Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection

3H-leucine-labeled rhodopsin and the dense-label region of 3H-22:6 migrated together, reaching the PRC tips at the same time.

“3H-leucine in parallel displayed narrow protein bands and, because the edge of the 3H-leucine-labeled band (rhodopsin) and the dense-label region of 3H-22:6, migrated together, reaching the PRC tips at the same time.”

DHA uptake in PRCs depends on AdipoR1.

“We have demonstrated that DHA uptake in PRCs depends on AdipoR1.”

The reduction in microseizures and pHFO was correlated with a lower number of spontaneous recurrent seizures.

“This reduction in microseizures and pHFO was correlated with lower number of SRS.”

The effect of NPD1 on epileptogenesis led to spontaneous recurrent seizure reduction at 3 weeks after status epilepticus onset.

“The effect of NPD1 on epileptogenesis led to SRS reduction at 3 weeks after SE onset.”

NPD1 remarkably limited dendritic spine loss in hippocampal layers.

“NPD1 remarkably limited dendritic spine loss in hippocampal layers.”

PRC-specific PCMS containing VLC-PUFAs are greatly reduced in AdipoR1−/− retinas.

“The PRC-specific PCMS containing VLC-PUFAs are greatly reduced in AdipoR1−/−.”

NPD1 reduced dentate gyrus hyper-excitability after status epilepticus.

“NPD1 reduced the DG hyper-excitability after SE.”

AdipoR1 promotes DHA uptake that enables its conversion to VLC-PUFA.

“AdipoR1 promotes DHA uptake that enables its conversion to VLC-PUFA.”

Systemic administration of NPD1 modulates aberrant neuronal networks during epileptogenesis.

“Systemic administration of NPD1 modulates aberrant neuronal networks during epileptogenesis.”

The DHA changes in AdipoR1−/− retinas are selective for the essential omega-3 fatty acid family, since total levels of arachidonic acid remained unchanged.

“Moreover, the DHA changes are selective for the essential omega-3 fatty acid family since total levels of arachidonic acid (AA) (from the essential omega-6 fatty acid family) remained unchanged in AdipoR1−/− retinas.”

After stimulating the dorsal dentate gyrus with sub-convulsive electrical impulses after status epilepticus in freely moving rats, sustained severe seizures and electrical responses were observed in 93% of the animals after 14 days of status epilepticus.

“We stimulated the dorsal DG with sub-convulsive electrical impulses after SE in freely moving rats and observed sustained severe seizures and electrical responses in 93% of the animals after 14 days of SE.”

NPD1 limited the number of hippocampal microseizures during epileptogenesis.

“Moreover, NPD1 limited the number of hippocampal microseizures during epileptogenesis.”

Reduced dentate gyrus hyper-excitability by NPD1 was associated with protection of somatostatin and calretinin interneuronal cells in the dentate gyrus.

“This study demonstrated that reduced DG hyper-excitability by NDP1 was associated with protection of somatostatin and calretinin interneuronal cells in DG.”

NPD1 administration for 5 days beginning 24 h after status epilepticus was able to reduce spontaneous recurrent seizures.

“NPD1 administration for 5 days beginning 24 h after SE was able to reduce SRS.”

NPD1 restricted spontaneous recurrent seizures, the hallmark of epilepsy.

“Moreover, NPD1 restricted spontaneous recurrent seizures, the hallmark of epilepsy.”

DHA and NPD1 enable cell survival in both in vitro and in vivo models of retinal preconditioning in a mechanism facilitated by 15-LOX-1, which synthesizes NPD1.

“DHA and NPD1 enable cell survival in both in vitro and in vivo models of retinal preconditioning in a mechanism facilitated by 15-LOX-1, which synthesizes NPD1.”

VLC-PUFAs, after shedding and phagocytosis of PRC apical disk membranes, appear transiently in RPE cells, from where they are recycled back to the inner segments of PRCs.

“Moreover, our data indicate that VLC-PUFAs, after shedding and phagocytosis of PRC apical disk membranes, appear transiently in RPE cells, from where they are recycled back to the inner segments of PRCs.”

Attenuation of pHFO during epileptogenesis by NPD1 limits spontaneous recurrent seizures.

“Our results show that attenuation of pHFO during epileptogenesis by NPD1 limits SRS.”

After addition of IL-1β, a time-dependent release of both Aβ40 and Aβ42 was found.

“After the addition of IL-1β, a potent inducer of reactive oxygen species and a promoter of oxidative stress a time-dependent release of both Aβ40 and Aβ42 was found.”

DHA downregulates secretion of Aβ peptides from aging HN cells.

“DHA downregulates secretion of Aβ peptides from aging HN cells.”

• Also stated in: § Alzheimer’s disease: Neuroprotection by NPD1 · plain

  “DHA attenuated Aβ peptide release.”

• Also stated in: § DHA and NPD1 induce pro-homeostatic gene-expression · plain

  “Conversely, DHA suppressed both Aβ40 and Aβ42 peptide release.”

NPD1 (50 nM) protected both neurons and glia from Aβ42-directed apoptosis, as evidenced by quantification of Hoechst 33258 staining of compacted nuclei.

“When NPD1 (50 nM) was added to this test system, NPD1 protected both neurons and glia from Aβ42-directed apoptosis, as evidenced by quantification of Hoechst 33258 staining of compacted nuclei in control, Aβ42-treated, and Aβ42+NPD1-treated cell fields.”

Apoptosis was found to occur in both neurons and glia after Aβ42 treatment.

“Apoptosis was found to occur in both neurons and glia.”

Amyloidogenic Aβ peptides were progressively secreted from HN cells into the incubation medium throughout 8 weeks of culture.

“Amyloidogenic Aβ peptides were progressively secreted from HN cells into the incubation medium throughout 8 weeks of culture.”

Aβ42 peptide-mediated apoptosis in both neurons and glia was counteracted by NPD1 to protect HN cells against Aβ42-induced cytotoxicity.

“The Aβ42 peptide-mediated apoptosis in both neurons and glia were shown to be counteracted by NPD1 to protect HN cells against Aβ42-induced cytotoxicity.”

Aβ42 elevated NPD1 pool size in the presence of added DHA.

“Aβ42 elevated NPD1 pool size in the presence of added DHA.”

NPD1 inhibited Aβ42-induced apoptosis in both glial and neuronal cell populations in a stressed HN cell model.

“In turn, NPD1 inhibited Aβ42-induced apoptosis in both glial and neuronal cell populations in a stressed HN cell model are in concordance with the findings of others on apoptosis in glial and neuronal cells in AD brain (Kitamura et al., 1999; Kobayashi et al., 2004; Paradisi et al., 2004).”

• cites Kitamura et al., 1999 sourceNot checked yet

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• cites Kobayashi et al., 2004 sourceNot checked yet

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• cites Paradisi et al., 2004 sourceNot checked yet

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Bfl-1(A1) was upregulated by DHA and NPD1 to about 4- and 6-fold.

“The antiapoptotic Bcl-2 family member Bfl-1 (A1) was upregulated by DHA and NPD1 to about 4- and 6-fold.”

In HN cells, DHA induced a 5-fold increase in NPD1 at 4 weeks of culture.

“In HN cells, DHA was induced a 5-fold increase in NPD1 at 4 weeks of culture;”

Aβ42-mediated upregulation occurred in expression of genes encoding cytokines IL-1β, CEX-1, TNF-α, COX-2, B94, and proapoptotic Bax and Bik proteins.

“These analyses indicated significant Aβ42-mediated upregulation in the expression of a family of genes encoding the cytokines IL-1β, CEX-1, and TNF-α, COX-2, B94, and the proapoptotic Bax and Bik proteins (Guo et al., 1998; Metcalfe et al., 2004; Tarte et al., 2004).”

• cites Guo et al., 1998 sourceNot checked yet

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• cites Metcalfe et al., 2004 sourceNot checked yet

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• cites Tarte et al., 2004 sourceNot checked yet

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Neither Aβ42 nor sAPPα was able to promote unesterified DHA pool-size changes.

“showed that neither Aβ42 nor sAPPα was able to promote unesterified DHA pool-size changes,”

Exposure of HN cells to IL-1β significantly stimulated both Aβ40 and Aβ42 secretion as a function of HN cell aging.

“Interestingly, exposure of HN cells to the glial cell-derived, pro-inflammatory cytokine IL-1β significantly stimulated both Aβ40 and Aβ42 secretion as a function of HN cell aging.”

In HN cell culture, the Aβ40/Aβ42 ratio was about 10:1 throughout the 8-week period.

“and was about 10:1 throughout the 8-week period of cell incubation.”

Hippocampal CA1 from AD patients shows a dramatic reduction in NPD1.

“A further suggestion of the significance of NPD1 in AD is the observation that hippocampal CA1 from AD patients shows a dramatic reduction in NPD1.”

The complete structures and stereochemistry of elovanoids ELV-N32 and ELV-N34 from neuronal cultures were established through a direct comparison with compounds prepared via stereocontrolled total organic synthesis.

“The complete structures and stereochemistry of elovanoids ELV-N32 and ELV-N34 from neuronal cultures were established through a direct comparison with compounds prepared via stereocontrolled total organic synthesis by adapting our previous method (Petasis et al., 2012).”

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We have identified stereospecific messengers from docosahexaenoate-oxygenation pathways in a mouse stroke model.

“We have identified stereospecific messengers from docosahexaenoate-oxygenation pathways in a mouse stroke model.”

Synthetic ELVs with fully defined structures and stereochemistry allowed determination of the complete R/S configuration as well as the Z/E geometry of the double bonds in mixed neuronal cell culture-derived ELVs.

“These synthetic ELVs with fully defined structures and stereochemistry allowed us to determine the complete R/S configuration as well as the Z/E geometry of the double bonds in these mixed neuronal cell culture-derived ELVs.”

ELVs and their precursors were detected in neuronal cultures under OGD stress.

“ELVs and their precursors were detected in neuronal cultures under OGD stress (Jun et al., 2017).”

• cites Jun et al., 2017 sourceNot checked yet

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We have found a family of bioactive lipid mediators in retina that we call elovanoids (ELVs).

“We have found a family of bioactive lipid mediators in retina that we call elovanoids (ELVs).”

Both ELVs had UV maxima at 275 nm that are consistent with a conjugated triene structure.

“Both ELVs had UV maxima at 275 nm that are consistent with a conjugated triene structure.”

In neural cells in culture, 10,17S-docosatriene inhibited both interleukin 1-β-induced NF-κB activation and cyclooxygenase-2 expression.

“Further, in neural cells in culture, this lipid messenger also inhibited both interleukin 1-β-induced NF-κB activation and cyclooxygenase-2 expression.”

We have demonstrated in ischemia-reperfusion brain the formation of stereospecific DHA-oxygenation pathways that lead to the synthesis of novel messengers.

“Now, we have demonstrated in ischemia-reperfusion brain the formation of stereospecific DHA-oxygenation pathways that lead to the synthesis of novel messengers.”

ELVs protected neurons undergoing OGD or NMDA receptor-mediated excitotoxicity.

“We showed here that the newly identified ELVs protected neurons undergoing OGD or NMDA receptor-mediated excitotoxicity.”

Light-induced oxidative stress in mouse retinas triggers the production of free 32:6n3 and 34:6n3, as well as their mono- and di-hydroxy derivatives.

“Light-induced oxidative stress in mouse retinas triggers the production of free 32:6n3 and 34:6n3, as well as their mono- and di-hydroxy derivatives.”

When cells are confronted with UOS, paracrine or autocrine bioactivity of NPD1 and/or ELVs takes place.

“When cells are confronted with UOS, paracrine or autocrine bioactivity of NPD1 and /or ELVs takes place.”

ELVs target and enhance the expression of pro-survival and pro-homeostatic proteins in RPE cells undergoing UOS.

“Moreover, ELVs target and enhance the expression of pro-survival and pro-homeostatic proteins in the RPE cells undergoing UOS.”

In AdipoR1 KO mice, no detectable amounts of these molecules were found.

“In AdipoR1 KO mice, no detectable amounts of these molecules were found.”

Exogenous administration of 10,17S-docosatriene directly into the cerebroventricular system through continuous infusion during the initial 2 days of reperfusion did exert neuroprotection.

“Therefore, exogenous administration of 10,17S-docosatriene directly into the cerebroventricular system through continuous infusion during the initial 2 days of reperfusion did indeed exert neuroprotection.”

Treatment with ELV-N34 and ELVN34 attenuated NVU disruption induced by MCA-o.

“Treatment with ELV-N34 and ELVN34 attenuated NVU disruption induced by MCA-o.”

• Also stated in: § Docosanoids and ELVs in experimental ischemic stroke · plain

  “ELVs attenuated infarcts, rescued ischemic core and penumbra, diminished NVU damage, and promoted cell survival along with neurological/behavioral recovery (Fig. 3 and 4).”

ELV treatment 1 h after 2 h of MCAo protected neurons, astrocytes, and SMI-71-positive blood vessel cells in the cortex.

“ELV treatment 1 h after 2 h of MCAo protected both neurons, astrocytes and the SMI- 71–positive blood vessel cells in the cortex (Fig. 2).”

The pool size of free 32:6n3 and 34:6n3 in retinas of AdipoR1 KO mice is drastically decreased compared with WT.

“Thus, the pool size of free 32:6n3 and of 34:6n3 in retinas of AdipoR1 KO mice is drastically decreased as compared with that in WT.”

10,17S-docosatriene potently elicited neuroprotection in vivo by reducing the stroke infarct volume 48 h after MCAo.

“Overall, 10,17S-docosatriene potently elicited neuro-protection in vivo by reducing the stroke infarct volume 48 h after MCAo (middle cerebral artery occlusion).”

ELVs attenuated infarcts.

“ELVs attenuated infarcts, rescued ischemic core and penumbra, diminished NVU damage, and promoted cell survival along with neurological/behavioral recovery (Fig. 3 and 4).”

ELVs exerted neuroprotection in a preclinical model of ischemic stroke.

“ELVs exerted neuroprotection as well in a preclinical model of ischemic stroke and have helped us begin deciphering the thus-far elusive molecular principles of DHA-mediated neuroprotection.”

RPE cells play a central role in the conservation and delivery of rod outer segment-derived DHA back to PRCs through the interphotoreceptor matrix following daily phagocytosis of ROS tips.

“By participating in the recycling of DHA, from phagocytized disc membranes back to the retina, RPE cells play a central role in the conservation and delivery of rod outer segment (ROS)-derived DHA back to PRCs through the interphotoreceptor matrix following daily phagocytosis of ROS tips (Gordon et al., 1992).”

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NPD1 is made on demand when homeostatic disruptions such as protein misfolding, Aβ peptide challenge, and/or uncompensated oxidative stress emerge, prompting responses to counteract neuroinflammation and neurodegeneration.

“NPD1 is made on-demand when homeostatic disruptions, such as protein misfolding, Aβ peptide challenge, and/or uncompensated oxidative stress (UOS), emerge (Bazan et al., 2011a), prompting responses to counteract neuroinflammation consequences and neurodegeneration (Bazan, 2006).”

• cites Bazan et al., 2011aNot checked yet

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• cites Bazan, 2006 sourceNot checked yet

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CEX-1 is a marker for inflammatory and oxidative stress responses.

“CEX-1 (GenBank U64197) is a marker for inflammatory and oxidative stress responses (Colangelo et al., 2002; McGeer and McGeer, 2003),”

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• cites McGeer and McGeer, 2003Not checked yet

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ELOVL4 elongates DHA to 32-38 carbons (VLC-PUFAs) in PRCs.

“ELOVL4 (ELOngation of Very Long chain fatty acids-4) elongates DHA to 32-38 carbons (VLC-PUFAs) in PRCs.”

NPD1 restores neuronal network homeostasis during epileptogenesis.

“Therefore, NPD1 restores neuronal network homeostasis during epileptogenesis.”

A drop out of 11-41% of neurons is insufficient to account for the 20-fold reduction in NPD1 pool size in Alzheimer's disease hippocampus compared with age-matched controls.

“Thus, a drop out of 11–41% of neurons is insufficient to account for the 20-fold reduction in NPD1 pool size in AD hippocampus when compared with age-matched controls.”

AdipoR1 is necessary for the synthesis of VLC-PUFAs and their distribution in phospholipids in normal healthy retinas.

“Thus, AdipoR1 is necessary for the synthesis of VLC-PUFAs and their distribution of phospholipids in normal healthy retinas.”

Decreased abundance of NPD1 in Alzheimer's disease brain may be explained, at least in part, by a disruption in the expression and regulation of the PLA2 and/or 15-LOX-like enzymes essential for NPD1 biosynthesis.

“Decreased abundance of NPD1 in AD brain may be explained, at least in part, by a disruption in the expression and regulation of the PLA2 and/or 15-LOX-like enzymes essential for NPD1 biosynthesis.”

The finding that PC-VLC-PUFAs are reduced when AdipoR1 is ablated provides the first mechanistic explanation of the requirements to sustain the key pathway for PRC survival.

“Our findings that PC-VLC-PUFAs are reduced when AdipoR1 is ablated provides the first mechanistic explanation of the requirements to sustain this key pathway for PRC survival.”

RPE cells do not have the ability to biosynthesize VLC-PUFAs.

“Therefore, RPE cells do not have the ability to biosynthesize VLC-PUFAs.”

Mesencephalic TH-positive neuron cell damage and death is not a direct consequence of mitochondrial dysfunction alone, since rotenone did not elicit a similar effect.

“These findings suggest that mesencephalic TH-positive neurons cell damage and death is not a direct consequence of mitochondrial dysfunction alone (rotenone does not elicited a similar effect).”

There is a therapeutic window for downregulating epileptogenesis during the first week after status epilepticus under the present conditions.

“Therefore, our study indicates that there is a therapeutic window for a down regulating of epileptogenesis during the first week after SE under the present conditions.”

NPD1 rescues vulnerable dendritic spines overactivated after status epilepticus.

“Our results suggest that NPD1 rescues vulnerable dendritic spines overactivated after SE (Mattson and Duan, 1999; Tao and Rolls, 2011).”

• cites Mattson and Duan, 1999Not checked yet

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• cites Tao and Rolls, 2011Not checked yet

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The protective signaling demonstrated by preconditioning is specific to docosanoid signaling, despite the concomitant release of omega-6 arachidonic acid and eicosanoid synthesis.

“The protective signaling demonstrated by preconditioning is specific to docosanoid signaling, despite the concomitant release of the omega-6 AA and eicosanoid synthesis (Knott et al., 2018).”

• cites Knott et al., 2018 sourceNot checked yet

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Ablation of Mfsd2a does not lead to retinal degeneration.

“However, the ablation of Mfsd2a does not lead to retinal degeneration.”

Noxious stimuli orchestrate pathogenic gene-expression programs in stressed brain cells, linking caspase-mediated cell death pathways with apoptosis and neuronal demise.

“These noxious stimuli further orchestrate pathogenic gene-expression programs in stressed brain cells, thereby linking a cascade of caspase-mediated cell death pathways with apoptosis and neuronal demise (Bazan and Lukiw, 2002; Lahiri et al., 2003).”

• cites Bazan and Lukiw, 2002Not checked yet

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• cites Lahiri et al., 2003 sourceNot checked yet

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Since NPD1 inhibits Aβ42-induced apoptosis in HN cells, DHA protection in cells in culture and in in vivo models may involve NPD1 synthesis.

“Since NPD1 inhibits Aβ42-induced apoptosis in HN cells, DHA protection in cells in culture and in in vivo models may involve NPD1 synthesis.”

sAPPα may activate NPD1 biosynthetic enzymes PLA2 and/or a 15-LOX-like enzyme integral to NPD1 biosynthesis.

“sAPPα may activate NPD1 biosynthetic enzymes PLA2 and/or a 15-LOX– like enzyme integral to NPD1 biosynthesis (Calandria et al., 2009; Marcheselli et al., 2003).”

• cites Calandria et al., 2009 sourceNot checked yet

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• cites Marcheselli et al., 2003 sourceNot checked yet

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DHA attenuates lipid peroxides and reactive oxygen species in the cerebral cortex and the hippocampus of Aβ-infused rats.

“DHA attenuates lipid peroxides and reactive oxygen species in the cerebral cortex and the hippocampus of Aβ-infused rats, suggesting that DHA elicits neuroprotection by blocking Aβ40/Aβ42 neurotoxicity (Calon et al., 2004; Hashimoto et al., 2005)”

• cites Calon et al., 2004 sourceNot checked yet

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• cites Hashimoto et al., 2005 sourceNot checked yet

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Some of the neurotrophic activity of sAPPα may be elicited, at least in part, by an upregulation in the biosynthesis of NPD1 as a complementary cell-survival mechanism activated early in AD pathogenesis.

“Some of the neurotrophic activity of sAPPα may be elicited, at least in part, by an upregulation in the biosynthesis of NPD1 as a complementary cell-survival mechanism activated early in AD pathogenesis.”

Tight regulation of unesterified DHA may take place when sAPPα (100 μM) activates NPD1 production in the absence of added exogenous DHA.

“indicating that a tight regulation of unesterified DHA may take place when sAPPα (100 μM) activates NPD1 production in the absence of added exogenous DHA.”

Neural mechanisms leading toward NPD1 generation from DHA appear to redirect cellular fate toward successful brain cell aging.

“Neural mechanisms leading toward NPD1 generation from DHA thereby appear to redirect cellular fate toward successful brain cell aging.”

NPD1 biosynthesis is enhanced by the neurotrophic peptide sAPPα, a 612-amino acid fragment derived from α-secretase-mediated cleavage of βAPP.

“Furthermore, NPD1 biosynthesis is enhanced by the neurotrophic peptide sAPPα, a 612-amino acid fragment derived from α-secretase-mediated cleavage of βAPP (Guo et al., 1998; Selkoe and Kopan, 2003).”

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• cites Selkoe and Kopan, 2003Not checked yet

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sAPPα generated via the α-secretase pathway does not give rise to shorter amyloidogenic Aβ peptides.

“sAPPα generated via the α-secretase pathway does not give rise to the shorter amyloidogenic Aβ peptides;”

• cites Bahr et al., 1998 sourceNot checked yet

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• cites Bazan, 2003 sourceNot checked yet

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• cites Selkoe and Kopan, 2003Not checked yet

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Muscarine, a positive regulator of PLA2, is a potent inducer of sAPPα in human neuroblastoma SH-SY5Y cells.

“It is interesting that muscarine, a positive regulator of PLA2, is also a potent inducer of sAPPα in human neuroblastoma SH-SY5Y cells (Webster et al., 2002; Wood et al., 2000);”

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• cites Wood et al., 2000 sourceNot checked yet

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IL-1β directly stimulates γ-secretase-mediated cleavage of βAPP into Aβ peptides through a JNK-dependent MAPK pathway.

“IL-1β directly stimulates γ-secretase-mediated cleavage of βAPP into Aβ peptides through a JNK-dependent MAPK pathway (Liao et al., 2004).”

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Shunting βAPP into the α-secretase pathway may be beneficial by relative lowering of Aβ peptide abundance.

“hence, the shunting of βAPP into the α-secretase pathway may be beneficial by the relative lowering of Aβ peptide abundance”

DHA attenuation of Aβ peptide neurotoxicity in aging HN cells could be mediated, at least in part, by NPD1.

“suggesting that in aging HN cells, attenuation of the Aβ peptide neurotoxicity by DHA could be mediated, at least in part, by NPD1.”

Enzymatic pathways involving PLA2-mediated DHA and NPD1 biosynthesis may exhibit positive feedback regulation through sAPPα.

“therefore, the enzymatic pathways involving PLA2-mediated DHA and NPD1 biosynthesis may exhibit positive feedback regulation through sAPPα.”

The interplay of DHA-derived neuroprotective signaling aims to counteract proinflammatory, cell-damaging events triggered by multiple, converging cytokine and amyloid peptide factors in AD.

“Therefore, the interplay of DHA-derived neuroprotective signaling aims to counteract proinflammatory, cell-damaging events triggered by multiple, converging cytokine and amyloid peptide factors in AD.”

Reperfusion after experimental ischemic stroke triggers lipid peroxidation and cellular damage including neuronal injury.

“Reperfusion after experimental ischemic stroke triggers lipid peroxidation and cellular damage including neuronal injury.”

These ≥ 28 carbons VLC fatty acids are critical to brain function.

“These ≥ 28 carbons VLC fatty acids are critical to brain function (Bhattacharjee et al., 2017; Demaerschalk et al., 2016; Jun et al., 2017; Poulin et al., 2016; Rau et al., 2012; Tasca et al., 2015; Tasic et al., 2016; Zeisel et al., 2015; Zhang et al., 2014).”

• cites Bhattacharjee et al., 2017 sourceNot checked yet

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• cites Demaerschalk et al., 2016 sourceNot checked yet

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• cites Jun et al., 2017 sourceNot checked yet

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The precursors of ELVs are made by the elongase ELOVL4 that converts C26-derived fatty acids from eicosapentaenoic acid (EPA) or DHA to very long chain polyunsaturated fatty acids (≥C28).

“The precursors of ELVs are made by the elongase ELOVL4 that converts C26-derived fatty acids from eicosapentaenoic acid (EPA) or DHA to very long chain polyunsaturated fatty acids (≥C28).”

The pathways have the potential for exerting counter-regulatory cellular and molecular signaling in brain injury.

“The pathways have the potential for exerting counter-regulatory cellular and molecular signaling in brain injury.”

Further validation of the structural assignments was established by synthesizing stereochemically pure deuterium-labeled ELVs and matching them with endogenously produced molecules in neuronal cultures by liquid chromatography tandem mass spectrometry (LC-MS/MS).

“Further validation of these structural assignments was established by synthesizing stereochemically pure deuterium-labeled ELVs, and by matching them with endogenously produced molecules in neuronal cultures by liquid chromatography tandem mass spectrometry (LC-MS/MS), we further confirmed their structure and stereochemistry.”

In mouse brain undergoing ischemia/reperfusion, NPD1 increases during the initial 8 hours after 1 h of ischemia.

“In mouse brain undergoing ischemia/reperfusion, NPD1 increases during the initial 8 hours after 1 h of ischemia (Marcheselli et al., 2003).”

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DHA is the endogenous precursor to a neuroprotective signaling response mediator to ischemia-reperfusion.

“These results not only contest the notion that DHA participates solely in brain damage but also demonstrate that this fatty acid is the endogenous precursor to a neuroprotective signaling response mediator to ischemia-reperfusion.”

Shortage in key protective mediators derived from VLC-PUFAs may be a key factor in these diseases.

“Thus, shortage in key protective mediators derived from VLC-PUFAs may be a key factor in these diseases.”

DHA elicits neuroprotection by blocking Aβ40/Aβ42 neurotoxicity.

“suggesting that DHA elicits neuroprotection by blocking Aβ40/Aβ42 neurotoxicity”

NPD1 biosynthesis from DHA seems to redirect brain cell fate toward counteracting cell-aging events.

“NPD1 biosynthesis from DHA seems to redirect brain cell fate toward counteracting cell-aging events.”

In post-mortem brain, the differences found between age-matched controls and AD brains point to the relative inability of the AD CA1 region to accumulate NPD1.

“In the post-mortem brain, the differences found between age-matched controls and AD brains point to the relative inability of the AD CA1 region to accumulate NPD1.”

Neurons and PRCs express the elongase enzyme ELOVL4, which catalyzes the biosynthesis of (≥C28) omega-3 very long chain polyunsaturated fatty acids (VLC-PUFAs).

“Neurons and PRCs express the elongase enzyme ELOVL4, which catalyzes the biosynthesis of (≥C28) omega-3 (n-3) very long chain polyunsaturated fatty acids (VLC-PUFAs).”

During 24-72 h of reperfusion is when most brain leukocyte infiltration occurs.

“During 24–72 h of reperfusion is when most brain leukocyte infiltration occurs (Chatzipanteli et al., 2000; Chopp et al., 1996; Matsuo et al., 1994; Royo et al., 1999).”

• cites Chatzipanteli et al., 2000 sourceNot checked yet

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• cites Chopp et al., 1996 sourceNot checked yet

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• cites Matsuo et al., 1994 sourceNot checked yet

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The relatively large ischemic insult produced by 1 h of MCAo followed by several h of reperfusion may overcome the ability of the endogenously generated docosanoids to elicit neuroprotection.

“Thus, the relatively large ischemic insult produced by 1 h of MCAo followed by several h of reperfusion may overcome the ability of the endogenously generated docosanoids to elicit neuroprotection.”

ELV availability is abolished in the retinas of mice with genetically ablated AdipoR1.

“ELV availability is abolished in the retinas of mice with genetically ablated AdipoR1 (Jun et al., 2017).”

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DHA and NPD1 display potent neuroprotective bioactivity when given 1 hour after 2 hours of MCAo in rats.

“DHA and NPD1 display potent neuroprotective bioactivity when given 1 hour after 2 hours of MCAo in rats (Bazan et al., 2012; Belayev et al., 2018, 2017, 2011; Calandria et al., 2015; Eady et al., 2012; Hong et al., 2015, 2014; Serhan et al., 2011).”

• cites Bazan et al., 2012 sourceNot checked yet

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• cites Belayev et al., 2018, 2017, 2011Not matched

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• cites Calandria et al., 2015 sourceNot checked yet

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ELVs are the first identified bioactive mediators from VLC-PUFA,n-3, which are the biosynthetic products of elongase ELOVL4.

“ELVs are the first identified bioactive mediators from VLC-PUFA,n-3, which are the biosynthetic products of elongase ELOVL4.”

The pathway in which 32:6n-3 or 34:6n-3 yield novel mediators of 32 C or 34 C length contrasts with most known lipid mediators derived from 20 C or 22 C length precursors.

“This newly discovered pathway that 32:6n-3 or 34:6n-3 yield novel mediators of 32 C or 34 C in length, contrasts to most known lipid mediators derived from 20 C or 22 C length precursors.”

NPD1 is a neuroprotective mediator in ischemic stroke, as defined by cellular and molecular targets.

“NPD1 is highlighted here as a neuroprotective mediator in ischemic stroke, as defined by cellular and molecular targets, and demonstrated that the pathway that leads to its formation was enhanced in its neuroprotective bioactivity by the presence of aspirin (Marcheselli et al., 2003) by aspirin-triggered NPD1 (Bazan et al., 2012; Serhan et al., 2015; Serhan and Petasis, 2011).”

• cites Marcheselli et al., 2003 sourceNot checked yet

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• cites Bazan et al., 2012 sourceNot checked yet

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• cites Serhan et al., 2015 sourceNot checked yet

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AdipoR1 is necessary for DHA availability to PRCs.

“Recently, we found that AdipoR1 is necessary for DHA availability to PRCs (Rice et al., 2015)”

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In the RPE, UOS or other disruptors of homeostasis trigger the release of 32:6n3 and 34:6n3, which generate a hydroperoxyl and subsequently ELV-N32 or ELV-N34, respectively.

“In the RPE, UOS or other disruptors of homeostasis triggers the release of 32:6n3 and 34:6n3 that in turn generate a hydroperoxyl and subsequently an ELV-N32 or ELV-N34, respectively.”

Leukocytes accumulate in an area surrounding the infarct and are thought to possess a multifactorial ability to promote injury in brain ischemia-reperfusion.

“Leukocytes accumulate in an area surrounding the infarct and are thought to possess a multifactorial ability to promote injury in brain ischemia-reperfusion (Hallenbeck and Kochanek, 1998).”

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The findings of ELVs open a different mechanistic perspective compared with other endogenous pro-homeostatic and neuroprotective signaling because they stem from a phospholipid molecular species endowed with acyl chains with two different PUFA precursors of bioactive lipids, VLC-PUFAs and DHA.

“The findings of ELVs open a different mechanistic perspective as compared with other endogenous pro-homeostatic and neuroprotective signaling because they stem from a phospholipid molecular species that is endowed with acyl chains with two different PUFA precursors of bioactive lipids, VLC-PUFAs and DHA (Fig 1).”

PMN infiltration as well as amoeboid microglia along the edges of the stroke infarct may be responsible for expansion of the penumbra region, which occurs from 16 h onward after MCAo followed by reperfusion.

“Moreover, PMN in-filtration as well as amoeboid microglia along the edges of the stroke infarct may be responsible for expansion of the penumbra region, which occurs from 16 h onward after MCAo followed by reperfusion (Mabuchi et al., 2000).”

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VLC-PUFA,n-3 are precursors of novel bioactive mediators that elicit pro-homeostatic protective PRC bioactivity.

“These observations support the concept that VLC-PUFA,n-3 are precursors of novel bioactive mediators that elicit pro-homeostatic protective PRC bioactivity.”

The endogenous brain synthesis of 10,17S-docosatriene that peaks at 8 h of reperfusion may be a response of insufficient magnitude to counteract leukocyte infiltration and pro-inflammatory gene induction under the present experimental conditions.

“The endogenous brain synthesis of 10,17S-docosatriene that peaks at8hof reperfusion may be a response of such insufficient magnitude as to counteract leukocyte infiltration and pro-inflammatory gene induction under the present experimental conditions.”

Under conditions of stress, VLC-PUFAs are cleaved by phospholipase A1 (PLA1) for the synthesis of mono- and di-hydroxy VLC-PUFAs (ELVs).

“However, under conditions of stress, these VLC-PUFAs are cleaved by phospholipase A1 (PLA1) for the synthesis of mono- and di-hydroxy VLC-PUFAs (ELVs).”

A single amino acid mutation in AdipoR1 is causative of autosomal dominant retinitis pigmentosa.

“others have found that a single amino acid mutation in this receptor is causative of autosomal dominant retinitis pigmentosa (Zhang et al., 2016).”

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The outcome of infusing 10,17S-docosatriene (NPD1) is neuroprotective against ischemia-reperfusion damage.

“What is clear is that the outcome of infusing 10,17S-docosatriene (NPD1) is neuroprotective against ischemia-reperfusion damage.”

ELVs and docosanoids, including NPD1, drive the process by which a potential network of new pathways and synergies for neuroprotection might operate.

“The complex network of neuroinflammation responses, which is beneficially targeted by ELVs at the onset of reperfusion after an ischemic stroke, is also uncovering the transcriptional activation of genes; thus, ELVs and docosanoids, including NPD1 drive the process by which a potential network of new pathways and synergies for neuroprotection might operate.”

10,17S-docosatriene is neuroprotective.

“This observation implies that 10,17S-docosatriene is neuroprotective.”

Aspirin enhances the neuroprotective bioactivity of the pathway leading to NPD1 formation.

“NPD1 is highlighted here as a neuroprotective mediator in ischemic stroke, as defined by cellular and molecular targets, and demonstrated that the pathway that leads to its formation was enhanced in its neuroprotective bioactivity by the presence of aspirin (Marcheselli et al., 2003) by aspirin-triggered NPD1 (Bazan et al., 2012; Serhan et al., 2015; Serhan and Petasis, 2011).”

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• cites Bazan et al., 2012 sourceNot checked yet

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• cites Serhan et al., 2015 sourceNot checked yet

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The failure of brain cells to survive ischemia-reperfusion damage may not be due to biology gone awry, but rather due to specific signals and mechanisms intended to be protective in the face of homeostasis disruptions that lead to neural circuits dysfunctions.

“The mechanistic cellular and molecular principles unraveled thus far should be instructive for stroke treatment translation because the failure of brain cells to survive ischemia-reperfusion damage may not be due to biology gone awry, but rather due to specific signals and mechanisms intended to be protective in the face of homeostasis disruptions that lead to neural circuits dysfunctions (Bazan,”

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Despite low abundance of EPA in the retina compared to DHA, ELOVL4 uses EPA as a preferred substrate.

“Despite the low-abundance of EPA in the retina compared to DHA, ELOVL4 uses EPA as a preferred substrate (Yu et al., 2012).”

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The structure and stereochemistry of ELV-N32 and ELV-N34 was established.

“The structure and stereochemistry of ELVs with 32 and 34 carbons (ELV-N32, ELV-N34) was established (Bhattacharjee et al., 2017; Jun et al., 2017).”

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These findings revealed a different signal bifurcation pro-homeostatic and neuroprotective mechanism to sustain neural cell integrity.

“Therefore, these findings revealed a different signal bifurcation pro-homeostatic and neuroprotective mechanism to sustain neural cell integrity.”

The potent bioactivity of docosanoids and ELVs demonstrates the existence of endogenous critical defenses and targets for preventive and potential therapeutic neuroprotective interventions in diseases involving neuroinflammatory/immune components.

“The potent bioactivity of docosanoids and ELVs demonstrates the existence of endogenous critical defenses and targets for preventive (dietary/life style/behavioral modification strategies) and for potential therapeutic neuroprotective interventions in these diseases.”

• AssumptionRests on an assumption: Inflammation is a common early event in many chronic diseases, especially neurodegenerative diseases.

ELVs as a therapeutic agent have the potential for focal ischemic stroke and other conditions that engage inflammatory/homeostatic disruptions.

“ELVs as a therapeutic agent have the potential for focal ischemic stroke and other conditions that engage inflammatory/homeostatic disruptions.”

• AssumptionRests on an assumption: Inflammation is a common early event in many chronic diseases, especially neurodegenerative diseases.

The molecular protective preconditioning signaling of DHA and of NPD1 are the bases for acquired protection or resilience when the retina, an integral part of the CNS, is confronted with a lethal stimulus.

“Therefore, the molecular protective preconditioning signaling of DHA and of NPD1 are the bases for acquired protection or resilience when the retina, an integral part of the CNS, is confronted with a lethal stimulus.”