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Mold 105 - Ochratoxin A: Neurodegeneration, Iron Dysregulation, POTS, Glial Reactivity, Mast Cells, Hypoxia, Mito Dysfunction, and Ferroptosis.

This article is not health care or medical advice. Before starting and health related regimen seek the advice of your Primary Care Physician, or an M.D.


Our good friend Ochratoxin A, is at it again - below is some new research related to Ochratoxin A and how it effects some pathways that lead to many issues like : neurodegeneration, brain inflammation, iron dysregulation, POTS, Glial Cell Reactivity, Mast Cell Activation, Mitochondrial Dysfunction, Metabolic Dysfunction, and Ferroptosis (un mitigated cell death), Hypoxia, and massive fatigue.


The summary version:

  • OTA down regulates important anti oxidant enzymes NrF2, through Keap 1

  • Inhibits HMOX1 - stores iron into ferritin, controls NADPH/NOX/Mast Cell Activation

  • Upregulates iNOS (POTS), NFKB, and NADPH Oxidase, all NAD consuming

  • Excess nitrosation - peroxynitrite, damaging free radical

  • Lowered amino acid catabolism - higher amino levels, lower fatty acid oxidation, higher carnitine, and lowered Alinine

  • Mitochondrial Dysfunction (membrane potential compromise - phospholipid anc cell membrane oxidations)

  • Metabolic dysfunction (amino acid and fatty acid metabolism effected)

  • Glial cell reactivity, brain inflammation

  • Mast cells are stimulated by elevated iNOS, NADPH Oxidase, and impairment of HMOX1

  • Induction of Aryl Hydrocarbon Receptor - AHR - NMDA Receptor Activation

  • Induction of HIF1a - Hypoxia

  • Induction of Ferroptosis (unmitigated cell death) via GPX4 and FXR Inhibition and Iron Dysregulation - upregulation of iron importers and down regulation of iron exporters.


Ochratoxin A - Inhibits NrF2, HMOX1, and Likely Through Keap1

Yes, the mast controller of anti oxidant genes, like Glutathione, SOD, Catalase, NQO1 (NAD Recycling), and many others - Ochratoxin A inhibits NrF2. Also importantly it inhibits HMOX1 which - in my prior article on Ochratoxin A - is responsible for putting iron into Ferritin, Controlling Mast Cells (NOX), and putting billiverdin into billirubin. Circumin a known NrF2 activator has shown strong benefits, but it is also a known iron chelator, "The co-treatment OTA + CURC counteracted the harmful effects of chronic OTA treatment by regulating inflammation, reducing NO levels and oxidative DNA damage in kidney and liver tissues.".[3]


OTA Likely Inhibits NrF2 Through Keap 1 Modulation

However, its very important to know, that the mechanism by which Ochratoxin A inhibits NrF2 appears to be through Keap 1. This is important, because Keap1 controls NrF2 - its a chaperone into the cytosol for NrF2 and it must also release it once chaperoned into the cytosol. An important addition to any protocol with Ochratoxin A. "One of the key events is the inhibition of Nrf2 mobilization and thus translocation to the nucleus. While, the mechanism for this has not yet been elucidated, it has been shown that OTA binds strongly to actin filaments. This would likely interfere with cytoskeletal dynamics. For example we have shown that OTA strongly induced advillin, a member of the gelsolin superfamily which plays a role in actin remodeling. Since Keap-1 is an actin-bound protein, it is possible that OTA prevents the liberation of Nrf2 from the Keap-1 complex."[9]


Ochratoxin A - Raises IL-6, IL-4, IL-5, IL-2

Ochratoxin A lowers IL-10 which controls IL-6, so its not clear yet if the effect of Ochratoxin A is direct on IL-6, or just through IL-10.


Ochratoxin A - mediated DNA Damage and Protein Damage, Nitrosative and Oxidative Stress

"This end point was used as an indirect measure of 8-nitroguanine formation. Treatment of the cells with L-N(6)-(1-iminoethyl) lysine, a specific inhibitor of iNOS activity, inhibited the OTA-mediated overnitration of proteins but did not reduce the level of DNA abasic sites. It was found previously that nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) activators were able to restore the cellular defense against oxidative stress and could prevent DNA abasic sites in cell cultures. In the present study, pretreatment of the cells with activators of Nrf2 prevented OTA-mediated increase in lipid peroxidation, confirming the potential of Nrf2 activators to confer protection against OTA-mediated oxidative stress."[1] Its important to note that Nitrosative stress is usually a sign of excess peroxynitrite, and select peroxynitrite scavengers may prove helpful.


Ochratoxin A Induces iNOS / NOS2, NfKB, COX-2 - Uh Oh

"OTA was found to stimulate the formation of NO through a NF-κB–dependent induction of iNOS. The consequences of the increased NO production, together with oxidative stress, were then studied using markers of protein and DNA damage."[4]

"In the present study, OTA modulation of lipopolysaccharide (LPS)-induced inflammatory process is described in the macrophagic cell line, J774A.1 in order to better understand the mechanisms underlying OTA immunotoxicity. OTA (30 nM-100 microM) induces a time and concentration dependent cytotoxic effect, increased when cells were co-stimulated with LPS (100 ng/ml), a concentration that alone did not modify the cellular viability. Moreover, OTA (3 microM) alone induces a significant increase in cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, while at the highest concentration (10 microM) a reduced expression of both enzymes was shown, consistently with the mycotoxin cytotoxic profile. The role of nuclear factor-kB (NF-kB) in the mycotoxin effect was also demonstrated. Conversely, when cells were co-stimulated with LPS, OTA showed a concentration-dependent reduction of COX-2 and iNOS expression and their respective metabolites (PGE(2) and NO)."[5]


Ochratoxin A Effects iNOS, Gial Cell Reactivity, PPARG, and Brain Inflammation

"Previous observations in vitro showed that in the CNS, glial cells were particularly sensitive to OTA. In the search for the molecular mechanisms underlying OTA neurotoxicity, we investigated the relationship between OTA toxicity and glial reactivity, in serum-free aggregating brain cell cultures. Using quantitative reverse transcriptase-polymerase chain reaction to analyze changes in gene expression, we found that in astrocytes, non cytotoxic concentrations of OTA down-regulated glial fibrillary acidic protein, while it up-regulated vimentin and the peroxisome proliferator-activated receptor-gamma expression. OTA also up-regulated the inducible nitric oxide synthase and the heme oxygenase-1. These OTA-induced alterations in gene expression were more pronounced in cultures at an advanced stage of maturation. The natural peroxisome proliferator-activated receptor-gamma ligand, 15-deoxy-delta(12,14) prostaglandin J2, and the cyclic AMP analog, bromo cyclic AMP, significantly attenuated the strong induction of peroxisome proliferator-activated receptor-gamma and inducible nitric oxide synthase, while they partially reversed the inhibitory effect of OTA on glial fibrillary acidic protein. The present results show that OTA affects the cytoskeletal integrity of astrocytes as well as the expression of genes pertaining to the brain inflammatory response system, and suggest that a relationship exists between the inflammatory events and the cytoskeletal changes induced by OTA. Furthermore, these results suggest that, by inducing an atypical glial reactivity, OTA may severely affect the neuroprotective capacity of glial cells."[6]


OTA Effects Metabolic Pathways

"Numerous metabolites associated with interrelated pathways of energy metabolism including corresponding pathways of carbohydrate, amino acid and lipid catabolism were altered in OTA-exposed embryos. Both ATP and NADH, as the primary currency of cellular energetics, were significantly decreased in OTA-treated embryos. Concomitantly, significant increases in several amino acids including tryptophan (Trp), tyrosine (Tyr), leucine (Leu), isoleucine (Ile), valine (Val), glutamate (Glu), glutamine (Gln), glycine (Gly), cysteine (Cys), aspartate (Asp) and phenylalanine (Phe) were observed, consistent with impairment of amino acid catabolism, whereas a significant decrease was, in contrast, notably measured for alanine (Ala). Interestingly, the non-proteinogenic amino acid, γ-aminobutyric acid (GABA), also significantly increased (P < 0.05); although, GABA is most often associated with its function as neurotransmitter, emerging evidence suggests a possible role in hepatic damage. Metabolites associated with carbohydrate metabolism were also altered by OTA treatment including a significant decrease in lactate (Lac), and seemingly increased levels of glucose (Glc) and associated metabolites, specifically including glucose-6-phosphate (G6P) and glucose-1-phosphate (G1P)...... a significant increase in fatty acids (FA), but no significant difference in cholesterol (Chol), was also observed; and notably, alongside increased FA, a significant increase in carnitine as recognized co-factor in the β-oxidation of fatty acids (but not cholesterol catabolism) was measured.


A second general trend was alteration of metabolites directly or indirectly associated with oxidative stress and detoxification pathways. A significant decrease in glutathione (GSH) as both an antioxidant, and key metabolite in phase-II detoxification, was measured by HRMAS NMR following OTA exposure (compared to controls). Consistent, albeit indirectly, with a role of oxidative stress (i.e., ROS), and antioxidant and detoxification pathways, significant increases were observed for glycerophosphocholine (GPC), choline (Cho) and myo-inositol (m-Ins) which are typically associated with polar headgroups of phospholipids, and betaine as a biosynthetic product of choline, whereas trimethylamine N-oxide (TMAO) was significantly decreased. Increased levels of polar headgroup molecules have been suggested in previous studies to be an indicator of disruption of cell membranes, and specifically hydrolysis of phospholipids, which can occur as a consequence of oxidative stress (e.g., lipid peroxidation). Interestingly, betaine (although associated with a range of cellular functions) has been recently proposed to serve a role in the regulation of mitochondrial function including, in particular, fusion/fission which, in turn, has been linked to oxidative stress. On the other hand, TMAO has been proposed as potential biomarker of the impairment of liver (discussed below) where pathways of phase-I and II detoxification of xenobiotics are generally localized, and specifically, where phase-I oxidation to produce TMAO exclusively occurs."[7]


"An integrated model of the hepatotoxicity mechanism of ochratoxin A (OTA) in relation to observed changes in metabolic alterations. In liver, OTA affects detoxification pathways (I) associated with disruption of Nrf2 that is a key transcriptional factor for regulating detoxification pathways, and the synthesis of GSH as an antioxidant (II). This is evident by a decrease in GSH, and increase in its precursors Cys, Glu and Gly. The depletion of GSH leads to impaired redox homeostasis, and an increased production of ROS, and consequently, lipid peroxidation and membrane damage especially affecting mitochondrial membrane integrity (III). Mitochondrial membrane hydrolysis is reflected by an increase in Cho, GPC, and m-Ins, as polar headgroups of membrane phospholipids (IV). The loss of membrane integrity leads to impairment of the mitochondrial membrane potential (MMP), with consequent reduction of oxidative phosphorylation as reflected by decrease in ATP. Several pathways upstream of oxidative phosphorylation are consequently affected, as seen by changes in metabolites associated with glycolysis and/or gluconeogenesis, the malate/aspartate shuttle, β-oxidation of fatty acids, glutaminolysis, and the citric acid cycle (V). The energy deficiency and hindered oxidative phosphorylation activates mitochondrial fusions, possibly via elevated levels of betaine, as a “passive mechanism” to rescue mitochondrial integrity and energy metabolism (VI)."[7]


Role of Mitochondria [7]

"Key consequences of increased cellular ROS include lipid peroxidation and oxidation of membrane proteins which, in turn, lead to disruption of membranes, and loss of membrane function. Accordingly, OTA-induced oxidative stress has, in fact, been previously linked to both peroxidation of lipids and oxidation of proteins within, in particular, mitochondrial membranes; and consequent mitochondrial dysfunction is, in turn, one of the earliest events in OTA toxicity. Numerous metabolites altered by OTA exposure in the present study are, likewise, consistent with a role of mitochondrial disruption in the toxicity of OTA ." Lipid peroxidation is mediated by ....GPX4.


"Although lipid peroxidation, for example, was not directly measured in the present study, the significant increase in Cho, GPC and m-Ins , as polar headgroups of membrane phospholipids, is consistent with disruption of membranes as a consequence of oxidative stress. Peroxidation of membrane phospholipids has been consistently linked to hydrolysis, and release of both choline (e.g., GPC) and inositol moieties via both enzymatic (e.g., phospholipase) and non-enzymatic cleavage mechanisms. At least one study, in fact, suggests that phospholipid hydrolysis, rather than preceding lipid peroxidation, is the primary factor in the so-called mitochondrial permeability transition. Peroxidation-induced hydrolytic disruption of mitochondrial membranes, in turn, aligns with the consistently observed role of mitochondrial impairment in OTA toxicity which includes disruption of mitochondrial membrane potential (MMP), and consequently reduced ATP, as well as further increased production of ROS, and induction of both mitophagy and mitochondrial biogenesis coupled to disruption of mitochondrial fusion/fission. And generally aligned, in the current study, with impaired oxidative phosphorylation (due to disrupted MMP), ATP was significantly decreased by OTA exposure."[7]


Cell Membrane Integrity - Phospholipid Therapy

"In addition, however, it is proposed (based on altered metabolic profiles) that mitochondrial membrane disruption by OTA simultaneously interferes with uptake, and subsequent metabolism, of several metabolites that are associated with pathways upstream of oxidative phosphorylation . Reduced uptake, and functioning of these pathways, is likely to result from either general disruption of mitochondrial membrane integrity, or alternatively, oxidation of membrane proteins (i.e., transporters) due to increased cellular ROS. It was, in fact, reported more than four decades ago that OTA inhibits mitochondrial transport systems. And several of the metabolites altered by OTA, in the present study, align with such a mode of action. The observed decrease in Ala (compared to the significant increase for all other amino acids) is, for example, notable in this regard as it is one of only three amino acids (and the only one which significantly contributes to cellular energetics) not catabolized primarily within mitochondria. Rather, Ala is catabolized by alanine transaminase (ALT) in the cytoplasm of cells whereby the transamination of Ala (to Glu) directly generates Pyr for either use in the citric acid cycle, or alternatively, gluconeogenesis.


Indeed, several metabolites upstream of oxidative phosphorylation are significantly increased in OTA-exposed embryos suggesting likely impairment of their uptake, and/or subsequent metabolism. Most conspicuously, in this regard, were significant increases in Mal, Asp, Glu, Glu and αKG which are intermediates for interconnected pathways including (1) the malate/aspartate shuttle which transports glycolytic NADH to mitochondria; (2) glutaminolysis whereby Gln taken-up by mitochondria supplies Glu and αKG for both anaplerotic entry to the citric acid cycle, and support of the malate/aspartate shuttle; and (3) the citric acid cycle. Impairment of all three of these pathways, in turn, would align with observed decrease in both NADH, particularly from the citric acid cycle, and ATP subsequently derived from oxidative phosphorylation. Of the citric acid cycle intermediates resolved by HRMAS NMR, only Mal and αKG were altered; the increase in the latter is particularly revealing, perhaps, as the two irreversible, NADH-generating steps immediately preceding and following this metabolite in the citric acid cycle (i.e., isocitrate dehydrogenase and α-ketoglutate dehydrogenase, respectively) represent the two primary regulatory points of the cycle. Further correlated with dysfunction of mitochondrial uptake, both total fatty acids (FA) and Carn were significantly increased. Fatty acids, taken-up by mitochondria, supply precursors (i.e., acetyl CoA) of the citric acid cycle via β-oxidation, whereby carnitine is essential for transport (via carnitine palmitoyltransferases) of fatty acids into mitochondria. The role of mitochondrial uptake in this observation is highlighted by the observed lack of altered cholesterol: unlike FA, cholesterol is not catabolized by animals (rather removed as bile acids), whereas both are, in contrast, biosynthesized by overlapping pathways (i.e., citrate-derived acetyl CoA) in the cytoplasm.

Concurrent with a putative decrease in mitochondrial uptake and energy metabolism, upstream substrates of carbohydrate metabolism including Glc and associated metabolites were apparently increased. Although glucose and associated phosphates (i.e., G1P and G6P) could not be unambiguously resolved by 1D HRMAS NMR, the use of 2D COSY confirmed identity of all three metabolites, and the relative increase of cross-peaks (between treated and control embryos) in these experiments, likewise, consistent with a relative increases in all three metabolites. Increased levels of glucose- associated metabolites would be indicative of either decreased glycolysis, or alternatively, upregulated gluconeogenesis . Further supporting a role of modulated carbohydrate metabolism, a significant decrease in both Ala and Lac aligns with production of Pyr that could either supply gluconeogenesis, or compensate for reduced glycolytic production. Glucose synthesis from Ala- or Lac-derived Pyr might specifically function in the interplay of energy metabolism between the liver and muscles via Cahill and Cori Cycles which shuttle glycolytic Pyr (from muscle) as either Ala and Lac, respectively, for gluconeogenesis in the liver. That said, however, gluconeogenesis is a highly energy (i.e., ATP) demanding pathway, and considering the presumptive depletion of mitochondrial (i.e., oxidative phosphorylation) generated ATP, it is perhaps unlikely that hepatocytes would favor glucose production and export (to muscle cells) under these conditions. Accordingly, it is more likely that increased Pyr is compensatory for reduced glycolysis. Moreover, recent evidence points to down-regulation of glycolysis as a result of mitochondrial fusion, and it is posited, as part of our working model (as discussed further below), that OTA may inhibit glycolysis indirectly, and specifically via activation of this mitochondrial repair mechanisms.

The proposed role of mitochondrial repair is based, in part, on a recent study of OTA in intestinal epithelial cells which demonstrated alongside mitochondrial damage, and concurrent mitophagy and mitochondrial biogenesis altered expression of genes involved in mitochondrial fusion/fission. It was effectively concluded, in this study, that altered mitochondrial fusion/fission, in concert with mitochondrial biogenesis, may serve as a compensatory means to mitigate (by repair and replacement, respectively) mitochondrial damage by OTA. Such a mechanism is, in fact, supported by a prior study in Drosophila which similarly observed an increase in mitochondrial DNA copy number following exposure to OTA. Interestingly, in this regard, it has been recently shown that Nrf2, as demonstrated target of OTA, plays a key role in the regulation and post-translational modification (i.e., AMP-activated protein kinase) of the genes involved in mitochondrial biogenesis including PPARγ co-activator 1α (PGC1α) and Nrf1, and subsequently, transcription factor A mitochondrial (TFAM); and in turn, was shown that OTA activates the AMPA/PGC1α/TFAM pathway. More relevant to the current study, however, OTA was found in this same study to lead to altered, and specifically tubular, morphology of mitochondria indicative of fusion. It has, furthermore, been shown that mitochondrial fusion may serve to protect against autophagy and apoptosis, and moreover, support cells during energy deficiency including, in particular, hindered oxidative phosphorylation, as observed for OTA. And role of mitochondrial fusion was, likewise, demonstrated in a previous proteomics study of OTA nephrotoxicity which showed downregulation of genes (i.e., OPA1) associated with mitochondrial fusion.

With respect to the present results, it has been recently shown that betaine (which was increased) increases mitochondrial fusion, and alters expression of genes relevant to mitochondrial fusion/fission including increased mitofusin-2 (MFN2) and decreased dynamin-related protein 1 (DRP1), and is, thereby, able to rescue cells from inhibition of oxidative phosphorylation. It is proposed, therefore, that the significant increase in betaine observed, in the present study, may represent a “passive mechanism” to rescue mitochondrial integrity by stimulation of mitochondrial fusion to supplement energy metabolism, in light of mitochondrial dysfunction (and reduced oxidative phosphorylation). At the same time, it was shown in a recent study that MFN2 interacts with an isoform of pyruvate kinase (PKM2) that serves as key regulator of glycolysis, and serves to coordinate mitochondrial fusion (as a means of mitigating disruptions in oxidative phosphorylation) with the down-regulation of glycolysis. As such, betaine-activated mitochondrial fusion may simultaneously inhibit upstream glycolysis , consistent with the observed increase in metabolites (i.e., Glc, G6P and G1P) associated with carbohydrate metabolism. A potential compensatory role of betaine in relation to OTA-induced mitochondrial dysfunction would represent not only a previously unknown homeostatic pathway, but also a possibly novel therapeutic target against OTA toxicity."[7]


"... it is proposed that under the threat of losing mitochondrial membrane integrity, and functionality in performing oxidative phosphorylation, mitochondrial fusion/fission may provide a compensatory mechanism which may serve as a passive mechanism that may, in turn, be exploited as a possible therapeutic target against OTA toxicity...."[7]


HIF1A Induced As Well (Hypoxia):

"The decrease in Nrf2 activation induced by OTA was also observed in NRK-52E rat kidney cells were the influence of another oxidative stress regulator was suggested: hypoxia inducible factor 1α (HIF-1α) which activation was associated with angiogenesis ."[8]


Induces The Aryl Hydrocarbon Receptor [11]

"The aim of this study was to investigate OTA-induced toxicity in human proximal tubule HK-2 cells. OTA decreased cell viability, and the expression of kidney injury molecule-1 (KIM-1), a kidney damage marker, was increased when HK-2 cells were exposed to OTA. Additionally, OTA treatment of cells increased intracellular reactive oxygen species and malondialdehyde and decreased glutathione levels. OTA-treated cells induced the aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) genes followed by induction of the cytochrome P450 1A1 (CYP1A1), CYP1A2, and CYP3A4 genes representing phase I enzyme. The mRNA expression of phase II enzymes such as heme oxygenase-1, nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1, and glutamate cysteine ligase catalytic subunit were upregulated by activation of NF-E2-related factor 2 (Nrf2) translocation by treatment with OTA. The response of OTA-orally administered mice also showed marked increases in these enzymes as well as KIM-1. These results indicate that OTA induces phase I and II enzymes through the AhR, PXR, and Nrf2 signaling pathways in HK-2 cells, which may lead to modulation of proximal tubule injury."[11]


OTA: Induces Ferroptosis in Renal Cells - By Disrupting Iron Homeostasis

"The current study used human kidney cell lines to investigate whether and how intracellular iron contributed to OTA-induced ROS accumulation and how OTA-induced iron-dependent ferroptotic cell death. Our results showed that OTA treatment affected the cell viability and induced the typical characteristics of cell ferroptosis. Furthermore, gene and protein expression results indicated that OTA disrupted iron homeostasis by upregulating the expression levels of iron importer TFR1 and FTH, while downregulating the expression level of iron exporter FPN and dramatically increasing its negative regulator Hepcidin. The changes were consistent with the induction of intracellular iron accumulation and elevated levels of oxidative stress and lipid peroxidation. Additionally, co-treatment with OTA and an iron chelator significantly improved cell viability, reduced cellular total iron and ROS, and reversed OTA-induced changes in iron metabolism gene expression levels. Interestingly, the addition of a ROS scavenger also reversed cell death and changes in mRNA and protein expression levels of iron metabolism genes but to a lesser degree than that of the iron-chelating agent. Our results revealed that OTA induced ferroptosis in renal cells by disrupting iron homeostasis and increasing ROS."[12]


Ferroptosis Also Induced By GPX4/FXR Inhibition: FXR Activation Rescued Ferroptosis in Ochratoxin A Toxicity

"The mycotoxin ochratoxin A (OTA) causes nephrotoxicity, hepatotoxicity, and immunotoxicity in animals and humans. The farnesoid X receptor (FXR) is a member of the NR family and is highly expressed in the kidney, which has an antilipid production function. Ferroptosis is an iron-dependent form of regulated cell death involved in several pathophysiological cell death and kidney injury. The present study aims to evaluate the role of FXR and ferroptosis in OTA-induced nephrotoxicity in mice and HK-2 cells. Results showed that OTA induced nephrotoxicity as demonstrated by inducing the histopathological lesions and neutrophil infiltration of the kidney, increasing serum BUN, CRE, and UA levels, increasing Ntn-1, Kim-1, and pro-inflammatory cytokine expression, and decreasing IL-10 expression and the cell viability of HK-2 cells. OTA treatment also induced FXR deficiency, ROS release, MDA level increase, GSH content decrease, and 4-HNE production in the kidney and HK-2 cells. OTA treatment induced ferroptosis as demonstrated by increasing labile iron pool and lipid peroxidation levels as well as Acsl4, TFR1, and HO-1 mRNA and protein levels, decreasing GPX4 and FTH mRNA and protein expressions, and inducing mitochondrial injury. The FXR activator (GW4064) rescued the accumulation of lipid peroxides, intracellular ROS, and Fe2+, inhibited ferroptosis, and alleviated OTA-induced nephrotoxicity. The ferroptosis inhibitor (Fer-1) prevented ferroptosis and attenuated nephrotoxicity. Collectively, this study elucidates that FXR played a critical role in OTA-induced nephrotoxicity via regulation of ferroptosis, which provides a novel strategy against OTA-induced nephrotoxicity."[13]


OTA Increases NADPH Oxidase and Calpain

"OTA dose-dependently induced expression of ER stress markers including phospho-PERK, phospho-eIF2α, GRP78, GRP94, and CHOP. Apoptosis events including cleavage of caspase-12, caspase-7, and PARP are also observed. OTA activated oxidative stress and increased NADPH oxidase activity. NADPH oxidase inhibitor, apocynin, significantly attenuated OTA-induced cell apoptosis. Moreover, OTA markedly increased the calpain activity which significantly inhibited by apocynin."[11]


References

  1. Ochratoxin A-mediated DNA and protein damage: roles of nitrosative and oxidative stresses

  2. Peroxynitrite scavenger reference

  3. Curcumin Modulates Nitrosative Stress, Inflammation, and DNA Damage and Protects against Ochratoxin A-Induced Hepatotoxicity and Nephrotoxicity in Rats. by Consiglia Longobardi, Sara Damiano, et. al. Department of Mental, Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, Naples, Largo Madonna delle Grazie 1, 80138 Napoli, Italy. Antioxidants 2021, 10(8), 1239; https://doi.org/10.3390/antiox10081239

  4. Differential modification of inflammatory enzymes in J774A.1 macrophages by ochratoxin A alone or in combination with lipopolysaccharide. By M C Ferrante 1G Mattace Raso. Toxicol Letters. . 2008 Sep;181(1):40-6. doi: 10.1016/j.toxlet.2008.06.866. Epub 2008 Jul 5.

  5. Unusual astrocyte reactivity caused by the food mycotoxin ochratoxin A in aggregating rat brain cell cultures. By M-G Zurich 1S Lengacher, et. al. Neuroscience. 2005;134(3):771-82.

  6. An integrated systems-level model of ochratoxin A toxicity in the zebrafish (Danio rerio) embryo based on NMR metabolic profiling. By Muhamed N. H. Eeza, Narmin Bashirova, et. al. Nature. Scientific reports. Published: 15 April 2022. Scientific Reports volume 12, Article number: 6341 (2022)

  7. Nrf2: a main responsive element in cells to mycotoxin-induced toxicity. By Marta Justyna Kozieł,# Karolina Kowalska. Arch Toxicol. 2021; 95(5): 1521–1533. Published online 2021 Feb 8. doi: 10.1007/s00204-021-02995-4. PMCID: PMC8113212. PMID: 33554281

  8. A Review of the Evidence that Ochratoxin A Is an Nrf2 Inhibitor: Implications for Nephrotoxicity and Renal Carcinogenicity. By Alice Limonciel, Paul Jennings, et. al.

  9. Astaxanthin Protects Ochratoxin A-Induced Oxidative Stress and Apoptosis in the Heart via the Nrf2 Pathway. By Gengyuan Cui,Lin Li,Weixiang Xu. Oxidative Medicine and Cellular Longevity. 2020. Article ID 7639109 | https://doi.org/10.1155/2020/7639109.

  10. Ochratoxin A induces ER stress and apoptosis in mesangial cells via a NADPH oxidase-derived reactive oxygen species-mediated calpain activation pathway. By Meei-Ling Sheu, Chin-Chang Shen, et. al. Oncotarget. 2017 Mar 21; 8(12): 19376–19388.

  11. Renal toxicity through AhR, PXR, and Nrf2 signaling pathway activation of ochratoxin A-induced oxidative stress in kidney cells. By Hyun Jung Lee 1Min Cheol Pyo Food Chem Toxicol. . 2018 Dec:122:59-68. doi: 10.1016/j.fct.2018.10.004. Epub 2018 Oct 3. PMID: 30291945. DOI: 10.1016/j.fct.2018.10.004

  12. Ochratoxin A Induces Renal Cell Ferroptosis by Disrupting Iron Homeostasis and Increasing ROS. By Sen Wang, Hui Ren. J. Agric. Food Chem. 2024, 72, 3, 1734–1744. Publication Date:December 22, 2023. https://doi.org/10.1021/acs.jafc.3c04495.

  13. Farnesoid X Receptor Plays a Key Role in Ochratoxin A-Induced Nephrotoxicity by Targeting Ferroptosis In Vivo and In Vitro. Jiangyu Tang, Junya Zeng,et. al. FOOD SAFETY AND TOXIcology. J. Agric. Food Chem. 2023, 71, 39, 14365–14378. Publication Date:September 26, 2023. https://doi.org/10.1021/acs.jafc.3c04560




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