Bindarit (AF 2838) / Angelini Group - LARVOL DELTA

CCL2 Inhibitor Bindarit Improve Postoperative Cognitive Function by Attenuating Pericyte Loss-Related Blood-Brain Barrier Disruption and Neuroinflammation. (PubMed, Mediators Inflamm) - "This study demonstrates that the CCL2 inhibitor Bindarit significantly reduces the incidence of PND by preventing PC loss, thereby protecting the BBB and alleviating neuroinflammation. These findings suggest that targeting CCL2 could be a potential therapeutic strategy for preventing and treating PND."

Journal • Anesthesia • CNS Disorders • Cognitive Disorders • Developmental Disorders • Inflammation • Musculoskeletal Diseases • Orthopedics • CCL2 • CLDN5 • GFAP • OCLN

A pH-responsive guanidino-based covalent organic framework nanodrugs for enhanced neuroprotection against subarachnoid hemorrhage by targeting NLRP3 inflammasome. (PubMed, Biomaterials) - "Bindarit, a β-blocker with anti-inflammatory properties, has demonstrated potential in mitigating NLRP3-mediated pyroptosis...The development of B@COFDT-R constitutes a substantial advancement in the treatment of SAH. Through the enhancement of drug delivery mechanisms and the targeted modulation of critical inflammatory pathways, this nanocarrier holds the potential to significantly improve therapeutic outcomes for patients suffering from SAH."

Journal • Cardiovascular • Hematological Disorders • Inflammation • Subarachnoid Hemorrhage • NLRP3

Engineering blood-brain barrier microphysiological systems to model Alzheimer's disease monocyte penetration and infiltration. (PubMed, Biomater Sci) - "Moreover, we also tested the interventions including Minocycline and Bindarit, and found they can effectively inhibit AD monocyte infiltration, subsequently reducing neuroinflammation and neuronal apoptosis. We believe these scalable and user-friendly BBB-MPS models may hold promising potential in modeling and advancing therapeutics for neurodegenerative and neuroinflammatory diseases."

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

Elucidating the therapeutic potential of indazole derivative bindarit against K-ras receptor: An in-silico analysis using molecular dynamics exploration. (PubMed, Biochem Biophys Rep) - "Consequently, further downstream signalling of the K-Ras pathway would be blocked and this could lead to the inhibition of K-Ras dependent cancer cell proliferation. However, further validation of present study can be done through experimental assay such as cytotoxic and protein expression analysis."

Journal • Colon Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Bindarit attenuates neuroinflammation after subarachnoid hemorrhage by regulating the CCL2/CCR2/NF-κB pathway. (PubMed, Brain Res Bull) - "Endogenous CCL2 expression was upregulated in the rat SAH model. Bindarit improved neurological functions and reduced neuroinflammation by regulating the CCL2/CCR2/NF-κB pathway in early brain injury after SAH."

Journal • CNS Disorders • Hematological Disorders • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology • CCL2 • CCR2

Circulating monocyte adhesion repairs endothelium-denuded injury through downstream of kinase 3-mediated endothelialization. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "However, this process was inhibited by the CCR2B inhibitor INCB3344...Bindarit, a selective MCP1 inhibitor, suppressed endothelialization following CCAED surgery in WT mice but not in DOK3-/- mice. In conclusion, endothelialization mediated by circulating monocytes repairs endothelium-denuded injury to compensate for endothelial functions through MCP1/DOK3/CCR2B/Ca2+ signaling. Our findings indicate that circulating monocyte adhesion is an important endothelial wound healing mechanism."

Journal • Cardiovascular • Hematological Disorders • Thrombosis • CCL2 • CCR2

Impact of Bindarit, a CCL2 Chemokine Synthesis Inhibitor, on Macrophage-Based Biofouling and Continuous Glucose Monitoring in vivo. (PubMed, Biosens Bioelectron X) - "These results not only confirm the major role monocytes/macrophages play, but directly demonstrate that CCL2 drives Mo/MQ recruitment and biofouling of glucose sensors in vivo. These findings support future studies incorporating Mo/MQ migration/chemotaxis inhibitors, like CCL2, on sensor coatings to improve glucose sensor accuracy and lifespan in vivo."

Journal • Preclinical • Diabetes • Fibrosis • Immunology • Inflammation • Metabolic Disorders • CCL2 • CCR2

Unraveling morphine tolerance: CCL2 induces spinal cord apoptosis via inhibition of Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis. (PubMed, Brain Behav Immun) - "Our data emphasize that chemokine CCL2 inhibited the Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis, alleviating the occurrence of apoptosis in spinal cord, thereby participating in morphine tolerance. This may provide new targets for the treatment of morphine tolerance."

Journal • Inflammation • Neuralgia • Pain • CCL2

Exploring and Validating the Mechanism of Ulinastatin in the Treatment of Sepsis-Associated Encephalopathy Based on Transcriptome Sequencing. (PubMed, J Inflamm Res) - "A total of 106 hub - gene - related drugs were predicted, among which BINDARIT - CCL2 and LIFITEGRAST - ICAM1 showed particularly high affinities. In conclusion, ICAM-1, IRF7, IL-1β, CCL2, IL-6, and SOCS3 were identified as potential therapeutic targets in SAE mice treated with UTI. This study offers theoretical support for UTI as a treatment option for SAE."

Journal • CNS Disorders • Infectious Disease • Septic Shock • CCL2 • ICAM1 • IL1B • IL6 • IRF7 • SOCS3

Choroid plexus CCL2‒CCR2 signaling orchestrates macrophage recruitment and cerebrospinal fluid hypersecretion in hydrocephalus. (PubMed, Acta Pharm Sin B) - "Furthermore, the administration of CCR2 antagonist (INCB 3284) reduces ChP macrophage accumulation and ventriculomegaly. This study not only unveils the ChP CCL2‒CCR2 signaling in the pathophysiology of hydrocephalus but also unveils Bindarit as a promising therapeutic choice for the management of posthemorrhagic hydrocephalus."

Journal • CNS Disorders • Hematological Disorders • Inflammation • Ventriculomegaly • CCL2 • CCR2 • TNFA • TNFRSF1A

CCL2 promotes EGFR-TKIs resistance in non-small cell lung cancer via the AKT-EMT pathway. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - "Conversely, CCL2 suppression by CCL2 synthesis inhibitor, bindarit, or CCL2 knockdown can reverse this resistance...In summary, CCL2 promotes the development of acquired EGFR-TKIs resistance and EMT while activating AKT signaling in NSCLC. These insights suggest a promising avenue for the development of CCL2-targeted therapies that prevent EGFR-TKIs resistance in NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCL2

Bindarit treatment results in minor effects in the FKRP-P448Lneo- mutant mouse (New Directions 2024) - No abstract available

Preclinical • Fibrosis • Immunology • Inflammation

CCL2-CCR2 AXIS MEDIATES DECIDUAL MONOCYTE/MACROPHAGE INFILTRATION AND INFLAMMATION IN OBSTETRIC ANTIPHOSPHOLIPID SYNDROME (EULAR 2024) - "The monocyte/macrophage infiltration and inflammation of blocking CCL2-CCR2 signaling in OAPS mice was investigated by bindarit, a CCL2 inhibitor, and RS504393, a CCR2 antagonist... The CCL2-CCR2 axis mediates monocyte/macrophage infiltration from peripheral blood to decidua, and subsequent inflammation, among OAPS. We provide a new insight into the mechanism and therapeutic target for OAPS."

Genetic Disorders • Hematological Disorders • Inflammation • Obstetrics • CCL2 • CCR2 • IFNG • TNFA

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8high macrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy. (PubMed, J Transl Med) - "Hypofractionated radiotherapy enhances the infiltration of CCL8high macrophages and amplifies their roles in macrophage recruitment through the CCL signaling pathway, leading to an immunosuppressive tumor microenvironment. These findings highlight the potential of targeting TAMs and introduces a novel combination to improve the efficacy of hypofractionated radiotherapy."

Journal • Preclinical • Lung Cancer • Oncology • Solid Tumor • CCL2 • CCL8 • MRC1

Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis. (PubMed, Acta Pharmacol Sin) - "Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 μM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 μM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Infarction • CCL2

Astragaloside IV alleviates LPS-induced cardiomyocyte hypertrophy and collagen expression associated with CCL2-mediated activation of NF-κB signaling pathway. (PubMed, Biochem Biophys Res Commun) - "Additionally, a classical inhibitor of CCL2 (bindarit) were used to further explore whether the anti-inflammatory effect of AS-IV was dependent on this chemokine. Our results indicated that AS-IV could exert a potent inhibitory effect on CCL2 expression and down-regulated NF-κB signaling pathway in a CCL2-dependent manner. These findings provided a scientific basis for promoting the treatment of HF with AS-IV."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Inflammation • CCL2

CCL2 is a key regulator and therapeutic target for periodontitis. (PubMed, J Clin Periodontol) - "CCL2 is a pivotal chemokine that binds to CCR2 during the progression of periodontitis, and targeting CCL2 may be a feasible option for controlling periodontitis."

Journal • Dental Disorders • Inflammation • Osteoporosis • Periodontitis • CCL2 • CCL8 • CCR2 • IL1B • IL6 • TNFA • TRAP

STING signaling activation modulates macrophage polarization via CCL2 in radiation-induced lung injury. (PubMed, J Transl Med) - "The cGAS-STING signaling pathway plays a crucial role in regulating the recruitment and polarization of macrophages, partly through CCL2, during the pathogenesis of RILI."

Journal • Oncology • Pneumonia • Respiratory Diseases • CCL2

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice. (PubMed, Sci Rep) - "Treatment of mice prior to and during EcoHIV infection with the CCL2 transcriptional inhibitor, bindarit, prevented brain infection and NCI and reduced macrophage infection...Based on these findings we propose that HIV enters the brain mainly through infected monocytes but that resident brain cells are sufficient to maintain NCI. These findings suggest that NCI therapy must act within the brain."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Human Immunodeficiency Virus • Infectious Disease • CCL2 • CCR2

Bioinformatics-integrated screening of systemic sclerosis-specific expressed markers to identify therapeutic targets. (PubMed, Front Immunol) - "Potential RNA regulatory pathways, including MALAT1-miR-206-CCL2, let-7a-5p-IL6, and miR-196a-5p-SERPINE1, contribute to our knowledge of SSc. Furthermore, the analysis of drug-hub gene interactions predicted TIPLASININ, CARLUMAB and BINDARIT as candidate drugs for SSc."

Journal • Fibrosis • Hematological Disorders • Immunology • Scleroderma • Systemic Sclerosis • CCL2 • IL6 • ISG15 • MALAT1 • MIR206 • SERPINE1

5-Oxoproline Enhances 4-Hydroxytamoxifen-induced Cytotoxicity by Increasing Oxidative Stress in MCF-7 Breast Cancer Cells. (PubMed, Anticancer Res) - "5-OP enhances 4-OHT-induced cytotoxicity in ER-positive breast cancer cells under normal glucose conditions."

Journal • Breast Cancer • Diabetes • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HIF1A • MCT1

Inhibition of monocarboxylate transporters (MCT) 1 and 4 reduces exercise capacity in mice. (PubMed, Physiol Rep) - "Further, we showed that MCT4 inhibition by bindarit administration (50 mg/kg of body weight) reduced the treadmill running duration at 40 m/min...A negative correlation was observed between exercise duration at 40 m/min and muscle lactate concentration immediately after exercise. Our results suggest that lactate transport via MCT1 and MCT4 plays a pivotal role in sustaining exercise."

Journal • Preclinical

Bindarit Encapsulated Nanoparticles Prevent Venous Neointimal Hyperplasia and Restenosis in a Murine Angioplasty Model. (PubMed, Transl Res) - "We hypothesized that adventitial delivery of Bindarit, an oral selective inhibitor of MCP-1, -2, and -3 encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (BN NP) could prevent VNH/VS formation in a murine model of PTA with AVF. Translational Significance: Adventitial administration of BN NP to the outflow vein after PTA results in decreased VNH/VS."

Journal • Preclinical • Cardiovascular • Fibrosis • Immunology

Monocyte Chemotactic Proteins Mediate the Effects of Hyperglycemia in Chondrocytes: In Vitro Studies. (PubMed, Life (Basel)) - "Bindarit, a specific inhibitor of monocyte chemotactic proteins (MCPs), was used to determine the role of MCPs in mediating the effects of high glucose conditions in chondrocyte cells...Moreover, treatment of chondrocytes with ascorbic acid reduced the effect of high glucose conditions on the expression of chemokines and Mmps. These data together suggest that MCPs mediate the catabolic effect of high glucose in chondrocytes."

Journal • Preclinical • Diabetes • Immunology • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • Osteoarthritis • Pain • Rheumatology • MMP13

Peritoneal GATA6-positive macrophage drives hepatic immunopathogenesis and maintains the T cell niche in the liver. (PubMed, Immunology) - "Peritoneal macrophages deletion by injection with clodronate-containing liposomes (LC) led to an attenuated hepatic pathology and the inflammatory microenvironment, while adoptive transfer of macrophages into the abdominal cavity, by contrast, results in restoring liver pathology. Importantly, there are a set genes of chemoattractant protein (MCP)-1, 2, and 3 that are highly related to recruit GATA6 macrophages during S. japonicum infection, while administration of bindarit, a selective inhibitor of MCPs synthesis, dramatically decreased the hepatic expression of GATA6 macrophages and thus attenuated hepatic pathology. Furthermore, in vivo study showed that peritoneal macrophages promote hepatic immunopathology is dependent on the accumulation of regulatory T cells (Tregs) in the liver. Altogether, these data provide the first clear evidence that GATA6 peritoneal macrophages play critical roles in both the formation of hepatic immunopathology and the accumulation of..."

Journal • Fibrosis • Hepatology • Immunology • Infectious Disease • Liver Failure • GATA6