AP001 / Anida Pharma - LARVOL DELTA

Cerebrospinal Fluid Profile of Lipid Mediators in Alzheimer's Disease. (PubMed, Cell Mol Neurobiol) - "Resolvin (Rv) D4, RvD1, neuroprotectin D1 (NPD1), maresin 1 (MaR1), and RvE4 were lower in AD and/or MCI compared to SCI...RvD4 was also negatively correlated to AD tangle biomarkers, and positive correlations to cognitive test scores were observed for both pro-resolving LMs and their precursor fatty acids. In this exploratory study of the lipidome in CSF of AD, MCI, and SCI, the results indicate a shift in the LM profile from pro-resolving to pro-inflammatory in progression to AD, suggesting that it may be of use as a biomarker when followed by confirmation by replication studies."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Immunology • Inflammation

Intranasal delivery of pro-resolving lipid mediators rescues memory and gamma oscillation impairment in App mice. (PubMed, Commun Biol) - "A mixture of the pro-resolving LMs resolvin (Rv) E1, RvD1, RvD2, maresin 1 (MaR1) and neuroprotectin D1 (NPD1) was administered to stimulate their respective receptors...The treatment ameliorated memory deficits accompanied by a restoration of gamma oscillation deficits, together with a dramatic decrease in microglial activation. These findings open potential avenues for therapeutic exploration of pro-resolving LMs in AD, using a non-invasive route."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Immunology • Inflammation

Identification of Scytalone Dehydratase Inhibitors Effective against Melanin Biosynthesis Dehydratase Inhibitor-Resistant Pyricularia oryzae. (PubMed, J Agric Food Chem) - "NPD13731 strongly inhibited the activity of wild-type and mutant SDH1. The structure-activity relationship data were used to create a more potent inhibitor 16, which controlled rice blast disease in rice plants infected with MBI-D-resistant P. oryzae. Compound 16, which we named melabiostin, may be used to develop fungicides for controlling rice blast infections."

Journal • Infectious Disease • SDHB

Effective Combination Therapy For Experimental Stroke: Synergistic Neuroprotection By Lau-0901 And At-npd1 (ISC 2022) - "Following small bioactive molecules were investigated: LAU-0901 (LAU), PAF-R antagonist that blocks pro-inflammatory signaling, and aspirin-triggered neuroprotectin D1 (AT-NPD1), which activates cell-survival pathways, and their combination that exerts potent anti-inflammatory activity in the brain. LAU-0901 and AT-NPD1 alone provide high-grade neuroprotection. Combination therapy with LAU-0901 and AT-NPD1 is more effective than the single therapy, affording synergistic neuroprotection with improved behavior when administered up to 6 h after MCAo in rats."

Combination therapy • Cardiovascular • CNS Disorders • Immunology • Inflammation • Vascular Neurology

Favorable Outcome In Intracerebral Hemorrhage Is Associated With With Higher 15-lox-1 Expression (ISC 2022) - "The increased expression of 15-LOX-1 suggests a significant synthesis and abundance of NPD1 in patients with MRS 0-3 compared with patients with MRS 4-6 and suggests that early synthesis and abundance of NPD1 is likely an important protective mediator in ICH pathophysiology"

Cerebral Hemorrhage • Hematological Disorders • ALOX15 • GAPDH

Docosanoids Protect Inflammation-induced Brain Damage And Lead To Neurological Recovery In Experimental Stroke (ISC 2022) - "We show that NPD1, RvD1 alone provides high-grade neuroprotection against inflammation and elicit neurological recovery in the MCAo model. Combination therapy with NPD1 and RvD1 is more effective than the single therapy when administered up to 6h after focal cerebral ischemia in rats. Thus, we hypothesize that these treatments may potentially be used in treating focal ischemic stroke in the clinical setting."

Cardiovascular • CNS Disorders • Immunology • Inflammation • Ischemic stroke • Vascular Neurology

Multi-pathway i n vitro pharmacological characterisation of specialised pro-resolving G protein-coupled receptors (SPM-GPCRs). (PubMed, Mol Pharmacol) - "We also identified neuroprotectin D1 as a new BLT agonist, implying an alternative target for the neuroprotective effects of the ligand...This study investigates receptor poly-pharmacology and discovers new ligand pairings, refutes others, and identifies biased agonism in FPR2/ALX pharmacology. This study further highlights the potential of these receptors in treating specific autoimmune diseases including rheumatoid arthritis, systemic scleroderma, and systemic lupus erythematosus."

Journal • Fibrosis • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Multiple Sclerosis • Rheumatoid Arthritis • Rheumatology • Scleroderma • Systemic Lupus Erythematosus • Systemic Sclerosis • ARRB1 • CD8 • FPR2

Computational studies to identify the common type-I and type-II inhibitors against the CDK8 enzyme. (PubMed, J Cell Biochem) - "Apart from one of the complexes of DMG-in (5XS2-UNPD163102), all other complexes displayed stable dynamic behavior. The interaction and stability studies of the docked complexes were compared with the references selected from the two conformations (DMG-in and out) of the protein. The current work leads to the identification of three common DMG-in and out hits with diverse scaffolds which can be employed as the initial leads for the design of the novel CDK8 inhibitors."

Journal

Neuroprotectin D1, a lipid anti-inflammatory mediator, in patients with intracerebral hemorrhage. (PubMed, Biochimie) - "NPD1 was abundant and significantly higher in ICH patients with MRS 0-3.15-LOX-1 was significantly under-expressed in patients with MRS 4-6. Early synthesis and abundance of NPD1 is likely an important protective mediator in ICH pathophysiology."

Clinical • Journal • Cerebral Hemorrhage • Hematological Disorders • ALOX15 • OLR1

Neuroprotection by PAF-receptor antagonist plus a lipid mediator against experimental focal cerebral ischemia (Neuroscience 2021) - "Two different types of small bioactive molecules were investigated: LAU-0901 (LAU), PAF-R antagonist that blocks pro-inflammatory signaling, and aspirin-triggered neuroprotectin D1 (AT-NPD1), which activates cell-survival pathways, and their combination that exerts potent anti-inflammatory activity in the brain. In conclusion, these data suggest that LAU-0901 and AT-NPD1 alone in moderate doses provide high-grade neuroprotection in the MCAo model. Combination therapy with LAU-0901 and AT-NPD1 is more effective than the single therapy, affording synergistic neuroprotection with improved neurological recovery when administered up to 6 h after focal cerebral ischemia in rats.; Grant Support: Brazilian CAPES (88881.311939/2018-01); NIH Grant R01NS104117; NIH Grant R01109221"

CNS Disorders • MRI

Neuroprotectin D1 analogue modulates spinal cord synaptic transmission in a mouse model of chronic itch (Neuroscience 2021) - "2010; 16(5):592-7Nesman et al., Org Biomol Chem. 2021; 19(12):2744-2752."

Preclinical • CNS Disorders

Protecting against experimental ischemic stroke with pro-homeostatic docosanoids (Neuroscience 2021) - "This study focuses on the neuroprotective bioactivity of docosanoid (DOC) mediators: Neuroprotectin D1 (NPD1), Resolvin D1 (RvD1), and their combination (NPD1+RvD1) against experimental ischemic stroke...These treatments might provide the basis for future therapeutics for patients suffering from ischemic stroke. This study was supported by NIH, NINDS grant R01NS104117, R01109221 (NGB and LB), and Brazilian CAPES (88881.311939/2018-01) (CRR); Grant Support: Brazilian CAPES (88881.311939/2018-01); NIH, NINDS grant R01109221; NIH, NINDS grant R01NS104117"

CNS Disorders • MRI

AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration. (PubMed, Commun Biol) - "Downstream of ADIPOR1 sustained activation of AMPK renders it insensitive to changes in AMP/ATP ratio resulting in defective lipid metabolism, reduced Neuroprotectin D1(NPD1) secretion, lower mitochondrial respiration, and reduced ATP production. Gene augmentation of L-ORD-iRPE with WT CTRP5 or modulation of AMPK, by metformin, re-sensitize L-ORD-iRPE to changes in cellular energy status alleviating the disease cellular phenotypes. Our data suggests a mechanism for the dominant behavior of CTRP5 mutation and provides potential treatment strategies for L-ORD patients."

Journal • Metabolic Disorders • Ophthalmology • AMPK

Abrogation of SARS-CoV-2 interaction with host (NRP1) neuropilin-1 receptor through high-affinity marine natural compounds to curtail the infectivity: A structural-dynamics data. (PubMed, Comput Biol Med) - "We discovered that the binding affinity of CMNPD10175, CMNPD10017, CMNPD10114, CMNPD10115, CMNPD10020...Consequently, we hypothesized that these compounds might be the best lead candidates for therapeutic interventions hindering virus binding to the host cell. This study provides a strong impetus to develop novel drugs against the SARS-CoV-2 by targeting NRP1."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • NRP1

NPD1 Enhances Autophagy and Reduces Hyperphosphorylated Tau and Amyloid-β42 by Inhibiting GSK3β Activation in N2a/APP695swe Cells. (PubMed, J Alzheimers Dis) - "NPD1 might minimize cell apoptosis, downregulate Aβ expression, control tau hyperphosphorylation, and enhance autophagy activity in AD cell models to promote neuronal survival. NPD1's neuroprotective effects may be mediated via decreasing GSK-3β."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Metabolic Disorders

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Licensing / partnership

In Vitro Biosynthetic Pathway Investigations of Neuroprotectin D1 (NPD1) and Protectin DX (PDX) by Human 12-Lipoxygenase, 15-Lipoxygenase-1, and 15-Lipoxygenase-2. (PubMed, Biochemistry) - "Finally, 17S-HpDHA and PDX inhibited platelet aggregation, with EC values of approximately 1 and 3 μM, respectively. The in vitro results presented here may help advise in vivo PDX and NPD1 intermediate (i.e., 16S,17S-epoxyDHA) biosynthetic investigations and support the benefits of DHA rich diets."

Journal • Preclinical • PD-1

Virtual discovery of a hetero-cyclic compound from the Universal Natural Product Database (UNPD36) as a potential inhibitor of interleukin-33: molecular docking and dynamic simulations. (PubMed, J Biomol Struct Dyn) - "Six hundred compounds with high gastrointestinal absorption properties from the UNPD were retrieved and subjected to molecular docking using Autodock Vina, out of which four hetero-cyclic compounds (UNPD36, UNPD2045, UNPD8905, UNPD122514) were found to have binding energy score of < -7.0 Kcal/mol...Finally, chemoinformatic studies revealed that the UNPD36 had drug-like and pharmacokinetic profiles as well as potentials for oral and topical applications, in addition to good safety profile. Thus, it was concluded that a hetero-cyclic compound with chromone moiety (UNPD36) had a good and stable binding mode to serve as potential inhibitor of IL-33 and/or may provide a scaffold for further optimization toward the design of more potent inhibitors for application in the treatment of respiratory allergies.Communicated by Ramaswamy H. Sarma."

Journal • Allergy • Gastrointestinal Disorder • Immunology • Inflammation • Respiratory Diseases

[VIRTUAL] Pro-Homeostatic Docosanoids Exert Remarkable Neurological Recovery After Experimental Stroke (ISC 2021) - "We have shown that treatment with NPD1, RvD1 alone, and combination therapy provides high-grade neurobehavioral recovery and decreases ischemic core and penumbra volumes. Taken together, these findings support the potential clinical feasibility of administering novel docosanoid therapy to patients with acute ischemic stroke."

Late-breaking abstract • Anesthesia • Cardiovascular • Immunology • Inflammation • Ischemic stroke • MRI

[VIRTUAL] Concerted Neuroprotection by a PAF-Receptor Antagonist Plus an Inflammatory Response Modulator in Experimental Ischemic Stroke (ISC 2021) - "The following small molecules were investigated: LAU-0901 (LAU), a PAF-R antagonist that blocks pro-inflammatory signaling, Aspirin-triggered NPD1 (AT-NPD1), which activates cell-survival pathways, and their combination are exerting potent anti-inflammatory activity in the brain. SD rats were anesthetized and received 2h MCAo. Combination therapy with LAU-0901 and AT-NPD1 is more effective than the single therapy, affording synergistic neuroprotection with improved neurological recovery. Altogether, our findings support combinatory therapy as the basis for future therapeutics for ischemic stroke."

Late-breaking abstract • Anesthesia • Cardiovascular • Inflammation • Ischemic stroke • Solid Tumor • MRI

Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice. (PubMed, Nat Commun) - "Moreover, ablation of macrophages potentiated infection, sepsis, and their sequelae, whereas adoptive transfer of NPD1- or ARU-primed macrophages reduced infection, sepsis, and pain-like behaviors. Our findings reveal physiological actions of ARU in host cells by activating macrophages and suggest that GPR37 agonists may help to treat sepsis, bacterial infections, and malaria."

Journal • Preclinical • Infectious Disease • Malaria • Pain • Septic Shock

Overview of how N32 and N34 elovanoids sustain sight by protecting retinal pigment epithelial cells and photoreceptors. (PubMed, J Lipid Res) - "An important lesson on neuroprotection is highlighted by the ELV mediators that target the terminally differentiated PRC and RPE, sustaining a beautifully synchronized renewal process. The role of ELVs in PRC and RPE viability and function uncovers insights on disease mechanisms and the development of therapeutics for age-related macular degeneration (AMD), Alzheimer's disease (AD), and other pathologies."

Journal • Review • Age-related Macular Degeneration • Alzheimer's Disease • CNS Disorders • Complement-mediated Rare Disorders • Immunology • Inflammation • Macular Degeneration • Ophthalmology • Retinal Disorders

Docosanoid signaling modulates corneal nerve regeneration: effect on tear secretion, wound healing, and neuropathic pain. (PubMed, J Lipid Res) - No abstract available

Journal • Review • Dry Eye Disease • Neuralgia • Ophthalmology • Pain • Peripheral Neuropathic Pain

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Interview

Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke. (PubMed, Brain Circ) - "Combination therapy with LAU-0901 and selected docosanoids is more effective than the single therapy, affording synergistic neuroprotection, with restored pro-homeostatic lipid mediators and improved neurological recovery. Altogether, our findings support the combinatory therapy as the basis for future therapeutics for ischemic stroke."

Journal • Cardiovascular • Immunology • Inflammation • Ischemic stroke • Reperfusion Injury • MRI