paquinimod (ABR-215757) / Active Biotech - LARVOL DELTA

Identification of S100A9 as a target for diagnosis and treatment of Crohn's Disease after Vedolizumab treatment failure. (PubMed, Immunol Lett) - "Through flow cytometry, changes in the composition of immune cell populations in colon tissues were found after intragastric administration of paquinimod, an inhibitor of S100A9. It is important that blocking S100A9 inhibited the recruitment of neutrophils in the mice's colon. Our findings lay a foundation for the further exploration of the new targets for non-responders to vedolizumab in CD patients."

Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • S100A9

Targeting Calprotectin S100A8/A9 to Overcome AML Progression in DNMT3A-Mutant Cells. (PubMed, Curr Med Sci) - "Elevated S100A8/A9 expression contributes to the abnormal proliferation, migration, adhesion, and chemoresistance of DNMT3Amut AML cells. Targeting S100A8/A9 alone or in combination with other treatments represents a promising therapeutic strategy for DNMT3Amut AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • CCL2 • DNMT3A • ICAM1 • MMP2 • S100A8 • S100A9 • VCAM1

Fibroblast Growth Factor 20 Attenuates Colitis by Restoring Impaired Intestinal Epithelial Barrier Integrity and Modulating Macrophage Polarization via S100A9 in an NF-κB Dependent Manner. (PubMed, Cell Mol Gastroenterol Hepatol) - "These results suggest that FGF20 acts as a negative regulator of S100A9 and NF-κB, thereby inhibiting M1 macrophage polarization and restoring intestinal epithelial barrier integrity in mice with DSS-induced colitis. FGF20 may serve as a potential therapeutic target for the treatment of ulcerative colitis."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • S100A9

S100A8 induces Cyclophosphamide-Induced Alopecia via NCF2/NOX2-Mediated Ferroptosis. (PubMed, Free Radic Biol Med) - "Administration of the S100A8 inhibitor paquinimod (PAQ) alleviated alopecia and decreased markers of oxidative stress and ferroptosis. In vitro experiments using human outer root sheath keratinocytes (ORSKs) confirmed that S100A8 promotes ferroptosis via the NCF2/NOX2 pathway, as inhibition of NCF2 or NOX2 reversed these effects. These findings suggest that targeting the S100A8-NCF2/NOX2 axis may provide a novel therapeutic strategy for mitigating CIA induced by various chemotherapeutic agents."

Journal • Alopecia • Immunology • Inflammation • GPX4 • S100A8

Inhibition of S100A8/A9 ameliorates neuroinflammation by blocking NET formation following traumatic brain injury. (PubMed, Redox Biol) - "Finally, we established that the suppression of NET formation by S100A8/A9 inhibition is primarily mediated through the AMPK/Nrf2/HO-1 signaling pathway. These findings underscore the critical pathological role of S100A8/A9 in TBI and emphasize the need for further exploration of S100A8/A9 inhibitor Paquinimod as a potential therapeutic strategy for TBI."

Journal • CNS Disorders • Inflammation • Vascular Neurology • S100A8

S100A8/A9 Promotes Dendritic Cell-Mediated Th17 Cell Response in Sjögren's Dry Eye Disease by Regulating the Acod1/STAT3 Pathway. (PubMed, Invest Ophthalmol Vis Sci) - "Tear secretion, corneal fluorescein staining, and hematoxylin and eosin staining were used to evaluate the effect of paquinimod, a S100A8/A9 inhibitor, on dry eye disease in nonobese diabetic (NOD) mice...S100A8/A9 activated the Acod1/STAT3 pathway to promote DC-driven Th17 cell responses in SjDED. The S100A8/A9/Acod1/STAT3 pathway may represent a promising therapeutic target for SjDED."

Journal • Dry Eye Disease • Obesity • Ocular Inflammation • Ophthalmology • IL23A • S100A8

Mechanism of S100A9-mediated astrocyte activation via TLR4/NF-κB in Parkinson's disease. (PubMed, Int Immunopharmacol) - "C57BL/6J mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 15 mg/kg four times daily) and subsequently treated with Paquinimod, a S100A9 inhibitor (7 mg/kg, once daily for 7 days, totaling 8 doses)...In vitro, TLR4/NF-κB inhibitors mitigated inflammation and A1/A2 polarization of astrocytic MA cells induced by recombinant S100A9 (rS100A9). These findings suggest that S100A9 mediates astrocyte neuroinflammation and A1/A2 polarization via TLR4/NF-κB signaling, highlighting its potential as a therapeutic target for PD."

Journal • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • GFAP • IL1B • IL6 • PTX3 • S100A10 • S100A9 • TLR4 • TNFA

Single-cell RNA sequencing reveals S100A8/A9hi neutrophils-induced endothelial cell death and lymphocyte infiltration after ischemic stroke. (PubMed, Biochem Biophys Res Commun) - "Notably, the S100A8/A9 inhibitor paquinimod significantly protects neurons and reduces lymphocyte infiltration, suggesting that targeting S100A8/A9 could be a promising therapeutic strategy for reducing neurological deficits after ischemic stroke. Overall, these results enhance our understanding of the complex interactions between immune cells and the BBB in ischemic stroke, paving the way for innovative therapeutic approaches aimed at maintaining brain integrity and improving patient outcomes."

Journal • Cardiovascular • Inflammation • Ischemic stroke • CXCR2 • CXCR4 • S100A8

Retinal microglia-derived S100A9 incite NLRP3 inflammasome in a Western diet fed Ossabaw pig retina. (PubMed, bioRxiv) - "Inhibition of TLR4 with TAK242 and NLRP3 with MCC950 attenuated the production of IL-1β during S100A9 stimulus. Finally, pre-treatment with Paquinimod successfully reduced S100A9-driven increases of glycosylated-TLR4, NLRP3, ASC, Caspase-1, and IL-1β production. We demonstrated that microglial-derived S100A9 perpetuates pro-inflammatory responses via the NLRP3 inflammasome in the retina of young Western-diet-fed Ossabaw pigs exhibiting diabetic retinopathy."

Journal • Diabetes • Diabetic Retinopathy • Inflammation • Obesity • Retinal Disorders • Type 2 Diabetes Mellitus • CASP1 • CXCL8 • IL1B • IL6 • NLRP3 • S100A9 • TLR4

Blocking S100A9-signaling is detrimental to the initiation of anti-tumor immunity. (PubMed, Front Immunol) - "Surprisingly, we found that blocking the extracellular TLR4 signaling from S100A9 using the inhibitor Paquinimod, resulted in increased tumor growth and a detrimental effect on anti-PD-L1 efficacy in the CT26 tumor model...Intratumoral injection of recombinant S100A9 early after mice inoculation with CT26 cells had an anti-tumor effect. These findings indicate an important yet understudied role of S100A9 as an alarmin and immune stimulatory signal in cancer settings, and highlight the potential to exploit such signals to promote beneficial anti-tumor responses."

IO biomarker • Journal • Infectious Disease • Oncology • S100A9

Paquinimod attenuates retinal injuries by suppressing the S100A9/TLR4 signaling in an experimental model of diabetic retinopathy. (PubMed, Exp Eye Res) - "Our study validates the S100A9/TLR4 pathway in diabetic retinas and suggests its potential as a therapeutic target for DR. Targeting S100A9 could offer a novel approach to prevention and treatment."

IO biomarker • Journal • Diabetes • Diabetic Retinopathy • Inflammation • Metabolic Disorders • Oncology • Retinal Disorders • S100A9

The role of the S100A8/S100A9 in gastric tumor progression. (PubMed, Sci Rep) - "In vitro experiments verified that S100A9 can promote the proliferation and migration of AGS cells through the TLR4-NFκB signaling pathway, and the S100A8/S100A9 inhibitor Paquinimod can inhibit their proliferation and migration...Macrophages with high expression of S100A8/S100A9 are critical in the progression of gastric inflammation to cancer. Cytokine S100A9 can activate the TLR4-NFκB signaling pathway and promote the proliferation and migration of gastric adenocarcinoma cells."

Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • S100A8 • S100A9 • TLR4

S100A9 promotes renal calcium oxalate stone formation via activating the TLR4-p38/MAPK-LCN2 signaling pathway. (PubMed, Int J Biol Macromol) - "S100A9 promotes renal inflammatory injury by activating the TLR4-p38/MAPK-LCN2 pathway and then contributes to CaOx stone formation."

Journal • Inflammation • Metabolic Disorders • Nephrology • CD68 • CD80 • KIM1 • LCN2 • S100A9 • TLR4

Calprotectin is regulated by IL-17A and induces steroid hyporesponsiveness in asthma. (PubMed, Inflamm Res) - "These findings highlight calprotectin as a potential therapeutic target regulated by IL-17 in steroid hyporesponsive asthma. Targeting calprotectin may offer a promising approach to alleviate airway inflammation and restore steroid responsiveness in severe asthma. Further investigations are warranted to explore its therapeutic potential in clinical settings and elucidate its broader implications in steroid mechanisms of action."

Journal • Asthma • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • IL17A • S100A8 • S100A9

S100A9-TLR4 axis aggravates dry eye through the blockage of autophagy. (PubMed, Exp Eye Res) - "Autophagic blockage was predicted by the scRNA-seq data in DED, and further verified by decrease of LC3B-II/LC3B-I and increase of SQSTM1 and p-mTOR/mTOR, while S100A9 inhibitor paquinimod (PAQ) reversed the changes...Finally, signs of DED, chronic corneal inflammation and cell death got a remission after either inhibition of S100A9 or TLR4. In general, we deduced a S100A9-TLR4-Autophagic blockage pathway in the pathogenesis of DED."

Journal • Dry Eye Disease • Inflammation • Keratitis • Ocular Inflammation • Ophthalmology • S100A9 • SQSTM1 • TLR4

S100A9 as a Key Myocardial Injury Factor Interacting with ATP5 Exacerbates Mitochondrial Dysfunction and Oxidative Stress in Sepsis-Induced Cardiomyopathy. (PubMed, J Inflamm Res) - "Targeted S100A9 inhibition by paquinimod partially reversed myocardial mitochondrial dysfunction and oxidative stress. The interaction of S100A9 with ATP5 exacerbates myocardial damage in sepsis by inducing mitochondrial dysfunction and oxidative stress."

Journal • Cardiomyopathy • Cardiovascular • Infectious Disease • Inflammation • Metabolic Disorders • Septic Shock • CASP4 • LRG1 • NLRP3 • OSMR • S100A8 • S100A9 • SERPINA3 • SOCS3 • TFAM

Neutrophil Adhesion-related S100A8/A9 and Neutrophil Extracellular Traps Production: A Vicious Cycle in Antiphospholipid Syndrome Thrombosis (ISTH 2024) - "The use of the S100A8/A9 inhibitor, paquinimod, effectively reduced NETs and thrombosis in animal models... We observed enhanced release of NETs and neutrophil adhesion in APS patients compared to healthy subjects, which may be related to endothelial damage. Additionally, scRNAseq results showed an increase in the expression of S100A8 and S100A9 in neutrophils from APS patients. Furthermore, the S100A8/A9 exhibited significant upregulation in APS patients and APS models."

Cardiovascular • Genetic Disorders • Hematological Disorders • Immunology • Thrombosis • S100A8 • S100A9

THE TRADITIONAL CHINESE MEDICINE QILIAN-XIAOPI COMPOUND AMELIORATE GASTRIC MUCOSAL DYSPLASIA THROUGH THE S100A9/TLR4/NFκB SIGNALING PATHWAY (DDW 2024) - "Our data indicates that the traditional Chinese medicine QLXP can function similarly to the S100A9 inhibitor Paquinimod. Its mechanism likely involves modulating proliferation and apoptosis through the S100A9/TLR4/NFκB signaling pathway thereby alleviating gastric mucosal dysplasia."

IO biomarker • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • S100A9 • TLR4

Adjunctive treatments for pneumococcal meningitis: a systematic review of experimental animal models. (PubMed, Brain Commun) - "Adjunctive therapy that improved clinical outcomes in multiple studies was dexamethasone (6 studies), C5 antibodies (3 studies) and daptomycin (3 studies). HMGB1 inhibitors, matrix metalloproteinase inhibitors, neurotrophins, antioxidants and paquinimod also improved clinical parameters but only in single or small studies...In conclusion, 24 of 54 treatment regimens (44%) tested improved clinically relevant outcomes in experimental pneumococcal meningitis but few were tested in multiple well-designed studies. The most promising new adjunctive treatments are with C5 antibodies or daptomycin, suggesting that these drugs could be tested in clinical trials."

Journal • Preclinical • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Infectious Disease • Inflammation • Otorhinolaryngology • Pneumococcal Infections • Pneumonia • Psychiatry • Vascular Neurology • HMGB1

Identification of S100A8/A9 involved in thromboangiitis obliterans development using tandem mass tags-labeled quantitative proteomics analysis. (PubMed, Cell Signal) - "We observed that paquinimod reduces SMCs proliferation and migration, promotes phenotype switching and alleviates vascular stenosis in TAO rats. In conclusion, our study revealed that the early activation of S100A8/A9 in the femoral artery is implicated in TAO development, targeting S100A8/A9 signaling may provide a novel approach for TAO prevention and treatment."

Journal • Inflammation • S100A8

Calprotectin Is Associated with Vascular Calcification and Cardiovascular Complications During CKD (ISN-WCN 2024) - "We identified calprotectin as a key factor associated with vascular calcification, CV outcome and mortality in CKD patients. Blockade of calprotectin by paquinimod might be a promising strategy to reduce the burden of vascular calcification in CKD. These results have been presented as an oral presentation at the ASN Kidney Week in Philadelphia 2023."

Cardiovascular • Chronic Kidney Disease • Nephrology • Renal Disease • Transplantation

Targeting S100A9 Prevents β-Adrenergic Activation-Induced Cardiac Injury. (PubMed, Inflammation) - "In the current study, initially, we validated the role of S100A8/A9 in contributing to cardiac injury and heart failure via the overactivation of the β-adrenergic pathway and tested the potential use of paquinimod as a pharmacological intervention of S100A8/A9 activation in preventing cardiac dysfunction, collagen deposition, inflammation, and immune cell infiltration in β-adrenergic overactivation-mediated heart failure...Our results revealed that targeting S100A9 provides dual beneficial effects, which is not only a strategy to counteract cardiac inflammation but also preclude cardiac fibroblast-macrophage interactions. The findings of this study also indicate that targeting S100A9 could be a promising strategy for addressing cardiac fibrosis, potentially leading to future drug development."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Inflammation • S100A8 • S100A9

Identification of a shared gene signature and biological mechanism between diabetic foot ulcers and cutaneous lupus erythemnatosus by transcriptomic analysis. (PubMed, Front Physiol) - "Finally, the DGIbd database demonstrated that Paquinimod and Tasquinimod could be used to target S100A9 and Ribavirin could be used to target OASL. Our findings highlight common gene expression characteristics and signaling pathways between DFU and CLE, indicating a close association between these two diseases. This provides guidance for the development of targeted therapies and mutual interactions."

Gene Signature • Journal • Cutaneous Lupus Erythematosus • Dermatology • Immunology • Inflammation • Inflammatory Arthritis • Lupus • CEBPA • CEBPB • EPGN • GLI1 • KRT16 • KRT7 • MIR106A • MIR20A • MIR324 • MIR532 • MIR93 • OASL • S100A9

High S100A9 level predicts poor survival, and the S100A9 inhibitor paquinimod is a candidate for treating idiopathic pulmonary fibrosis. (PubMed, BMJ Open Respir Res) - "The present results indicate that increased S100A9 expression is associated with IPF progression and that the S100A9 inhibitor paquinimod is a potential treatment for IPF."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • S100A9

CD146 deficiency aggravates chronic obstructive pulmonary disease via the increased production of S100A9 and MMP-9 in macrophages. (PubMed, Int Immunopharmacol) - "Targeting S100A9 with paquinimod decreased lung inflammation and alleviated alveolar destruction in COPD-like mice. Collectively, our study suggests that CD146 negatively regulates MMP-9 production in macrophages via the S100A9 pathway in COPD."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • ELANE • MCAM • MMP9 • S100A9