine turnover and muscarinic receptor-coupled phosphoinositide turnover. Similar approaches of combination therapy might prove useful for the management of mental disorders associated with cholinergic dysfunction.
The fermented milk, so-called "Caspian Sea Yogurt" in Japan, consists of two bacterial strains isolated from traditional Caucasusian fermented milk. In the present study, those strains were identified and characterized. Strain FC was Gram-positive, facultatively anaerobic cocci and strain FA was Gram-negative, aerobic rods. Phylogenetic analysis based on 16S rDNA sequences showed that strain FC formed a cluster with Lactococcus lactis strains and was most closely related to L. lactis subsp. cremoris. Strain FA was included in the genus Acetobacter cluster and was most closely related to A. orientalis. The DNA G+C contents of strain FC and strain FA were 39.2 and 51.6 mol%, respectively. Biochemical tests and DNA-DNA hybridization clarified that strain FC belongs to L. lactis subsp. cremoris and strain FA belongs to A. orientalis. The culture supernatant of lactococcal strain FC inhibited the growth of L. lactis subsp. cremoris DSM 20069T and L. lactis subsp. hordniae JCM 1180T. The inhibitory activity was detected after incubation at 70 degrees C for 60 min or 100 degrees C for 30 min and was stable when the supernatant was adjusted to a pH ranging from 4.9 to 7.5. The antimicrobial activity was lost on treatment with proteolytic enzymes such as proteinase K, trypsin, pronase, and pepsin, although it was not affected by catalase. The gene of lactococcin B (lcnB) homolog was found in the strain FC. From the above results, the strain FC was thought to produce a bacteriocin-like substance.
: The transcription factor NFκB is activated by various signals associated with brain injury, including tumor necrosis factor (TNF), oxidative insults, and amyloid β-peptide (Aβ). We recently reported that TNFs activate NFκB in neurons and protect them against excitotoxic and oxidative insults, including Aβ toxicity. We now report that C2-ceramide (C2), a membrane-permeant activator of NFκB, protects cultured rat hippocampal neurons against death induced by glutamate, FeSO4, and Aβ. Protection was concentration dependent, specific (a ceramide analogue known not to activate NFκB was ineffective), required pretreatment, and was blocked by inhibitors of RNA and protein synthesis. Lipid peroxidation and accumulation of cellular peroxides induced by glutamate, FeSO4, and Aβ were significantly attenuated in neurons pretreated with C2. The data indicate that C2 induces antioxidant pathways in neurons and suggest novel approaches for reducing neuronal injury in both acute and chronic neurodegenerative conditions.
A wide range of evidence show that acetylcholinesterase (AChE) inhibitors can interfere with the progression of Alzheimer's Disease (AD). The successful development of these compounds was based on a well-accepted theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission. The earliest known AChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of Alzheimer's patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on ®nding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action with manageable adverse effects. Currently, there are about 19 new Alzhei-mer's drugs in various phases of clinical development. ALZHEIMER'S DISEASE Alzheimer's Disease, discovered by Dr Alois Alzheimer in 1907, is described as a degenerative disease of the central nervous system (CNS) characterized especially by premature senile mental deterioration. AD patients exhibit marked decline in cognitive ability and severe behavioral abnormalities such as irritability, anxiety, depression, disorientation, and restlessness. AD is a progressive disease, i.e. the onset of the disease may show mild symptoms but these symptoms will sooner or later become more and more severe until the patient loses his or her capacity to handle normal daily activities. While AD is commonly regarded as a senile disease, the symptoms can also manifest in presenile individuals.
The requirement of complex sphingolipid biosynthesis for growth of neurons was examined in developing rat cerebellar Purkinje neurons using a dissociated culture system. Purkinje cells developed well-differentiated dendrites and axons after 2 weeks in a serum-free nutrient condition. Addition of 2 µM fumonisin B1, a fungal inhibitor of mammalian ceramide synthase, inhibited incorporation of [3H]galactose/glucosamine and [14C]serine into complex sphingolipids of cultured cerebellar neurons. Under this condition, the expression of Purkinje cell-enriched sphingolipids, including GD1, 9-O-acetylated LD1 and GD3, and sphingomyelin, was significantly decreased. After 2 weeks' exposure to fumonisin B1, dose-dependent measurable decreases in the survival and visually discernible differences in the morphology were seen in fumonisin-treated Purkinje cells. The Purkinje cell dendrites exhibited two types of anomalies; one population of cells developed elongated but less-branched dendrites after a slight time lag, but their branches began to degenerate. In some cells, formation of elongated dendrite trees was severely impaired. However, treatment with fumonisin B1 also led to the formation of spinelike protrusions on the dendrites of Purkinje cells as in control cultures. In contrast to the alterations observed in Purkinje cells, morphology of other cell types including granule neurons appeared to be almost normal after treatment with fumonisin B1. These observations indicated strongly that membrane sphingolipids participate in growth and maintenance of dendrites and in the survival of cerebellar Purkinje cells. Indeed, these effects of fumonisin B1 were reversed, but not completely, by the addition of 6-[[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-amino]caproyl]sphingosine (C6-NBD-ceramide), a synthetic derivative of ceramide. Thus, we conclude that deprivation of membrane sphingolipids in a culture environment is responsible for aberrant growth of Purkinje cells.
1.1. [14C]Stearoyl-, [Me-3H]choline-and [3-3H]sphingosin-labeled sphingomyelins were fed to rats having a lymph fistula and to intact rats whose small intestinal content and intestinal wall or faeces were analysed. The same types of experiments were performed with [9,10-3H2]palmitoyl-sphingosin, [3-3H]sphingosin and [11,12-3H2]-dihydrosphingosin as substrates.2.2. Most of the fed sphingomyelin was metabolized in the small intestinal tract. 36–60% of the fatty acid was found in the lymph triglycreides and lecithin and 10–17% of the choline moiety appeared in the lymph lecithin. No evidence for absorption and transport by the lymph of intact dietary sphingomyelin, ceramide or sphingosyl-phosphoryl-choline was obtained.3.3. [11,12-3H2]Dihydrosphingosin was well absorbed and metabolized in the mucosal cells to C16 fatty acid which was incorporated mainly into chylomicron triglycerides. Indirect evidence was obtained, that much of the sphingosin portion of dietary sphingomyelin is absorbed and metabolized in a similar way. A part of the sphingosin bases was incorporated into ceramide and sphingomyelin in the mucosal cells.4.4. The hydrolysis of sphingomyelin is initiated in the small intestinal lumen where labeled ceramide and free sphingosin were found 3 h after the ingestion of a bile salt micellar solution of [3-3H]sphingosin-labeled sphingomyelin. The mucosal cells, however, may be the main site of the hydrolytic reactions.
Neurons from chick embryonic day 8 (E8) ciliary ganglia, E8 and E15 dorsal root ganglia, E8 forebrain, and from rat E18 hippocampus and striatum were cultured as monolayers in the presence or absence of GM1 ganglioside. All of the primary neurons tested were susceptible to an effect of GM1 on their neuritic outgrowth, resulting in a 2- to 3-fold stimulation over control, the recognition of which depended on selecting culture conditions appropriate to each case. The response of E8 ciliary ganglionic neurons required a serum-free medium containing ciliary neuronotrophic factor, and was most pronounced by 8 h at 3 × 10−8 M GM1. The neuritic response by either E8 or E15 dorsal root ganglionic neurons required serum (⩾ 0.3%), their appropriate neuronotrophic factor, and 100-fold higher GM1 concentrations (presumably reflecting the serum presence), with optimal response times of 12–24 h. For E8 chick forebrain and E18 rat central neurons, GM1 substantially increased the proportion of neurite-bearing neurons in a serum-free pyruvate-containing medium between 7 and 24 h, with an optimal GM1 concentration of 10−7 M. In all cases, the response to GM1 was a time-related gain, i.e. an earlier onset of neuritic regeneration rather than permanent increase in the number of neurite-bearing neurons.
Changes in certain microbiological, physicochemical, and sensory parameters of kefir were studied during refrigerated storage. Kefir batches were prepared using 1% and 5% added kefir grains, and samples for analysis were taken 24 h after inoculation and then after 2, 7, 14, 21, and 28 days of storage at 5 ± 1 °C. After fermentation for 24 h after inoculation, lactobacilli and lactococci were present at levels of 108 cfu/ml, and yeasts and acetic acid bacteria were present at levels of 105 and 106 cfu/ml, respectively. The lactic acid flora decreased by about 1.5 log units between days 7 and 14 and then stabilized at that level. Yeast and acetic acid bacterial counts, lactose, and pH all remained constant over the storage period, while the total fat content and dry matter decreased. The percentage inoculate did exert an influence, and the sample batches made using 1% added kefir grains had higher lactic acid bacterial counts, lactose, and pH, while the sample batches made using 5% added kefir grains had higher yeast and acetic acid bacterial counts and viscosity. The total fat and dry matter contents were similar in both sample batches. Sensory analysis of the kefir samples revealed maximum acceptability levels in the first 2 days of storage.
Acetic acid bacteria have unique and highly pure membrane lipid components, such as 2-hydroxypalmitoyl-sphinganine (dihydroceramide) and can grow and produce acetic acid at around pH 3.0, suggesting that ceramide in cell membranes may be involved in the tolerance to acidic pH. Acetobacter malorum S24 was selected for the production of ceramide and grown in YPG medium containing 0.8% ethanol. Ceramide biosynthesis was induced at pH 4 and below, suggesting that ceramide biosynthesis is induced by low pH stress. Elevation of ceramide was also induced by high temperature stress (40-70 degrees C). After the strain was cultured in an optimal growth medium, the cells were collected and treated at pH 3 and 40 degrees C for 4 days, resulting in a 30-fold elevation of both the yield and content of ceramide.
The three ornithine-containing lipids of Gluconobacter cerinus were isolated from each other. One of the three lipids was postulated as Nalpha-3-hydroxypalmitoylornithine, to the fatty acid moiety of which 2-hydroxy fatty acid is linked by an ester linkage. The 2-hydroxy acid was possibly cis-11, 12-methylene-2-hydroxyoctadecanoate. Such an ornithine-containing lipid was found to be distributed in other acetic acid bacteria.
The effects of GM1 ganglioside (30 mg/kg i.p.) administration for 22 days on choline acetyltransferase (ChAT) activity and noradrenaline (NA) levels in the cerebral cortex and on the acquisition of active and passive avoidance-conditioned responses were investigated in both sham-operated rats and in rats with a unilateral electrolytic lesion of the magnocellular forebrain nuclei (MFN). A statistically significant ChAT decrease in cortical areas ipsilateral to the lesion was found in saline-treated lesioned rats. In the lesioned GM1-treated rats, ChAT activity was only reduced in the frontoparietal areas and was significantly increased in the ipsilateral parietooccipital areas as well as in both contralateral regions. NA levels in the cortex were neither significantly affected by the lesion nor by GM1 treatment. The lesion impaired the acquisition of active and passive conditioned avoidance responses. GM1 treatment improved acquisition of the active avoidance response in the lesioned rats as indicated by a larger number of avoidances and a smaller number of escape failures during training in comparison with saline treatment. Ganglioside had no effect on the passive avoidance responses. These results demonstrate that GM1 administration facilitates the recovery of the cortical cholinergic system and of behavioral responses impaired by an electrolytic lesion of the cholinergic forebrain nuclei.
1. 1. [14C]Stearoyl-, [Me-3H]choline-and [3-3H]sphingosin-labeled sphingomyelins were fed to rats having a lymph fistula and to intact rats whose small intestinal content and intestinal wall or faeces were analysed. The same types of experiments were performed with [9,10-3H2]palmitoyl-sphingosin, [3-3H]sphingosin and [11,12-3H2]-dihydrosphingosin as substrates. 2. 2. Most of the fed sphingomyelin was metabolized in the small intestinal tract. 36-60% of the fatty acid was found in the lymph triglycreides and lecithin and 10-17% of the choline moiety appeared in the lymph lecithin. No evidence for absorption and transport by the lymph of intact dietary sphingomyelin, ceramide or sphingosyl-phosphoryl-choline was obtained. 3. 3. [11,12-3H2]Dihydrosphingosin was well absorbed and metabolized in the mucosal cells to C16 fatty acid which was incorporated mainly into chylomicron triglycerides. Indirect evidence was obtained, that much of the sphingosin portion of dietary sphingomyelin is absorbed and metabolized in a similar way. A part of the sphingosin bases was incorporated into ceramide and sphingomyelin in the mucosal cells. 4. 4. The hydrolysis of sphingomyelin is initiated in the small intestinal lumen where labeled ceramide and free sphingosin were found 3 h after the ingestion of a bile salt micellar solution of [3-3H]sphingosin-labeled sphingomyelin. The mucosal cells, however, may be the main site of the hydrolytic reactions.
Ganglioside content and composition were studied in whole brains from 9 neurologically normal male individuals ranging from 25 to 85 years in age. The content of ganglioside-bound sialic acid decreased from 1,070 to 380 micrograms/g fresh tissue at 85 years. Ten individual ganglioside fractions were identified on high-performance thin-layer chromatography, seven of which were quantified. With age, ganglioside composition shifted to a more polar pattern due to an increase in the relative concentration of the more polar fractions GQ1b, GT1b and GD1b and a decrease in GD1a and GM1. Except for GQ1b, the absolute concentration of all gangliosides decreased with age. All changes were more pronounced in younger ages. Results are discussed in relation to structural changes occurring in the aging brain, and the involvement of gangliosides is suggested.
Choline acetyltransferase activity in discrete tissue punches from the nucleus of Meynert and in tissue from the temporal cortex was reduced by at least 90% and 75%, respectively, in 5 out of 6 elderly cases of Alzheimer's disease compared with 5 normal cases. In contrast, estimates of neurone density in these same cases revealed that there was only, on average, a 33% neurone loss in the nucleus of Meynert in Alzheimer's disease. These observations suggest that a key pathological change in Alzheimer's disease may be the 'down regulation' of transmitter-specific enzyme production in cholinergic neurones, and that neurone loss itself may be a secondary feature of the disease.
We examined the ability of ceramide and sphingomyelinase (SMase) to prevent neuronal programmed cell death (PCD). We found that a cell-permeable ceramide analogue prevented neuronal PCD when applied to established sympathetic neuron primary cultures at the time of nerve growth factor (NGF) deprivation. Other amphiphilic lipids such as oleic acid failed to prevent cell death. Exogenous SMase also showed the same effect, probably by raising the intracellular ceramide level by sphingomyelin (SM) breakdown. Phosphocholine, another hydrolytic product of SM by SMase, did not prevent cell death. Other phospholipases, such as phospholipase C and phospholipase A2, could not prevent cell death. Given the recent findings that the SM cycle is activated to increase the intracellular ceramide level on NGF binding to the low-affinity NGF receptor (LNGFR) and that NGF binding to LNGFR suppresses apoptosis in neuronal cell lines, our results suggest the possibility of the SM cycle as a signaling mechanism transducing the PCD-preventing activity of NGF.
Apart from a mixture of bacteriohopanetetrols already found in other Acetobacter species, four new 3 beta-methylhopanoids have been isolated from Acetobacter europaeus. All of them present an ether linkage between a bacteriohopanetetrol or a bacteriohopanepentol and a carbapseudopentose moiety often found in bacterial hopanoids. Three of these ethers were shown by comparison with synthetic reference hopanoids to posess a supplementary methyl group at C31. This novel series of methylhopanoids may be the precursor of yet unidentified molecular fossils found in sediments. [methyl-2H3]Methionine was efficiently incorporated into the 31-methylhopanoids with retention of all three deuterium atoms in the transferred methyl group. This labelling pattern might be consistent with a rather rarely found methylation reaction of an enol.
Gangliosides are glycosphingolipids localized to the outer leaflet of the plasma membrane of vertebrate cells. The highest ganglioside concentration of any organ is found in the mammalian brain, where the gangliosides are enriched in the neuronal membrane, particularly in the synapses. There are four major brain gangliosides with the same neutral tetrasaccharide core to which one to three sialic acids are linked--the simplest being the GM1-ganglioside. These gangliosides have been shown to have neuritogenic and neuronotrophic activity and to facilitate repair of neuronal tissue after mechanical, biochemical or toxic injuries. Mixtures of native bovine brain gangliosides were adopted for pharmacological use in the treatment of peripheral nerve damage, and GM1-ganglioside has been applied for the treatment of CNS injuries and diseases. Beneficial effects of GM1 have been documented in the treatment of stroke and spinal cord injuries, particularly when the treatment has been initiated within a few hours of the acute event. Continuous intraventricular infusion of GM1 has recently been shown to have a significant beneficial effect in Alzheimer disease of early onset (AD Type I).
We have identified a Saccharomyces cerevisiae gene necessary for the step in sphingolipid synthesis in which inositol phosphate is added to ceramide to form inositol-P-ceramide, a reaction catalyzed by phosphatidylinositol:ceramide phosphoinositol transferase (IPC synthase). This step should be an effective target for antifungal drugs. A key element in our experiments was the development of a procedure for isolating mutants defective in steps in sphingolipid synthesis downstream from the first step including a mutant defective in IPC synthase. An IPC synthase defect is supported by data showing a failure of the mutant strain to incorporate radioactive inositol or N-acetylsphinganine into sphingolipids and, by using an improved assay, a demonstration that the mutant strain lacks enzyme activity. Furthermore, the mutant accumulates ceramide when fed exogenous phytosphingosine as expected for a strain lacking IPC synthase activity. Ceramide accumulation is accompanied by cell death, suggesting the presence of a ceramide-activated death response in yeast. A gene, AUR1 (YKL004w), that complements the IPC synthase defect and restores enzyme activity and sphingolipid synthesis was isolated. Mutations in AUR1 had been shown previously to give resistance to the antifungal drug aureobasidin A, leading us to predict that the drug should inhibit IPC synthase activity. Our data show that the drug is a potent inhibitor of IPC synthase with an IC50 of about 0.2 nM. Fungal pathogens are an increasing threat to human health. Now that IPC synthase has been shown to be the target for aureobasidin A, it should be possible to develop high throughput screens to identify new inhibitors of IPC synthase to combat fungal diseases.
Soybean lecithin transphosphatidylated phosphatidylserine (SB-tPS) was prepared from soybean lecithin and L-serine by a transphosphatidylation reaction, and its effect on age-related memory impairment was evaluated in rats by the Morris water maze test. Continuous oral administration of SB-tPS (60 mg x kg(-1) x d(-1) for 60 d) to male aged rats (24-25 mo) significantly improved performance in the water maze escape test (P < 0.01 vs. control aged rats) similar to bovine brain cortex-derived phosphatidylserine, which restores cognitive function in patients with senile dementia. SB-tPS also increased acetylcholine release and the Na(+), K(+)-ATPase activity of the synaptosomes prepared from these aged rats to the level in young rats. The nootropic actions of SB-tPS in the present study can be partly explained by the changes in these biochemical activities.
Docosahexaenoic acid (DHA) administration controls extraggression (aggression against others) in young subjects under psychological stress. However, it is not known whether its administration affects extraggression of elderly subjects. Forty Thai subjects of 50-60 years of age (22 males and 18 females) were recruited from Silpakorn University and nearby villages. They were allocated to the control and DHA groups in a double-blind fashion, and took 10 mixed plant oil capsules and 10 DHA capsules (1.5g DHA/day) for 2 months, respectively. Extraggression was measured with a psychological test (PF Study) at the beginning and end of the study. Just prior to the PF Study at the end of the study, subjects were asked to watch a stressful videotape as a stressor component. The average DHA intake from food was 150-160mg/day. In the group of university employees, extraggression did not change over time with placebo, whereas extraggression significantly decreased (31 +/- 13 to 24 +/- 13%, P = 0.04 by the paired-t test, P = 0.04 by ANOVA). In the group of villagers, there was no significant difference between the control and DHA groups in extraggression. The DHA administration favorably controlled extraggression in at least elderly white-collar workers. The daily intake of 150-160 mg/day of DHA was not enough to control extraggression.
It has been implicated that glia activation plays a critical role in the progression of Alzheimer's disease (AD). However, the precise mechanism of glia activation is not clearly understood yet. In our present studies, we confirmed our previous results where change the levels of neuropeptides and peptidases in ibotenic acid (IBO) infusion into the rat nucleus basalis magnocellularis, an animal model of AD. Furthermore, we extended our study to investigate a possible protection effect of co-administration on the changes of neuropeptides, and neuronal and glial cells in IBO-infused rat brain by memantine treatment. The levels of substance P and somatostatin were decreased in the striatum and frontal cortex 1 week after IBO infusion, and recovered to the control level by memantine treatment, indicating the involvement of neuropeptides in AD pathology. Furthermore, the immunohistochemical and enzymatic studies of GFAP and CD 11b, and peptidylarginine deiminase, markers of glia, in the striatum and frontal cortex showed the increase in IBO-treated rat brain as compared with controls, while co-administration of memantine and IBO no increase of astrocytes and microglia activation was observed. The present biochemical and immunohistochemical results suggest that glia activation might play an important role to the pathology of AD, and correlate with the changes of neuropeptide levels in AD brain that is recovered by memantine treatment.
We investigated whether administration of docosahexaenoic acid (DHA), a major (n-3) fatty acid of the brain, ameliorates the impairment of learning ability in an animal model of Alzheimer's disease (AD), rats infused with amyloid-beta (Abeta) peptide (1-40) into the cerebral ventricle. Inbred 3rd generation male rats (20 wk old) fed a fish oil-deficient diet were randomly divided into 4 groups: a vehicle group, an Abeta peptide-infused group (Abeta group), a DHA group, and an Abeta + DHA group. A mini-osmotic pump filled with Abeta peptide or vehicle was implanted in the rats, and they were tested for learning ability-related reference and working memory in an 8-arm radial maze. The rats were then orally fed DHA dissolved in 5% gum Arabic solution at 300 mg/(kg . d) (DHA and Abeta + DHA groups) or vehicle alone (vehicle and Abeta groups) and tested again for learning ability. DHA administered for 12 wk significantly reduced the increase in the number of reference and working memory errors in the Abeta-infused rats, and increased both the cortico-hippocampal level of DHA and the molar ratio of DHA/arachidonic acid, suggesting an amelioration of the impaired spatial cognition learning ability. Furthermore, DHA suppressed the increases in the levels of lipid peroxide and reactive oxygen species in the cerebral cortex and the hippocampus of Abeta-infused rats, suggesting that DHA increases antioxidative defenses. DHA is thus a possible therapeutic agent for ameliorating learning deficiencies due to Alzheimer's disease.
Studies on lipid components in Acetobacter
- M Fujimori
Fujimori, M. Studies on lipid components in Acetobacter (in Japanese with English abstract).