Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Neal, Matthew D.; Jia, Hongpeng; Eyer, Benjamin R.; Good, Misty; Guerriero, Christopher J.; Sodhi, Chhinder P.; Afrazi, Amin; Prindle, Thomas; Ma, Congrong; Branca, Maria F.; Ozolek, John A.; Brodsky, Jeffrey L.; Wipf, Peter; Hackam, David J.

doi:10.1371/journal.pone.0065779

Cited by 110 publications

(124 citation statements)

References 35 publications

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“…While this research focuses on TLR4 ligation of unsaturated fatty acids and oxidised LDLs, opioids have been shown to act similarly as xenobiotics through MD2-TLR481 and opioid agonists have been shown to produce POMC cell hyperpolarisation and relative refractoriness44 while opioid antagonists have the reverse effect 82. Small molecule TLR4 inhibitors are under development for several therapeutic applications 83 84. The confluence then of these two important lines of recent research has the potential to produce major conceptual and therapeutic advances in this field.…”

Section: Discussionmentioning

confidence: 99%

Impact of lifetime opioid exposure on arterial stiffness and vascular age: cross-sectional and longitudinal studies in men and women

Reece

Hulse

2014

BMJ Open

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ObjectiveTo characterise and compare the potentiation of arterial stiffness and vascular ageing by opioids in men and women.DesignCross-sectional and longitudinal studies of 576 clinical controls and 687 opioid-dependent patients (ODP) on 710 and 1305 occasions, respectively, over a total of 2382 days (6.52 years), 2006–2011. Methodology Radial pulse wave analysis with Atcor SphygmoCor system (Sydney).SettingPrimary care.ParticipantsControls: General practice patients with non-cardiovascular disorders, and university student controls. ODP: Patients undergoing clinical management of their opioid dependence. Controls had lower chronological ages (CAs) than ODP (30.0±0.5 vs 34.5±0.3, mean±SEM, p<0.0001). 69.6% and 67.7% participants were men, and 16% and 92.3% were smokers (p<0.0001) for controls and ODP, respectively. 86.3%, 10.3% and 3.4% of ODP were treated with buprenorphine (6.98±0.21 mg), methadone (63.04±4.01 mg) or implant naltrexone, respectively. Body mass index (BMI) was depressed in ODP.InterventionsNil.Primary outcome measuresVascular Reference Age (RA) and the ratio of vascular age to chronological age (RA/CA).Secondary outcome measuresArterial stiffness including Augmentation Index.ResultsAfter BMI adjustment, RA in ODP was higher as a function of CA and of time (both p<0.05). Modelled mean RA in control and ODP was 35.6 and 36.3 years (+1.97%) in men, and 34.5 and 39.2 years (+13.43%) in women, respectively. Changes in RA and major arterial stiffness indices were worse in women both as a factor (p = 0.0036) and in interaction with CA (p = 0.0040). Quadratic, cubic and quartic functions of opioid exposure duration outperformed linear models with RA/CA over CA and over time. The opioid dose–response relationship persisted longitudinally after multiple adjustments from p=0.0013 in men and p=0.0073 in women.ConclusionsData show that lifetime opioid exposure, an interactive cardiovascular risk factor, particularly in women, is related to linear, quadratic, cubic and quartic functions of treatment duration and is consistent with other literature of accelerated ageing in patients with OD.

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Section: Discussionmentioning

confidence: 99%

Impact of lifetime opioid exposure on arterial stiffness and vascular age: cross-sectional and longitudinal studies in men and women

Reece

Hulse

2014

BMJ Open

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“…It inhibited TLR4 in enterocytes and macrophages in vitro and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. 156 …”

Section: Blocking Of Lps/attenuation Of Inflammation Sevelamermentioning

confidence: 99%

The Gut Microbiome, Kidney Disease, and Targeted Interventions

Ramezani

Raj

2014

Journal of the American Society of Nephrology

587

498

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The human gut harbors .100 trillion microbial cells, which influence the nutrition, metabolism, physiology, and immune function of the host. Here, we review the quantitative and qualitative changes in gut microbiota of patients with CKD that lead to disturbance of this symbiotic relationship, how this may contribute to the progression of CKD, and targeted interventions to re-establish symbiosis. Endotoxin derived from gut bacteria incites a powerful inflammatory response in the host organism. Furthermore, protein fermentation by gut microbiota generates myriad toxic metabolites, including p-cresol and indoxyl sulfate. Disruption of gut barrier function in CKD allows translocation of endotoxin and bacterial metabolites to the systemic circulation, which contributes to uremic toxicity, inflammation, progression of CKD, and associated cardiovascular disease. Several targeted interventions that aim to re-establish intestinal symbiosis, neutralize bacterial endotoxins, or adsorb gut-derived uremic toxins have been developed. Indeed, animal and human studies suggest that prebiotics and probiotics may have therapeutic roles in maintaining a metabolically-balanced gut microbiota and reducing progression of CKD and uremia-associated complications. We propose that further research should focus on using this highly efficient metabolic machinery to alleviate uremic symptoms.

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“…They prevent NEC in a rodent model [77], have shown promise in preventing NEC in a limited human trial [78], and seem to have generated a recent flurry of activity amongst patent lawyers. Another series of compounds that have potential use in preventing NEC is a new class of TLR4 inhibitors which, by preventing TLR4 activation, may inhibit the inflammatory cascade in NEC [79,80]. Of course, probiotics have polarized the neonatal community regarding their ability (or not) to prevent NEC [81].…”

Section: Preventionmentioning

confidence: 99%

Current Research on the Epidemiology, Pathogenesis, and Management of Necrotizing Enterocolitis

2017

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Despite decades of research on necrotizing enterocolitis, we still do not fully understand the pathogenesis of the disease, or how to prevent or how to treat it. However, as a result of recent significant advances in the microbiology, molecular biology, and cell biology of the intestine of preterm infants and infants with necrotizing enterocolitis, there is some hope that research into this devastating disease will yield some important translation into effective prevention, more rapid diagnosis, and novel therapies.

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Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Cited by 110 publications

References 35 publications

Impact of lifetime opioid exposure on arterial stiffness and vascular age: cross-sectional and longitudinal studies in men and women

Impact of lifetime opioid exposure on arterial stiffness and vascular age: cross-sectional and longitudinal studies in men and women

The Gut Microbiome, Kidney Disease, and Targeted Interventions

Current Research on the Epidemiology, Pathogenesis, and Management of Necrotizing Enterocolitis

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