TLR4 modulator program / GSK - LARVOL DELTA

Silencing FOXA1 suppresses inflammation caused by LPS and promotes osteogenic differentiation of periodontal ligament stem cells through the TLR4/MyD88/NF-κB pathway. (PubMed, Biomol Biomed) - "Notably, the application of the TLR4 agonist CRX-527 reversed the inhibitory effects of FOXA1 silencing on LPS-induced responses. In summary, silencing FOXA1 reduced cellular inflammation by inhibiting the TLR4/MyD88/NF-κB pathway and alleviated the suppressive effects of LPS on the osteogenic differentiation of hPDLSCs."

IO biomarker • Journal • Dental Disorders • Inflammation • Periodontitis • FOXA1 • MYD88 • TLR4

Morroniside ameliorates sevoflurane anesthesia-induced cognitive dysfunction in aged mice through modulating the TLR4/NF-κB pathway. (PubMed, Biomol Biomed) - "Morroniside (Mor) is a bioactive compound in Cornus officinalis with anti-inflammatory, neuroprotective and antioxidant properties. Mor blocked Sev-induced TLR4/NF-κB pathway activation in hippocampal tissues, and the TLR4 agonist CRX-527 attenuated the effect of Mor. In conclusion, Mor blocked the TLR4/NF-κB pathway, reducing hippocampal tissue damage and neuroinflammation caused by Sev, which in turn improving cognitive impairment in aged mice."

Journal • Preclinical • Alzheimer's Disease • Anesthesia • Cognitive Disorders • Inflammation

A synthetic TLR4 agonist significantly increases humoral immune responses and the protective ability of an MDCK-cell-derived inactivated H7N9 vaccine in mice. (PubMed, Arch Virol) - "We found that the CRX-527 adjuvant, a synthetic TLR4 agonist, significantly enhanced the humoral immune responses of the suspended-MDCK-cell-derived H7N9 vaccine, with significant antigen-sparing and immune-enhancing effects, including robust virus-specific IgG, hemagglutination-inhibiting (HI), neuraminidase-inhibiting (NI), and virus-neutralizing (VN) antibody responses, which are crucial for protection against influenza virus infection...Notably, NI and VN antibodies might play an important role in cross-protection against lethal influenza virus infections. This study showed that a synthetic TLR4 agonist adjuvant has a potent immunopotentiating effect, which might be considered worth further development as a means of increasing vaccine effectiveness."

Journal • Preclinical • Infectious Disease • Influenza • Respiratory Diseases • TLR4

Modulating the Mesenchymal Stromal Cell Microenvironment Alters Exosome RNA Content and Ligament Healing Capacity. (PubMed, Stem Cells) - "In this study, we used an in vitro system to compare the priming of human MSCs by two inflammatory inducers TNF-α and CRX-527 (a highly potent synthetic TLR4 agonist that can be used as a vaccine adjuvant or to induce anti-tumor immunity) on exosome molecular cargo, as well as on an in vivo rat ligament injury model to validate exosome potency...Additionally, a link was identified between altered exosomal microRNA levels and expression changes in microRNA targets in ligaments. These findings elucidate the nuanced interplay between MSCs, their exosomes, and tissue regeneration."

Journal • Stroma • Oncology • TLR4 • TNFA

The mucosal melanoma tumor microbiome is distinct from cutaneous with unfavorable proportions of immune-associated species (WRMC 2024) - "Overall, the tumor microbiomes of CM and MM are significantly different and may be a critical factor underlying the “cold” tumor microenvironment and poor ICB response of MM. Furthermore, these effects may be partly mediated through interactions of LPS with the TLR4 signaling cascade directly on tumor cells. Unlike LPS, CRX-527 is a synthetic lipid A mimetic that does not require the cofactor CD14 to activate TLR4 signaling, likely explaining its ability to better activate T1IFN and inflammatory signaling than standard LPS."

IO biomarker • Cutaneous Melanoma • Infectious Disease • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • CD14 • CXCL8 • IFIH1 • IL1B

Interferons Prime Endothelium for TLR-Mediated Prothrombotic Transformation (ASH 2023) - "Stimulation of thrombin generation by TLR4 agonists, including LPS and CRX-527, was significantly enhanced by IFNγ, but not IFNα...This model indicates that endothelial cells possess a verification system wherein a robust thrombotic response is only initiated if the type of IFN released by alveolar macrophages and epithelium is consistent with the type of TLR sensed by the endothelium. These observations provide a mechanistic basis for microvascular thrombosis in cytokine storm and raise the possibility of targeting interferons to prevent thrombotic complications in this setting."

IO biomarker • Cardiovascular • Hematological Disorders • Infectious Disease • Respiratory Diseases • Thrombosis • CCL4 • IFNA1 • IFNB1 • IFNG • IL10 • IL1B • IL6 • THBD • TLR2 • TLR4 • TNFA

Neurotropin alleviates cognitive impairment by inhibiting TLR4/MyD88/NF-κB inflammation signaling pathway in mice with vascular dementia. (PubMed, Neurochem Int) - "Further, we showed that administration of a TLR4 inhibitor TAK242 had a similar effect to NTP, while the TLR4 agonist CRX-527 attenuated the effect of NTP in the VD mice. Collectively, our study suggested that NTP alleviates cognitive impairment by inhibiting TLR4/MyD88/NF-κB inflammation signaling pathway in the VD mice. Thus, NTP may be a promising therapeutic approach and a potential TLR4 inhibitor for VD."

Journal • Preclinical • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Dementia • Inflammation • Pain • IL1B • IL6 • MYD88 • TLR4 • TNFA

Quercetin protects against Aspergillus fumigatus keratitis by reducing fungal load and inhibiting TLR-4 induced inflammatory response. (PubMed, Cytokine) - "Quercetin plays a protective role in mouse A. fumigatus keratitis by inhibiting fungal load, disrupting hyphae structure, macrophage infiltration, and suppressing inflammation response in macrophages via TLR-4 mediated signaling pathway."

IO biomarker • Journal • Infectious Disease • Inflammation • Keratitis • Ocular Inflammation • Ophthalmology • IL1B • IL6 • TLR4 • TNFA

A TLR4 agonist liposome formulation effectively stimulates innate immunity and enhances protection from bacterial infection. (PubMed, Innate Immun) - "Lipo-CRX is a formulation in which the TLR4 agonist CRX-527 is incorporated into lipid membranes in liposomes. While lipo-CRX or the antibiotic ampicillin alone did not alter B. abortus burdens in the lung, the combination had a synergistic beneficial effect. Our data suggest that stimulating the innate immune system with lipo-CRX, either alone or when combined with antibiotics, can enhance bacterial clearance in the mouse model of brucellosis."

Journal • Infectious Disease • TLR4

Peroxiredoxin 6 alleviates high glucose-induced inflammation and apoptosis in HK-2 cells by inhibiting TLR4/NF-κB signaling. (PubMed, Ann Transl Med) - "The administration of CRX-527 or PMA reversed the effects of PRDX6 on the cell viability, apoptosis, and inflammation of the HG-exposed HK-2 cells. To conclude, PRDX6 appears to protect HG-exposed HK-2 cells against inflammation and apoptosis by inhibiting TLR4/NF-κB signaling."

IO biomarker • Journal • Diabetes • Diabetic Nephropathy • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • NF-κβ • PRDX6 • TLR4

Exosomes from Crx-527 Stimulated MSCs Suppress T Cell Activation and Xenogeneic Gvhd While Preserving GVL (TCT-ASTCT-CIBMTR 2023) - "CRX-exosomes are superior to exosomes from unstimulated MSCs at preventing xenogeneic GVHD. Interestingly, CRX-exosome treatment does not prevent GVL activity despite the induction of Tregs. CRX-exosome treatment does not directly alter T cell biology but does cause dramatic differences in the transcriptome of monocytes, increasing IL-6 and IL-10 expression which may impact T cell activation."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Malignancies • Immune Modulation • Immunology • Infectious Disease • Leukemia • Oncology • Transplantation • CD4 • IFNG • IL10 • IL2RA • IL6 • TLR4

CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage. (PubMed, Front Immunol) - "Furthermore, After the use of mice, we found that CRX-527 had no significant protective effect on the hematopoietic and intestinal systems of irradiated TLR4-/- mice. in conclusion, CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage."

Journal • Hematological Disorders • TLR4

Lipid A analog CRX-527 conjugated to synthetic peptides enhances vaccination efficacy and tumor control. (PubMed, NPJ Vaccines) - "This translates into enhanced tumor protection upon prophylactic and therapeutic vaccination via intradermal injection against B16-OVA melanoma and HPV-related TC1 tumors. These results highlight the potential of CRX-527 as an adjuvant for molecularly defined cancer vaccines, and support the design of adjuvant-peptide conjugates as a strategy to optimize vaccine formulation."

Journal • Melanoma • Oncology • Solid Tumor • TLR4

Isoflurane Attenuates Cerebral Ischaemia-Reperfusion Injury via the TLR4-NLRP3 Signalling Pathway in Diabetic Mice. (PubMed, Oxid Med Cell Longev) - "Ischaemic stroke is a severe disease worldwide. The TLR4-specific agonist CRX-527 reversed the neuroprotective effects of ISO. In summary, our study indicated that ISO exerts neuroprotective effects against the neuroinflammation and autophagy observed during diabetic stroke via the TLR4-NLRP3 signalling pathway."

Journal • Preclinical • Anesthesia • Cardiovascular • Diabetes • Immunology • Inflammation • Ischemic stroke • Metabolic Disorders • Reperfusion Injury • NLRP3 • TLR4