-
Ecotoxicology and Environmental Safety Jun 2024Microplastics (MPs) and okadaic acid (OA) are known to coexist in marine organisms, potentially impacting humans through food chain. However, the combined toxicity of OA...
Microplastics (MPs) and okadaic acid (OA) are known to coexist in marine organisms, potentially impacting humans through food chain. However, the combined toxicity of OA and MPs remains unknown. In this study, mice were orally administered OA at 200 μg/kg bw and MPs at 2 mg/kg bw. The co-exposure group showed a significant increase in malondialdehyde (MDA) content and significant decreases in superoxide dismutase (SOD) activity and glutathione (GSH) level compared to the control, MPs and OA groups (p < 0.05). Additionally, the co-exposure group exhibited significantly higher levels of IL-1β and IL-18 compared to other groups (p < 0.05). These results demonstrated that co-exposure to MPs and OA induces oxidative stress and exacerbates inflammation. Histological and cellular ultrastructure analyses suggested that this combined exposure may enhance gut damage and compromise barrier integrity. Consequently, the concentration of OA in the small intestine of the co-exposure group was significantly higher than that in the OA group. Furthermore, MPs were observed in the lamina propria of the gut in the co-exposure group. Transcriptomic analysis revealed that the co-exposure led to increased expression of certain genes related to the NF-κB/NLRP3 pathway compared to the OA and MPs groups. Overall, this combined exposure may disrupt the intestinal barrier, and promote inflammation through the NF-κB/NLRP3 pathway. These findings provide precious information for the understanding of health risks associated with MPs and phycotoxins.
PubMed: 38905936
DOI: 10.1016/j.ecoenv.2024.116628 -
Molecules (Basel, Switzerland) Jun 2024GSK-3β, IKK-β, and ROCK-1 kinases are implicated in the pathomechanism of Alzheimer's disease due to their involvement in the misfolding and accumulation of amyloid β...
Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer's Disease-Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors.
GSK-3β, IKK-β, and ROCK-1 kinases are implicated in the pathomechanism of Alzheimer's disease due to their involvement in the misfolding and accumulation of amyloid β (Aβ) and tau proteins, as well as inflammatory processes. Among these kinases, GSK-3β plays the most crucial role. In this study, we present compound , a novel, remarkably potent, competitive GSK-3β inhibitor (IC = 8 nM, K = 2 nM) that also exhibits additional ROCK-1 inhibitory activity (IC = 2.3 µM) and demonstrates anti-inflammatory and neuroprotective properties. Compound effectively suppresses the production of nitric oxide (NO) and pro-inflammatory cytokines in the lipopolysaccharide-induced model of inflammation in the microglial BV-2 cell line. Furthermore, it shows neuroprotective effects in an okadaic-acid-induced tau hyperphosphorylation cell model of neurodegeneration. The compound also demonstrates the potential for further development, characterized by its chemical and metabolic stability in mouse microsomes and fair solubility.
Topics: tau Proteins; Glycogen Synthase Kinase 3 beta; Alzheimer Disease; Animals; Thiazoles; Humans; rho-Associated Kinases; Mice; I-kappa B Kinase; Neuroprotective Agents; Protein Kinase Inhibitors; Cell Line; Anti-Inflammatory Agents; Microglia; Nitric Oxide; Lipopolysaccharides; Protein Aggregates; Neuroinflammatory Diseases
PubMed: 38893493
DOI: 10.3390/molecules29112616 -
Harmful Algae May 2024This article presents the first results on shellfish toxicity in the Slovenian sea (Gulf of Trieste, Adriatic Sea) since the analytical methods for the detection of...
Okadaic acid as a major problem for the seafood safety (Mytilus galloprovincialis) and the dynamics of toxic phytoplankton in the Slovenian coastal sea (Gulf of Trieste, Adriatic Sea).
This article presents the first results on shellfish toxicity in the Slovenian sea (Gulf of Trieste, Adriatic Sea) since the analytical methods for the detection of biotoxins (PSP, ASP, DSP and other lipophilic toxins) in bivalve molluscs were included in the national monitoring program in 2013. In addition to toxins, the composition and abundance of toxic phytoplankton and general environmental characteristics of the seawater (surface temperature and salinity) were also monitored. During the 2014-2019 study period, only lipophilic toxins were detected (78 positive tests out of 446 runs), of which okadaic acid (OA) predominated in 97 % of cases, while dinophysistoxin-2 and yessotoxins only gave a positive result in one sampling event each. The number of samples that did not comply with the EC Regulation for the OA group was 17 or 3.8 % of all tests performed, all of which took place from September to November, while a few positive OA tests were also recorded in December, April, and May. This toxicity pattern was consistent with the occurrence pattern of the five most common DSP-producing dinoflagellates, which was supported by the development of warm and thermohaline stratified waters: Dinophysis caudata, D. fortii, D. sacculus, D. tripos and Phalacroma rotundatum. The strong correlation (r = 0.611, p < 0.001) between D. fortii, reaching abundances of up to 950 cells L, and OA suggests that D. fortii is the main cause of OA production in Slovenian waters. Strong interannual variations in OA and phytoplankton dynamics, exacerbated by the effects of anthropogenic impacts in this coastal ecosystem, reduce the predictability of toxicity events and require continuous and efficient monitoring. Our results also show that the introduction of the LC-MS/MS method for lipophilic toxins has improved the management of aquaculture activities, which was not as accurate based on mouse bioassays.
Topics: Okadaic Acid; Animals; Phytoplankton; Marine Toxins; Slovenia; Mytilus; Seafood; Seawater; Dinoflagellida
PubMed: 38830710
DOI: 10.1016/j.hal.2024.102632 -
Toxins Apr 2024In Western Europe, the incidence of DST is likely the highest globally, posing a significant threat with prolonged bans on shellfish harvesting, mainly caused by species...
In Western Europe, the incidence of DST is likely the highest globally, posing a significant threat with prolonged bans on shellfish harvesting, mainly caused by species of the dinoflagellate genus . Using a time series from 2014 to 2020, our study aimed (i) to determine the concentration of in water at which shellfish toxin levels could surpass the regulatory limit (160 µg OA equiv kg) and (ii) to assess the predictability of toxic events for timely mitigation actions, especially concerning potential harvesting bans. The analysis considered factors such as (i) overdispersion in the data, (ii) distinct periods of presence and absence, (iii) the persistence of cells, and (iv) the temporal lag between cells in the water and toxins in shellfish. Four generalized additive models were tested, with the Tweedie (TW-GAM) model showing superior performance (>85%) and lower complexity. The results suggest existing thresholds currently employed (200 and 500 cells L) are well-suited for the Portuguese coast, supported by empirical evidence (54-79% accuracy). The developed algorithm allows for thresholds to be tailored on a case-by-case basis, offering flexibility for regional variations.
Topics: Dinoflagellida; Marine Toxins; Shellfish Poisoning; Shellfish; Animals; Portugal; Environmental Monitoring; Food Contamination
PubMed: 38787056
DOI: 10.3390/toxins16050204 -
EXCLI Journal 2024Phycotoxins are responsible for foodborne intoxications. Symptoms depend on the ingested toxins but mostly imply gastro-intestinal and neurological disorders....
Phycotoxins are responsible for foodborne intoxications. Symptoms depend on the ingested toxins but mostly imply gastro-intestinal and neurological disorders. Importantly, humans are exposed to combinations of several phycotoxins, resulting in possible mixture effects. Most previous studies, however, have been focused on single toxin effects. Thus, the aim of this study was to examine the effects of binary mixtures of three main phycotoxins, okadaic acid (OA), azaspiracid-1 (AZA1) and yessotoxin (YTX), on human intestinal Caco-2 cells. The focus was placed on cell viability studies and inflammation responses using a multi-parametric approach to assess cell population (nuclei staining), cell metabolism/viability (reductase activity and lysosomal integrity), and release of inflammation markers (e.g., interleukins). Mixture effects were evaluated using the concentration addition (CA) and independent action (IA) models. Our assays show that none of the toxins had an impact on the cell population in the tested concentration range. Only OA modulated reductase activity, while all three toxins had strong effects on lysosomal integrity. Furthermore, all toxins triggered the release of interleukin 8 (IL-8), with OA being most potent. Mixture effect analysis showed additivity in most cases. However, supra-additivity was observed in regards to IL-6 and IL-8 release for combinations implying high concentrations of OA. This study extends the knowledge on mixture effects of phycotoxins in human cells.
PubMed: 38741723
DOI: 10.17179/excli2023-6884 -
Biochimica Et Biophysica Acta.... Aug 2024Alzheimer's disease (AD) research started several decades ago and despite the many efforts employed to develop new treatments or approaches to slow and/or revert disease...
Alzheimer's disease (AD) research started several decades ago and despite the many efforts employed to develop new treatments or approaches to slow and/or revert disease progression, AD treatment remains an unsolved issue. Knowing that mitochondria loss of function is a central hub for many AD-associated pathophysiological processes, there has been renewed interest in exploring mitochondria as targets for intervention. In this perspective, the present study was aimed to investigate the possible beneficial effects of 2,4 dinitrophenol (DNP), a mitochondrial uncoupler agent, in an in vitro model of AD. Retinoic acid-induced differentiated SH-SY5Y cells were incubated with okadaic acid (OA), a neurotoxin often used as an AD experimental model, and/or with DNP. OA caused a decrease in neuronal cells viability, induced multiple mitochondrial anomalies including increased levels of reactive oxygen species, decreased bioenergetics and mitochondria content markers, and an altered mitochondria morphology. OA-treated cells also presented increased lipid peroxidation levels, and overactivation of tau related kinases (GSK3β, ERK1/2 and AMPK) alongside with a significant augment in tau protein phosphorylation levels. Interestingly, DNP co-treatment ameliorated and rescued OA-induced detrimental effects not only on mitochondria but also but also reinstated signaling pathways homeostasis and ameliorated tau pathology. Overall, our results show for the first time that DNP has the potential to preserve mitochondria homeostasis under a toxic insult, like OA exposure, as well as to reestablish cellular signaling homeostasis. These observations foster the idea that DNP, as a mitochondrial modulator, might represent a new avenue for treatment of AD.
Topics: Alzheimer Disease; Okadaic Acid; Humans; 2,4-Dinitrophenol; Mitochondria; Reactive Oxygen Species; Cell Line, Tumor; Cell Survival; tau Proteins; Neurons; Lipid Peroxidation; Glycogen Synthase Kinase 3 beta; Tretinoin
PubMed: 38729530
DOI: 10.1016/j.bbadis.2024.167222 -
Journal of Traditional and... May 2024Royal jelly is an anti-inflammatory, antioxidant, and neuroprotective bee product. There are several sources for royal jelly and one of them is Indian Royal Jelly (IRJ)....
BACKGROUND
Royal jelly is an anti-inflammatory, antioxidant, and neuroprotective bee product. There are several sources for royal jelly and one of them is Indian Royal Jelly (IRJ). However, the neuroprotective actions of IRJ and the underlying molecular mechanisms involved are not well known.
OBJECTIVE
To evaluate the neuroprotective effect of IRJ in the okadaic acid (OKA)-induced Alzheimer's disease (AD) model in rats.
METHODS
In male Wistar rats, OKA was intracerebroventricularly (ICV) administered, and from day 7, they were treated orally with IRJ or memantine for 21 days. Spatial and recognition learning and memory were evaluated from days 27-34; employing the Morris water maze (MWM) and the novel object recognition tests (NORT), respectively. biochemical measurements were taken of the cholinergic system and oxidative stress markers. In silico docking was used to find the role of tau protein kinase and phosphatase in the pharmacological action.
RESULTS
In OKA-induced rats, IRJ decreased the escape latency and path length in MWM and increased the exploration time for novel objects and the discrimination index in NORT. ICV-OKA rats had higher free radicals and cytokines that caused inflammation and their level of free radical scavengers was back to normal with IRJ treatment. IRJ increased the level of acetylcholine and inhibited acetylcholinesterase. Moreover, the in silico docking study revealed the strong binding affinity of 10-hydroxy-2-decenoic acid (10-HDA), a bioactive constituent of IR, to the tau protein kinases and phosphatases.
CONCLUSION
IRJ may serve as a nootropic agent in the treatment of dementia, and owing to its capacity to prevent oxidative stress and neuroinflammation, and increase cholinergic tone; it has the potential to be explored as a novel strategy for the treatment of dementia and AD. More studies may be needed to develop 10-HDA as a novel drug entity for AD.
PubMed: 38707922
DOI: 10.1016/j.jtcme.2023.11.005 -
Toxins Apr 2024Okadaic acid (OA) is one of the most potent marine biotoxins, causing diarrheal shellfish poisoning (DSP). The proliferation of microalgae that produce OA and its...
Okadaic acid (OA) is one of the most potent marine biotoxins, causing diarrheal shellfish poisoning (DSP). The proliferation of microalgae that produce OA and its analogues is frequent, threatening human health and socioeconomic development. Several methods have been tested to remove this biotoxin from aquatic systems, yet none has proven enough efficacy to solve the problem. In this work, we synthesized and characterized low-cost composites and tested their efficacy for OA adsorption in saltwater. For the synthesis of the composites, the following starting materials were considered: chitosan of low and medium molecular weight (CH-LW and CH-MW, respectively), activated carbon (AC), and montmorillonite (MMT). Characterization by vibrational spectroscopy (FTIR), X-ray diffraction (XRD), and microscopy revealed differences in the mode of interaction of CH-LW and CH-MW with AC and MMT, suggesting that the interaction of CH-MW with MMT has mainly occurred on the surface of the clay particles and no sufficient intercalation of CH-MW into the MMT interlayers took place. Among the composites tested (CH-LW/AC, CH-MW/AC, CH-MW/AC/MMT, and CH-MW/MMT), CH-MW/MMT was the one that revealed lower OA adsorption efficiency, given the findings evidenced by the structural characterization. On the contrary, the CH-MW/AC composite revealed the highest average percentage of OA adsorption (53 ± 11%). Although preliminary, the results obtained in this work open up good perspectives for the use of this type of composite material as an adsorbent in the removal of OA from marine environments.
Topics: Adsorption; Chitosan; Okadaic Acid; Bentonite; Charcoal; Marine Toxins; Shellfish Poisoning
PubMed: 38668625
DOI: 10.3390/toxins16040200 -
Scientific Reports Apr 2024Parkinson's disease (PD) is the second most frequently diagnosed neurodegenerative disease, and it is characterized by the intracellular and extracellular accumulation...
Parkinson's disease (PD) is the second most frequently diagnosed neurodegenerative disease, and it is characterized by the intracellular and extracellular accumulation of α-synuclein (α-syn) and Tau, which are major components of cytosolic protein inclusions called Lewy bodies, in the brain. Currently, there is a lack of effective methods that preventing PD progression. It has been suggested that the plasminogen activation system, which is a major extracellular proteolysis system, is involved in PD pathogenesis. We investigated the functional roles of plasminogen in vitro in an okadaic acid-induced Tau hyperphosphorylation NSC34 cell model, ex vivo using brains from normal controls and methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, and in vivo in a widely used MPTP-induced PD mouse model and an α-syn overexpression mouse model. The in vitro, ex vivo and in vivo results showed that the administered plasminogen crossed the blood‒brain barrier (BBB), entered cells, and migrated to the nucleus, increased plasmin activity intracellularly, bound to α-syn through lysine binding sites, significantly promoted α-syn, Tau and TDP-43 clearance intracellularly and even intranuclearly in the brain, decreased dopaminergic neurodegeneration and increased the tyrosine hydroxylase levels in the substantia nigra and striatum, and improved motor function in PD mouse models. These findings indicate that plasminogen plays a wide range of pivotal protective roles in PD and therefore may be a promising drug candidate for PD treatment.
Topics: Animals; Mice; alpha-Synuclein; Disease Models, Animal; DNA-Binding Proteins; Dopamine; Neurodegenerative Diseases; Parkinson Disease; Plasminogen; Serine Proteases; tau Proteins; Dopaminergic Neurons
PubMed: 38615036
DOI: 10.1038/s41598-024-59090-8 -
Experimental Cell Research Apr 2024Plasma saturated free fatty acid (FFA)-induced endothelial dysfunction (ED) contributes to the pathogenesis of atherosclerosis and cardiovascular diseases. However, the...
Plasma saturated free fatty acid (FFA)-induced endothelial dysfunction (ED) contributes to the pathogenesis of atherosclerosis and cardiovascular diseases. However, the mechanism underlying saturated FFA-induced ED remains unclear. This study demonstrated that palmitic acid (PA) induced ED by activating the NADPH oxidase (NOX)/ROS signaling pathway to activate protein phosphatase 4 (PP4) and protein phosphatase 2A (PP2A), thereby reducing endothelial nitric oxide synthase (eNOS) phosphorylation at Ser633 and Ser1177, respectively. Okadaic acid (OA) and fostriecin (FST), which are inhibitors of PP2A, inhibited the PA-induced decreases in eNOS phosphorylation at Ser633 and Ser1177. The antioxidants N-acetylcysteine (NAC) and apocynin (APO) or knockdown of gp91phox or p67phox (NOX subunits) restored PA-mediated downregulation of PP4R2 protein expression and eNOS Ser633 phosphorylation. Knockdown of the PP4 catalytic subunit (PP4c) specifically increased eNOS Ser633 phosphorylation, while silencing the PP2A catalytic subunit (PP2Ac) restored only eNOS Ser1177 phosphorylation. Furthermore, PA dramatically decreased the protein expression of the PP4 regulatory subunit R2 (PP4R2) but not the other regulatory subunits. PP4R2 overexpression increased eNOS Ser633 phosphorylation, nitric oxide (NO) production, cell migration and tube formation but did not change eNOS Ser1177 phosphorylation levels. Coimmunoprecipitation (Co-IP) suggested that PP4R2 and PP4c interacted with the PP4R3α and eNOS proteins. In summary, PA decreases PP4R2 protein expression through the Nox/ROS pathway to activate PP4, which contributes to ED by dephosphorylating eNOS at Ser633. The results of this study suggest that PP4 is a novel therapeutic target for ED and ED-associated vascular diseases.
Topics: Humans; Phosphorylation; Nitric Oxide Synthase Type III; Palmitic Acid; Serine; Reactive Oxygen Species; Cells, Cultured; Protein Phosphatase 2; Vascular Diseases; Nitric Oxide; Phosphoprotein Phosphatases
PubMed: 38513962
DOI: 10.1016/j.yexcr.2024.113998