Our findings reveal a new therapeutic approach for the treatment of inflammatory and demyelinating diseases such as MS. The molecular nature of the aptamer exerts not only an anti-inflammatory effect but also neuroprotective and remyelinating effects. The excellent safety profile demonstrated by ApTOLL in animals and humans opens the door to future clinical trials in MS patients.

Hangeshashinto, like Toll-like receptor (TLR) signaling inhibitors (resatorvid and C29) and an immunosuppressant (dexamethasone), exhibited the ability to suppress TLR-mediated activation of the transcription factor nuclear factor-κB (NF-κB) in response to PAMP stimulation. This study suggests that the anti-inflammatory effects of hangeshashinto may be attributed to the inhibition of TLR signal transduction pathways including NF-κB activation, thereby suppressing NF-κB-dependent gene expression.

Subsequently, after antagonizing the TLR4 pathway with antagonists (TAK242, PDTC, KG501, SR11302, LY294002), the expression of IL-6, TNF-α, iNOS, and IL-1β mRNA were detected by RT-qPCR. Furthermore, JXY inhibited M1-related molecules such as IL-6, TNF-α, iNOS, and IL-1β after antagonizing the TLR4 pathway. Obviously, JXY could exhibit inhibitory effects on the development of colon tumors in mice with CAC by promoting M1 polarization through TLR4-mediated signaling and impeding M2 polarization of macrophages.

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.

MTT and flow cytometry were used to assess cell viability and apoptosis in EC18 and TE1 cells, while wound healing and transwell assays were used to investigate cell migration and invasion in vitro...I3C promoted ESCC apoptosis and inhibited cell migration and invasion by downregulating β-catenin, c-myc, and cyclin D1 in vitro and decreased the tumor growth in vivo; this process was reversed by LiCl treatment. In summary, I3C inhibits ESCC malignant behavior by suppressing the Wnt/β-catenin signaling pathway, thus deeming it a promising drug for ESCC treatment.

The TLR4-dependent immunoregulatory effect of functional oligosaccharides was shown by measuring the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in RAW264.7 cells treated with different functional oligosaccharides, both with and without Resatorvid [TAK-242] (a Toll-like receptor 4 [TLR4] inhibitor)...The fluorescence spectra and molecular docking results revealed that the main mechanisms by which these oligosaccharides attach to the TLR4 active pocket are hydrogen bonds and van der Waals forces. Functional oligosaccharides were ranked according to their affinity for TLR4, as follows: MOS > COS > XOS, indicating that oligosaccharides or polysaccharides containing mannose units may confer significant advantages for immune enhancement.

P2, N=300, Not yet recruiting, Allodynic Therapeutics, Inc | Trial completion date: Jul 2025 --> Jul 2026 | Trial primary completion date: Mar 2025 --> Jul 2026

P2, N=60, Recruiting, University of Colorado, Denver | Trial completion date: Jan 2029 --> Jan 2030 | Trial primary completion date: Nov 2028 --> Nov 2029

P2, N=92, Completed, Allodynic Therapeutics, Inc

The cells in the model group were treated with 500 ng/mL HMGN1, while the antagonist group was treated with 500 ng/mL TAK-242 (resatorvid), a Toll-like receptor 4 (TLR4) antagonist, in addition to HMGN1...The results of Western blot suggested that the protein expression levels of iNOS, TLR4, MyD88, NF-κB p65 and IKK-β decreased significantly in the antagonist group. Conclusion HMGN1 may induce the activation of BV2 microglial cells by upregulating pro-inflammatory mediators through activating the TLR4/MyD88/NF-κB p65/IKK-β signaling pathway.

The selective inhibitors MMG-11 and TAK-242 were used to demonstrate involvement of toll-like receptors (TLR) 2 and 4, respectively, in H1-induced NO secretion by BV-2 microglia...We conclude that H1, and to a lesser extent H3, when released extracellularly, have the potential to act as a CNS DAMPs. Inhibition of the DAMP-like effects of extracellular histones on microglia and their neurotoxic activity represents a potential strategy for combating neurodegenerative diseases that are characterized by the adverse activation of microglia and neuronal death.

P2, N=300, Not yet recruiting, Allodynic Therapeutics, Inc | Trial completion date: Nov 2024 --> Jul 2025 | Trial primary completion date: Sep 2024 --> Mar 2025

GAPDH is a promising immunization candidate protein for targeting virulence and enhancing immune-mediated protection. Further investigations are warranted to understand the mechanisms underlying the activation of BMDCs by rGAPDH in a TLR2- and TLR4-dependent manner and the regulation of inflammatory cytokines contributing to mastitis pathogenesis.

G-Re might alleviate motor impairment of EAE and its pathological/inflammatory events in the spinal cord by preventing BBB disruption via downregulation of TLR4/MyD88/NF-κB signaling pathways. These findings for the first time suggest that G-Re might be a potential therapeutic for MS through maintenance of BBB integrity.

P3, N=439, Completed, BioVie Inc. | Active, not recruiting --> Completed | N=316 --> 439

L. casei & L. reuteri alleviate pancreatic cancer by inhibiting TLR4 to promote macrophage M1 polarization and regulate gut microbial homeostasis.

These data suggest that the pathophysiology of dementia and cognitive impairment in probable AD are driven by inflammatory factors that are present in both Aβ-positive and -negative populations. Additionally, the study findings suggest that the current diagnostic criteria for AD based on Aβ status may be too stringent and may inadvertently prevent development of therapies for patients with probable AD.

Targeting TLR4 inhibition could be a potential therapeutic strategy to protect RGCs from COH damage.

A loss of the stimulatory effects of HM on COX-2, PGE2 and IL-6 production and secretion was observed in TAK242 and NS-398-pre-treated AGS cells, confirming the role of TLR4 signaling and COX-2 generated in the HM gastroprotective effects. In conclusion, our results showed that HM enhances TLR4/COX-2-mediated secretion of gastroprotective markers PGE2 and IL-6, and upregulates mucin 4 gene expression in the human gastric epithelial cell line AGS, which may contribute to the promising beneficial gastroprotective effect of HM for human gastric prevention and treatment.

The combined application of TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib alleviates HCC progression and metastasis induced by the HMGB1-KLF7 axis. HMGB1-induced KLF7 overexpression facilitates HCC progression and metastasis by upregulating TLR4 and PTK2. Genetic ablation of KLF7 via AAV gene therapy and combined blockade of TLR4 and PTK2 represents promising therapy strategies for KLF7-positive HCC patients.

Results Of the 5564 pts who met the inclusion criteria (median age: 57 yrs), 63% were post-menopausal and 52% had stage I eBC at diagnosis...This study confirmed long-term toxicity of ET, particularly pain. Better management of symptoms and supportive interventional strategies are needed to further improve QoL in eBC.

However, TAK242 (TLR4 inhibitor) or PDTC (NF-κB inhibitor) could eliminate the inflammatory and EMT-promoting effects of LPS. In total, our results suggested that LPS exacerbated to the migration, invasion, and epithelial-mesenchymal transition of EC109 cells by TLR4/NF-κB axis. High level LPS may have a critical effect on the occurrence and development of EC.

Combined application of TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib alleviated HCC progression and metastasis mediated by the HMGB1-KLF7 axis. HMGB1-induced KLF7 overexpression facilitated HCC progression and metastasis by upregulating TLR4 and PTK2 expression. Combined administration of TLR4 and PTK2 inhibitors, or genetic ablation of KLF7 via AAV gene therapy represented promising therapy strategies for KLF7-positive HCC patients.

Conclusions Correlations among improved cognitive function, reduced inflammation, and changes in the clinician-observed GRC (overall impression of patient’s abilities) were consistent with the hypothesized activities of NE3107. Preliminary examination of metabolic and functional brain imaging supports hypothesis-based directional changes in accordance with the expected mechanism of action.

Intrathecal gabapentin injection reduced late-phase but not early-phase pruritus...Collectively, we have established a mouse model of neuropathic and cancer itch with relevance to human disease. Our findings also suggest distinct mechanisms underlying acute, chronic, and neuropathic itch.

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.

In the other experiment, cells were treated with morphine with or without TLR4 agonist (LPS) or antagonist (TAK-242). Morphine increases the progression of melanoma cancer and may be related to the increased expression of TLR4. Our results suggest that morphine should be used with caution in patients with melanoma.HighlightsMorphine increases the expression of TLR4 in melanoma.Morphine increases melanoma progression.These effects are mostly observed with chronic and escalating morphine administration.

The clinical development of TLR4 antagonists is urgently needed to counteract the pathological effects of dysbiosis on the liver and other organs. Further nutrigenomic studies are required to understand better how the diet influences the gut microbiota and its adverse effects on the liver.

Then, 2 weeks later, rats began daily subcutaneous injections of the Toll-like receptor 2 and 4 (TLR2-TLR4) antagonist (+)-naltrexone [(+)-NTX] or saline for an additional 13 days...These findings characterize an optimized MOG-induced SD rat model of EAE for the study of pain with minimal motor impairments/disabilities. Finally, these studies support the role of TLR2-TLR4 antagonists as a potential treatment for MS-related pain and other pain and inflammatory-related disorders.

Finally, cell deconvolution analysis revealed that TAK-242 treatment resulted in reduced hepatic populations of endothelial cells and myeloid-derived immune cells (Kupffer cells, Siglec-H high dendritic cells and NGP high neutrophils), while the proportion of MT-ND4 high hepatocytes significantly increased, suggesting a decrease in hepatic inflammation and concomitant increase in mitochondrial function and oxidative phosphorylation upon TLR4 inhibition. In conclusion, this study identified treatment strategies and novel molecular and cellular mechanisms associated with the prevention of HCC in the context of NASH that merit further investigations.

IAXO-102 was able to attenuate symptomatic parameters of GIM induced by CPT-11 as well as reduce tissue injury in the colon. However, there was no effect on cell proliferation and apoptosis. As such, TLR4 activation plays a partial role in GIM development but further research is required to understand the specific inflammatory signals underpinning tissue-level changes.

Furthermore, systemic administration of ACT001 attenuated allodynia induced by peripheral nerve injury and activation of microglia and astrocyte in vivo. Given the well-established role of neuroinflammation in neuropathic pain, these data imply that ACT001 could be a potential drug candidate for the treatment of chronic neuropathic pain.

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.

On the other hand, exactly opposite effects were observed in the ULPS-RS treated groups indicating the nephroprotective effect of this compound against IRI at both tested doses. The findings reveal for the first time that ULPS-RS has the therapeutic potential of attenuating the renal dysfunction induced by IRI.

Cells were treated for 1 h with a selective TLR4 inhibitor (TAK242), or appropriate control, prior to exposure to 5, 2.5, and 1 µM PCP...This suggests that PCP uses (to some extent) the TLR4 receptor to stimulate the production of IL-1β in human immune cells. These findings provide insight into the mechanism by which PCP may lead to chronic inflammation and its associated pathologies.

We found that cell toxicity and mitochondrial depolarization by BTZ were increased upon inhibition of HO-1 and TLR4 by using tin protoporphyrin IX (SnPP) and TAK-242, respectively. Interestingly, treatment of cells with either hemin, an HO-1 inducer, or supplementation with carbon monoxide (CO), a by-product of HO-1 enzymatic activity, increased TLR4 expression. In conclusion, we showed that treatment of MM cells with BTZ triggers the TLR4/HO-1/CO axis, serving as a stress-responsive signal that leads to increased cell survival while protecting mitochondria against BTZ and ultimately promoting drug resistance.

Despite TAK-242's high molecular weight and hydrophobicity, it can permeate through reconstructed human epidermis from all formulations. The findings, reported for the first time in this study, emphasize the capabilities of the topical application of TAK-242 via these multiple innovative topical drug delivery formulation platforms.

TLR4-regulated p38 MAPK and SIRT1 pathways are involved in Cim-protected hepatic lipotoxicity. Cim is a potential candidate for improving hepatic metabolic disorders mediated by lipotoxicity.

EC-18 can effectively inhibit the growth of HNSCC and alleviate the side effects caused by existing anticancer drugs at the same time. Therefore, it can be a desirable therapy for HNSCC patients.

Our data provide further evidence that activation of the TLR4 pathway promotes the development of UV-induced non-melanoma skin cancer mediated at least in part on its negative effects on DNA damage. Moreover, treatment with the TLR4 inhibitor TAK-242 may be effective for prevention of skin cancer.

Our results collectively suggest that TLR4 signaling pathways are involved in the elevated expression of BR3 and CD16 in human monocytes.

Selective inhibition of TLR4 specifically reduced the MM MSC ability to support growth of MM cells in an IL-6-dependent manner and delayed the development of MM in the Vk*MYC mouse model by altering the early disease phase in vivo. For the first time, we demonstrate that specific targeting of the pathological bone-marrow microenvironment via TLR4 signaling could be an innovative approach to alter MM pathology development.