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Nutrients Aug 2022In this study, the effects of cinnamaldehyde and curcumin on Akt2, a serine/threonine protein kinase central to the insulin signaling pathway, were examined in...
In this study, the effects of cinnamaldehyde and curcumin on Akt2, a serine/threonine protein kinase central to the insulin signaling pathway, were examined in preadipocytes. Cinnamaldehyde or curcumin treatment increased Akt2 phosphorylation at multiple sites including T450 and Y475, but had no effect on Akt2 phosphorylation at S474, which is critical for Akt2 activation. Surprisingly, insulin treatment with cinnamaldehyde or curcumin increased p-Akt2 (S474) by 3.5-fold versus insulin treatment alone. Furthermore, combined cinnamaldehyde, curcumin, and insulin treatment increased p-Akt2 (S474) by 7-fold versus insulin treatment alone. Interestingly, cinnamaldehyde and curcumin inhibited both serine/threonine phosphatase 2A (PP2A) and protein tyrosine phosphatase 1B (PTP1B). Akt2 activation is a multistep process that requires phosphorylation at T450 for proper folding and maturation, and phosphorylation of both Y475 and S474 for stabilization of the catalytic domain. It is plausible that by inhibiting PP2A and PTP1B, cinnamaldehyde and curcumin increase phosphorylation at T450 and Y475, and prime Akt2 for insulin-stimulated phosphorylation at S474. Notably, the combination of a PP2A inhibitor, okadaic acid, and a PTP1B inhibitor increased p-Akt2 (S474), even in the absence of insulin. Future combinations of PP2A and PTP1B inhibitors provide a rational platform to engineer new therapeutics for insulin resistance syndrome.
Topics: Acrolein; Curcumin; Enzyme Inhibitors; Insulin; Phosphorylation; Serine
PubMed: 36014807
DOI: 10.3390/nu14163301 -
Harmful Algae Mar 2021Published baseline data on biotoxin exposure in cetaceans is sparse but critical for interpreting mortality events as harmful algal blooms increase in frequency and...
Published baseline data on biotoxin exposure in cetaceans is sparse but critical for interpreting mortality events as harmful algal blooms increase in frequency and duration. We present the first synthesis of domoic acid (DA), saxitoxin (STX), okadaic acid (OA), and microcystin detections in the feces and urine of stranded and bycaught southern California cetaceans, over an 18 year period (2001-2018), along with corresponding stomach content data. DA was detected in 13 out of 19 cetacean species, most often in harbor porpoise (Phocoena phocoena) (81.8%, n = 22) and long-beaked common dolphins (Delphinus delphis bairdii) (74%, n = 231). Maximum DA concentrations of 324,000 ng/g in feces and 271, 967 ng/ml in urine were observed in D. d. bairdii. DA was detected more frequently and at higher concentrations in male vs. female D. d. bairdii. Higher fecal DA concentrations in D. d. bairdii were associated with a greater proportion of northern anchovy (Engraulis mordax) in the diet, indicating it may be a primary vector of DA. Fecal DA concentrations for D. d. bairdii off Point Conception were greater than those from animals sampled off Los Angeles and San Diego counties, reflecting greater primary productivity and higher Pseudo-nitzschia spp. abundance in that region and a greater abundance of E. mordax in the diet. STX was detected at low levels (fecal max = 7.5 ng/g, urine max = 17 ng/ml) in 3.6% (n = 165) of individuals from 3 out of 11 species. The occurrence of E. mordax in 100% of the 3 examined stomachs suggests this species could be a primary vector of the detected STX. OA was detected in 2.4% of tested individuals (n = 85) at a maximum fecal concentration of 422.8 ng/g. Microcystin was detected in 14.3% (n = 7) of tested individuals with a maximum liver concentration of 96.8 ppb.
Topics: Animals; California; Cetacea; Environmental Monitoring; Harmful Algal Bloom; Saxitoxin
PubMed: 33980440
DOI: 10.1016/j.hal.2021.102000 -
Marine Drugs Nov 2022The frequent occurrence of marine dinoflagellates producing palytoxin (PLTX) or okadaic acid (OA) raises concern for the possible co-presence of these toxins in seafood,...
The frequent occurrence of marine dinoflagellates producing palytoxin (PLTX) or okadaic acid (OA) raises concern for the possible co-presence of these toxins in seafood, leading to additive or synergistic adverse effects in consumers. Thus, the acute oral toxicity of PLTX and OA association was evaluated in mice: groups of eight female CD-1 mice were administered by gavage with combined doses of PLTX (30, 90 or 270 μg/kg) and OA (370 μg/kg), or with each individual toxin, recording signs up to 24 h (five mice) and 14 days (three mice). Lethal effects occurred only after PLTX (90 or 270 μg/kg) exposure, alone or combined with OA, also during the 14-day recovery. PLTX induced scratching, piloerection, abdominal swelling, muscle spasms, paralysis and dyspnea, which increased in frequency or duration when co-administered with OA. The latter induced only diarrhea. At 24 h, PLTX (90 or 270 μg/kg) and OA caused wall redness in the small intestine or pale fluid accumulation in its lumen, respectively. These effects co-occurred in mice co-exposed to PLTX (90 or 270 μg/kg) and OA, and were associated with slight ulcers and inflammation at forestomach. PLTX (270 μg/kg alone or 90 μg/kg associated with OA) also decreased the liver/body weight ratio, reducing hepatocyte glycogen (270 μg/kg, alone or combined with OA). No alterations were recorded in surviving mice after 14 days. Overall, the study suggests additive effects of PLTX and OA that should be considered for their risk assessment as seafood contaminants.
Topics: Mice; Animals; Female; Okadaic Acid; Cnidarian Venoms; Acrylamides; Liver
PubMed: 36547882
DOI: 10.3390/md20120735 -
Toxins Mar 2022The cockle is a commercially important species in many European Countries. It can accumulate okadaic acid (OA) and other toxins in its group, which makes it unsuitable...
The cockle is a commercially important species in many European Countries. It can accumulate okadaic acid (OA) and other toxins in its group, which makes it unsuitable for human consumption, producing harvesting bans to avoid intoxications. The duration of those bans depends in part on the depuration kinetics of the toxin in this species. In this work, this kinetics was studied by means of fitting different models to depuration data experimentally obtained, using naturally contaminated cockles. Cockles depurated OA faster than most other bivalve species studied. Models that include Michaelis-Menten kinetics describe the depuration better than those using a first order exponential decrease to describe the first (or the only) compartment. One-compartment models were not able to describe the final part of the depuration curve, in which OA was depurated very slowly. Therefore, two-compartment models were needed. Esters were depurated at a much faster rate than the free form of the toxin; however, no significant esterification was detected during the process. The slow depuration rate suggests that other bivalve species could be used as sentinels to monitor cockle populations, but caution should be taken when toxin concentrations are very high.
Topics: Animals; Bivalvia; Cardiidae; Esterification; Europe; Humans; Okadaic Acid
PubMed: 35324713
DOI: 10.3390/toxins14030216 -
International Journal of Molecular... May 2021Alzheimer's disease (AD) is the most common neurodegenerative disease, and it manifests as progressive memory loss and cognitive decline. However, there are no effective...
BACKGROUND
Alzheimer's disease (AD) is the most common neurodegenerative disease, and it manifests as progressive memory loss and cognitive decline. However, there are no effective therapies for AD, which is an urgent problem to solve. Evodiamine, one of the main bioactive ingredients of , has been reported to ameliorate blood-brain barrier (BBB) permeability and improve cognitive impairment in ischemia and AD mouse models. However, whether evodiamine alleviates tauopathy remains unclear. This study aimed to examine whether evodiamine ameliorates tau phosphorylation and cognitive deficits in AD models.
METHODS
A protein phosphatase 2A inhibitor, okadaic acid (OA), was used to induce tau phosphorylation to mimic AD-like models in neuronal cells. Protein expression and cell apoptosis were detected using Western blotting and flow cytometry, respectively. Spatial memory/cognition was assessed using water maze, passive avoidance tests, and magnetic resonance imaging assay in OA-induced mice models, and brain slices were evaluated further by immunohistochemistry.
RESULTS
The results showed that evodiamine significantly reduced the expression of phosphor-tau, and further decreased tau aggregation and neuronal cell death in response to OA treatment. This inhibition was found to be via the inhibition of glycogen synthase kinase 3β, cyclin-dependent kinase 5, and mitogen-activated protein kinase pathways. In vivo results indicated that evodiamine treatment ameliorated learning and memory impairments in mice, whereas Western blotting and immunohistochemical analysis of the mouse brain also confirmed the neuroprotective effects of evodiamine.
CONCLUSIONS
Evodiamine can decrease the neurotoxicity of tau aggregation and exhibit a neuroprotective effect. Our results demonstrate that evodiamine has a therapeutic potential for AD treatment.
Topics: Alzheimer Disease; Animals; Apoptosis; Brain; Cell Line; Cognition; Cognition Disorders; Disease Models, Animal; Humans; Male; Maze Learning; Mice; Mice, Inbred ICR; Neurodegenerative Diseases; Neurons; Neuroprotection; Neuroprotective Agents; Okadaic Acid; Phosphorylation; Quinazolines; Spatial Memory; Tauopathies; tau Proteins
PubMed: 34069531
DOI: 10.3390/ijms22105347 -
RSC Advances Aug 2022In this study, a simple electrochemical aptasensor for saxitoxin (STX) detection was developed based on a short anti-STX aptamer with a methylene blue (MB) incorporated...
In this study, a simple electrochemical aptasensor for saxitoxin (STX) detection was developed based on a short anti-STX aptamer with a methylene blue (MB) incorporated at the 3'-end. The aptamer was immobilized on the surface of gold electrode and served as the recognition element. The aptasensor was successfully used as a highly selective and sensitive biosensor for STX detection because of the selection of aptamer along with the excellent electrocatalytical properties of MB. With the increase of the dynamic concentration of STX from 1 nM to 1 μM, the aptasensor exhibited a sensitivity with a peak current change of 2.92 μA per decade and a low detection limit of 1 nM. In addition, the aptasensor demonstrated excellent selectivity to STX, which prevented the interferences from neo-STX, okadaic acid and common metal ions. Using the proposed principle, several other aptasensors with improved performance can be constructed the modification of the electrochemical sensor with appropriate aptamers.
PubMed: 36093254
DOI: 10.1039/d2ra03690h -
Antioxidants (Basel, Switzerland) Aug 2022Nowadays, most stroke patients are treated exclusively with recombinant tissue plasminogen activator, a drug with serious side effects and limited therapeutic window....
Nowadays, most stroke patients are treated exclusively with recombinant tissue plasminogen activator, a drug with serious side effects and limited therapeutic window. For this reason, and because of the known effects of oxidative stress on stroke, a more tolerable and efficient therapy for stroke is being sought that focuses on the control and scavenging of highly toxic reactive oxygen species by appropriate small molecules, such as nitrones with antioxidant properties. In this context, herein we report here the synthesis, antioxidant, and neuroprotective properties of twelve novel polyfunctionalized α-phenyl--butyl(benzyl)nitrones. The antioxidant capacity of these nitrones was investigated by various assays, including the inhibition of lipid peroxidation induced by AAPH, hydroxyl radical scavenging assay, ABTS-decoloration assay, DPPH scavenging assay, and inhibition of soybean lipoxygenase. The inhibitory effect on monoamine oxidases and cholinesterases and inhibition of β-amyloid aggregation were also investigated. As a result, ()--benzyl-1-(2-(3-(piperidin-1-yl)propoxy)phenyl)methanimine oxide () was found to be one of the most potent antioxidants, with high ABTS scavenging activity (19%), and potent lipoxygenase inhibitory capacity (IC = 10 µM), selectively inhibiting butyrylcholinesterase (IC = 3.46 ± 0.27 µM), and exhibited neuroprotective profile against the neurotoxicant okadaic acid in a neuronal damage model. Overall, these results pave the way for the further in-depth analysis of the neuroprotection of nitrone in in vitro and in vivo models of stroke and possibly other neurodegenerative diseases in which oxidative stress is identified as a critical player.
PubMed: 36139811
DOI: 10.3390/antiox11091735 -
Sensors (Basel, Switzerland) Apr 2021In the past twenty years marine biotoxin analysis in routine regulatory monitoring has advanced significantly in Europe (EU) and other regions from the use of the mouse... (Review)
Review
In the past twenty years marine biotoxin analysis in routine regulatory monitoring has advanced significantly in Europe (EU) and other regions from the use of the mouse bioassay (MBA) towards the high-end analytical techniques such as high-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS). Previously, acceptance of these advanced methods, in progressing away from the MBA, was hindered by a lack of commercial certified analytical standards for method development and validation. This has now been addressed whereby the availability of a wide range of analytical standards from several companies in the EU, North America and Asia has enhanced the development and validation of methods to the required regulatory standards. However, the cost of the high-end analytical equipment, lengthy procedures and the need for qualified personnel to perform analysis can still be a challenge for routine monitoring laboratories. In developing regions, aquaculture production is increasing and alternative inexpensive Sensitive, Measurable, Accurate and Real-Time (SMART) rapid point-of-site testing (POST) methods suitable for novice end users that can be validated and internationally accepted remain an objective for both regulators and the industry. The range of commercial testing kits on the market for marine toxin analysis remains limited and even more so those meeting the requirements for use in regulatory control. Individual assays include enzyme-linked immunosorbent assays (ELISA) and lateral flow membrane-based immunoassays (LFIA) for EU-regulated toxins, such as okadaic acid (OA) and dinophysistoxins (DTXs), saxitoxin (STX) and its analogues and domoic acid (DA) in the form of three separate tests offering varying costs and benefits for the industry. It can be observed from the literature that not only are developments and improvements ongoing for these assays, but there are also novel assays being developed using upcoming state-of-the-art biosensor technology. This review focuses on both currently available methods and recent advances in innovative methods for marine biotoxin testing and the end-user practicalities that need to be observed. Furthermore, it highlights trends that are influencing assay developments such as multiplexing capabilities and rapid POST, indicating potential detection methods that will shape the future market.
Topics: Animals; Asia; Europe; Marine Toxins; Mice; Okadaic Acid; Saxitoxin
PubMed: 33916687
DOI: 10.3390/s21072499 -
Marine Drugs Jun 2021Okadaic acid (OA) is an important liposoluble shellfish toxin distributed worldwide, and is mainly responsible for diarrheic shellfish poisoning in human beings. It has...
Okadaic acid (OA) is an important liposoluble shellfish toxin distributed worldwide, and is mainly responsible for diarrheic shellfish poisoning in human beings. It has a variety of toxicities, including cytotoxicity, embryonic toxicity, neurotoxicity, and even genotoxicity. However, there is no direct evidence of its developmental toxicity in human offspring. In this study, using the chicken () embryo as the animal model, we investigated the effects of OA exposure on neurogenesis and the incidence of neural tube defects (NTDs). We found that OA exposure could cause NTDs and inhibit the neuronal differentiation. Immunofluorescent staining of pHI3 and c-Caspase3 demonstrated that OA exposure could promote cell proliferation and inhibit cell apoptosis on the developing neural tube. Besides, the down-regulation of Nrf2 and increase in reactive oxygen species (ROS) content and superoxide dismutase (SOD) activity in the OA-exposed chicken embryos indicated that OA could result in oxidative stress in early chick embryos, which might enhance the risk of the subsequent NTDs. The inhibition of bone morphogenetic protein 4 (BMP4) and Sonic hedgehog (Shh) expression in the dorsal neural tube suggested that OA could also affect the formation of dorsolateral hinge points, which might ultimately hinder the closure of the neural tube. Transcriptome and qPCR analysis showed the expression of lipopolysaccharide-binding protein (LBP), transcription factor AP-1 (JUN), proto-oncogene protein c-fos (FOS), and C-C motif chemokine 4 (CCL4) in the Toll-like receptor signaling pathway was significantly increased in the OA-exposed embryos, suggesting that the NTDs induced by OA might be associated with the Toll-like receptor signaling pathway. Taken together, our findings could advance the understanding of the embryo-fetal developmental toxicity of OA on human gestation.
Topics: Animals; Biomarkers; Blotting, Western; Chickens; Dose-Response Relationship, Drug; Embryonic Development; Flow Cytometry; Fluorescent Antibody Technique; In Situ Hybridization; Microscopy, Fluorescence; Neural Tube Defects; Neurogenesis; Okadaic Acid; Oxidative Stress; Real-Time Polymerase Chain Reaction; Teratogens; Toxicity Tests; Transcriptome
PubMed: 34199615
DOI: 10.3390/md19060322 -
Ecotoxicology and Environmental Safety Sep 2023Okadaic acid (OA) is one of the most prevalent marine phycotoxin with complex toxicity, which can lead to toxic symptoms such as diarrhea, vomiting, nausea, abdominal...
Okadaic acid (OA) is one of the most prevalent marine phycotoxin with complex toxicity, which can lead to toxic symptoms such as diarrhea, vomiting, nausea, abdominal pain, and gastrointestinal discomfort. Studies have shown that the main affected tissue of OA is digestive tract. However, its toxic mechanism is not yet fully understood. In this study, we investigated the changes that occurred in the epithelial microenvironment following OA exposure, including the epithelial barrier and gut bacteria. We found that impaired epithelial cell junctions, mucus layer destruction, cytoskeletal remodeling, and increased bacterial invasion occurred in colon of rats after OA exposure. At the same time, the gut bacteria decreased in the abundance of beneficial bacteria and increased in the abundance of pathogenic bacteria, and there was a significant negative correlation between the abundance of pathogenic bacteria represented by Escherichia/Shigella and animal body weight. Metagenomic analysis inferred that Escherichia coli and Shigella spp. in Escherichia/Shigella may be involved in the process of cytoskeletal remodeling and mucosal layer damage caused by OA. Although more evidence is needed, our results suggest that opportunistic pathogens may be involved in the complex toxicity of OA during OA-induced epithelial barrier damage.
Topics: Animals; Rats; Okadaic Acid; Body Weight; Colon; Escherichia coli
PubMed: 37597294
DOI: 10.1016/j.ecoenv.2023.115376