Role Of Antagonists Research Articles

In silico study of ligand binding site of toll-like receptor 5

Background:Toll-like receptor-5 (TLR-5) is a member of TLRs family and responsible for bacterial flagellin recognition. The activation of TLR-5 with flagellin leads to initiation of signaling cascades, which in turn results in transcription of pro-inflammatory cytokines. Regarding the critical role of TLR-5 agonists and antagonists in activation of innate immune responses, an increasing number of studies have focused on their therapeutic applications in drug and vaccine design. In this study, to identify the most critical region and residues of TLR-5 for interaction with flagellin, different truncated forms of TLR-5 were designed and subjected to protein-protein interaction studies.Materials and Methods:The interactions of the full native TLR-5 and its truncated forms with bacterial flagellin (FliC) were evaluated using Hex docking server and molecular interaction analysis was performed using Dimplot analysis.Results:According to our in silico results, truncated form C (an amino acid sequence containing residues 174-401 of TLR-5) has the most suitable interaction with FliC and seven amino acids within this region were found to be crucial for the interaction with flagellin.Conclusions:These results provide new insights in to potential drug target sites of TLR-5, which may guide future TLR-5 targeting studies.

Wnt and the Wnt signaling pathway in bone development and disease

Wnt signaling affects both bone modeling, which occurs during development, and bone remodeling, which is a lifelong process involving tissue renewal. Wnt signals are especially known to affect the differentiation of osteoblasts. In this review, we summarize recent advances in understanding the mechanisms of Wnt signaling, which is divided into two major branches: the canonical pathway and the noncanonical pathway. The canonical pathway is also called the Wnt/β-catenin pathway. There are two major noncanonical pathways: the Wnt-planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt-Ca² pathway). This review also discusses how Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists affect both the bone modeling and bone remodeling processes. We also review the role of Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists in bone as demonstrated in mouse models. Disrupted Wnt signaling is linked to several bone diseases, including osteoporosis, van Buchem disease, and sclerosteosis. Studying the mechanism of Wnt signaling and its interactions with other signaling pathways in bone will provide potential therapeutic targets to treat these bone diseases.

Medical expulsive therapy

The objective of this review article is to present the current literature on medical expulsive therapy (MET) and help guide practitioners in the appropriate use of MET for treatment of stone disease. Kidney stones can be treated with multiple modalities including medical therapy, ureteroscopy, shock wave lithotripsy (SWL), percutaneous nephrostolithotomy, open/laparoscopic stone removal, and/or combinations of these modalities. The choice of intervention depends on patient factors, anatomical considerations, surgeon preference, and stone location and characteristics. MET is an excellent treatment modality in the appropriately selected patient. The AUA/EAU guidelines suggest MET as a reasonable treatment choice in select patients. A review of the data suggests the use of alpha antagonist and calcium channel blockers can improve stone expulsion rates. Most data suggests alpha antagonists as superior to calcium channel blockers. There are numerous available alpha antagonists, all of which have supporting data for their use in MET. Evidence suggests that MET can decrease colic events, narcotic use, and hospital visits. MET may also reduce medical costs and prevent unnecessary surgeries and the associated risks. Further, there is a role for alpha antagonists and calcium channel blockers in improving stone passage and decreasing pain in those subjects treated with other modalities (i.e. SWL and ureteroscopy). Despite this evidence, MET remains underutilized as a treatment modality.

Unpredictable Nature of Tolvaptan in Treatment of Hypervolemic Hyponatremia: Case Review on Role of Vaptans

Hyponatremia is one of the most commonly encountered electrolyte abnormalities occurring in up to 22% of hospitalized patients. Hyponatremia usually reflects excess water retention relative to sodium rather than sodium deficiency. Volume status and serum osmolality are essential to determine etiology. Treatment depends on several factors, including the cause, overall volume status of the patient, severity of hyponatremic symptoms, and duration of hyponatremia at presentation. Vasopressin antagonists like tolvaptan seem promising for the treatment of euvolemic and hypervolemic hyponatremia in heart failure. Low sodium concentrations cause cerebral edema, but the overly rapid sodium correction can also lead to iatrogenic cerebral osmotic demyelination syndrome. Demyelination may occur days after sodium correction or initial neurologic recovery from hyponatremia. The following case report analyzes the role of vasopressin antagonists in the treatment of hyponatremia and the need for daily dosing of tolvaptan and the monitoring of serum sodium levels to avoid rapid overcorrection which can result in osmotic demyelination syndrome (ODS).

Pharmacological and Clinical Importance of Integrin Antagonists in Treatment of Cancer

Integrins are heterodimeric molecules that are composed of 18 α-subunits and 8 β-subunits. They exist in 24 distinctive shapes based on combination of these sub-units and are mainly responsible for the adhesion of extracellular matrix (ECM) and immunoglobulin family molecules. Integrins mediate adhesion of epithelial cells to the basement membrane and also help in the migration, proliferation and survival of tumor cells. Studies also reveal that certain integrins act as markers for tumor cells and they also assist in both tumor progression and apoptosis. Studies reveal that unligated integrins in association with caspase 8 result in inhibition of ECM adhesion might result and integrin mediated death (IMD) on the other hand integrins in association with oncogenes or receptor tyrosine kinases can result in enhanced tumorigenesis. Among several types of integrins, αvβ3 and α5β1 have gained importance in anti-angiogenesis studies. Hence the role of antiangiogenesis antagonists has come into light. These include a variety of monoclonal antibodies and peptides. Each one of them has their own mechanism of action and antiangiogenesis activity. Current review aims at studying the phase 1 and 2 trails of these antagonists for anti-angiogenic function.

5-HT6 receptor antagonists as treatment for age-related cognitive decline

The 5-HT6 receptor (5-HT6R) is one of the most recently discovered serotonin receptors and has received much attention after observations showing its procognition properties. Indeed, 5-HT6R appears to be a promising target to treat cognitive decline, particularly via its modulatory function of cholinergic and glutamatergic systems. 5-HT6Rs are present mostly in the central nervous system, in brain structures known to be particularly involved in memory. Growing evidence suggests that blockade of 5-HT6R can not only improve memory processes in adult rodents but also reverse age-related and pharmacologically induced deficits. 5-HT6R blockade could also have a beneficial effect on neuronal plasticity. Regarding these findings, several 5-HT6R antagonists are currently going through clinical trials. This review provides an overview of the major findings arguing in favour of a role for 5-HT6R antagonists in developing treatment for cognitive disorders related to ageing and neurodegenerative diseases.

Calcitonin and Parathyrin are Glucoregulating Hormones

The comprehensive literature data and our findings about calcium-regulating hormones participant in the glucose metabolism is analyzed. It is showed calcitonin hyperglycemic effect and its mechanisms, established contra-insulin effect of calcitonin to insulin under the pre-receptor, cell level and liver. It is ascertained the impairment of glucose metabolism under calcitonin - hyperglycemia, insulin resistance and glucose intolerance. It is showed the data of combinative effect of calcitonin and calcium antagonists on glucose metabolism. It is discussed calcitonin diabetogenic effect and the role of calcium antagonists in the correction of hyperglycemia and tissue's insulin resistance. It was revealed the effect of parathyrin on glucose, occurring in decreasing the glucose level and increases glucose tolerance. It is concluded about participant of calcium-regulating hormones in the regulation of glucose metabolism.

Targeting Inflammation: Impact on Atherothrombosis

Atherothrombosis is a worldwide epidemic accounting for an unacceptable toll of deaths and disabilities. Its pathophysiology is complex and hardly referable to a specific mechanism; however, in the last 20years, a growing amount of evidence has demonstrated that inflammatory processes play a major role from the very beginning to the ultimate complication of atherothrombosis. These evidences are addressing a growing interest toward anti-inflammatory agents as preventive or curative treatments of atherothrombosis. At present, accumulated data are not conclusive, but strong evidence exists in favor of an anti-inflammatory positive effect for several drugs as statins or renin-angiotensin inhibitors. More conclusive data are expected from ongoing trials directly exploring the role of specific cytokines antagonists.

Aldosterone Antagonists in Heart Failure

Chronic, systolic heart failure is an increasing and costly health problem, and treatments based on pathophysiology have evolved that include the use of aldosterone antagonists. Advances in the understanding of neurohormonal responses to heart failure have led to better pharmacologic treatments. The steroid hormone aldosterone has been associated with detrimental effects on the cardiovascular system, such as ventricular remodeling and endothelial dysfunction. This article will review the literature and guidelines that support the use of aldosterone antagonists in the treatment of chronic, systolic heart failure. Aldosterone antagonists are life-saving drugs that have been shown to decrease mortality in patients with New York Heart Association class III to IV heart failure and in patients with heart failure after an acute myocardial infarction. Additional studies are being conducted to determine if the role of aldosterone antagonists can be expanded to patients with less severe forms of heart failure. Aldosterone antagonists are an important pharmacologic therapy in the neurohormonal blockade necessary in the treatment of systolic heart failure. These drugs have been shown to decrease mortality and reduce hospital readmission rates. The major complication of aldosterone antagonists is hyperkalemia, which can be avoided with appropriate patient selection and diligent monitoring.

Role of Interleukin-1/Interleukin-1 Receptor Antagonist Family of Cytokines in Long-Term Continuous Glucose Monitoring In Vivo

Glucose-sensor-induced tissue reactions (e.g., inflammation and wound healing) are known to negatively impact sensor function in vivo. The roles of cytokine networks in controlling these tissue reactions (i.e., sensor biofouling) is not understood. In the present study, we investigated the role of interleukin-1 receptor antagonist (IL-1Ra), a key anti-inflammatory antagonist of the proinflammatory interleukin-1 cytokines [i.e. interleukin-1 (IL-1) alpha and IL-1 beta] in controlling continuous glucose monitoring (CGM). To investigate the role of IL-1Ra in long-term CGM in vivo, we compared CGM in transgenic mice that overexpress IL-1Ra [interleukin-1 receptor antagonist overexpresser (IL-1Ra~OE), B6.Cg-Tg(IL1rn)1Dih/J] or are deficient in IL-1Ra [interleukin-1 receptor antagonist knockout (IL-1Ra~KO), B6.129S-IL1rn(tm1Dih)/J] with mice that have normal levels of IL-1Ra (C57BL/6) over a 28-day time period. Mean absolute relative difference (MARD) analysis of CGM results among the mice of varying IL-1Ra levels demonstrated that during the first 21 days, IL-1~KO mice had the greatest tissue inflammation and the poorest sensor performance (i.e., higher MARD values) when compared with normal or IL-1Ra~OE mice. By 28 days post-sensor implantation, the inflammatory reactions had subsided and were replaced by varying degrees of fibrosis. These data support our hypothesis on the importance of the IL-1 family of agonists and antagonists in controlling tissue reactions and sensor function in vivo. These data also suggest that local delivery of IL-1Ra genes or recombinant proteins (anakinra) or other IL-1 antagonists such as antibodies or soluble IL-1 receptors would suppress sensor-induced tissue reactions and likely enhance glucose sensor function by inhibiting inflammation and wound healing at sensor implantation sites.

Prostaglandin D2 receptord-type prostanoid receptor 2 mediates eosinophil trafficking into the esophagus

Eosinophilic esophagitis is characterized by eosinophil-predominant inflammation in the esophagus. How eosinophils migrate and infiltrate into the esophagus, however, is less clear. Our previous study demonstrated that mast cell activation led to eosinophil infiltration in the esophagus. Prostaglandin D2 (PGD2) is an important mediator released from activated mast cells. The present study aims to determine whether PGD2 induces eosinophil infiltration into the esophagus via a d-type prostanoid receptor 2 (DP2) receptor-dependent mechanism. Using an in vivo guinea pig model, PGD2, d-type prostanoid receptor 1 (DP1) agonist, or DP2 agonist were injected into the esophagus. Esophageal tissues were removed 2 hours after injections and proceeded to either hematoxylin-eosin (HE) staining or immunofluorescent staining of eosinophil major basic protein (MBP) to compare each treatment-induced eosinophil infiltration in the esophagus. In a separate study, ovalbumin (OVA)-sensitized guinea pigs were pretreated with either DP2 or DP1 antagonists, followed by inhalation of OVA to induce mast cell activation. Esophageal tissues were then processed for immunofluorescent staining of MBP. PGD2 injection in the esophagus led to an increase of eosinophil infiltration in esophageal epithelium at the injection site as revealed by HE staining. Increased infiltration of eosinophils was further confirmed by the increased presence of MBP-labeled immunopositive (MBP-LI) cells in esophageal epithelium. Injection with DP2 agonist 15(R)-PGD2, but not DP1 agonist BW 245C, mimicked the PGD2-induced response. In OVA-sensitized animals, antigen inhalation increased MBP-LI cells in esophageal epithelium. Pretreatment with DP2 antagonist BAY-u3405, but not DP1 antagonist BW 868C, inhibited the antigen inhalation-induced increase of MBP-LI cells in esophageal epithelium. These data support the hypothesis that PGD2 induces eosinophil trafficking into the esophageal epithelium via a DP2-mediated pathway, suggesting a role of DP2 antagonist in the prevention of eosinophilic esophagitis.

Evaluation of role of gnrh antagonist in intrauterine insemination (IUI) cycles with mild ovarian hyperstimulation (MOH)

Evaluation of role of gnrh antagonist in intrauterine insemination (IUI) cycles with mild ovarian hyperstimulation (MOH)

The Systemic Immune Network in Recent Onset Type 1 Diabetes: Central Role of Interleukin-1 Receptor Antagonist (DIATOR Trial)

BackgroundThe hypothesis was tested that the systemic immune milieu in recent-onset type 1 diabetes is associated with residual beta cell function and other metabolic patient characteristics.Methods and FindingsAll patients (n = 89, 40% female) of the Diabetes and Atorvastatin (DIATOR) Trial were analyzed at recruitment, i.e. prior to receiving the study medication. Inclusion criteria were insulin dependent diabetes for 2 weeks to 3 months, age range 18–39 years, and islet cell autoantibodies. Blood samples were analyzed for 14 immune mediators by standard methods. Concentrations of all mediators correlated with at least one other mediator (p<0.05, Spearman correlation) giving rise to a network. Interleukin 1 receptor antagonist (IL1-RA) held a central position and was associated with both pro- and anti-inflammatory mediators. Further central elements were the pro-inflammatory mediators CRP and IL-6, the soluble adhesion molecules sICAM-1 and E-selectin, and MCP-4 which held a central position in the chemokine network. The two Th1-associated mediators IFNγ and IP-10 remained outside the network but correlated with each other. All correlations were positive (r = 0.25–0.72), i.e., high levels of pro-inflammatory mediators were accompanied by increased levels of anti-inflammatory mediators. IL-1RA was the only mediator associated with fasting and liquid mixed meal stimulated C-peptide concentrations (r = 0.31 and 0.24, p = 0.003 and 0.025, after adjustment for age, sex, BMI). There were associations between the immune mediator network and BMI (IL-1RA, CRP, IL-6, MCP-4, MIP-1ß) but few or no associations with HbA1c, insulin dose, lipid parameters, age or sex.ConclusionsIn patients with recent onset type 1 diabetes, systemic acute phase proteins, cytokines, chemokines and soluble adhesion molecules form a network. Among the few central elements IL-1RA has a dominant role. IL-1RA is associated with all other groups of mediators and is the only mediator which correlates (positively) with residual beta cell function.Trial registrationClinicalTrials.gov registration number: NCT00974740

Protective Role of GnRH Antagonist on Chemotherapy-induced Spermatogenesis Disorder: A Morphological Study.

Anti cancer drugs is one of the most important chemotherapeutic factors which can influence spermatogenesis process and germinal epithelium. Since dividing cells are mainly affected by anticancer drugs, the aim of the present study is to investigate the preventive effect of GnRH antagonist on spermatogenic defect produced by anticancer drugs. In the present study thirty adult male mice aging 6-8 weeks were divided into 3 groups as: Control, Experimental 1 and Experimental 2. Experimental 1 group received Cisplatin for 5 days as 2.5 mg/kg intraperitoneally and Experimental 2 group received 0.25 mg/kg cetrorelix (GnRH antagonist) one week before cisplatin treatment and continued for 3 weeks. The mice in all groups were sacrificed 35 days after the last injection and testis specimens were fixed in boueins, formaldehyde fixative and 2.5% Glutaraldehide then prepared for light and electron microscopic examination. Light microscopy (LM) study showed that the number of spermatogonial cells, thickness of germinal epithelium, was decreased in Experimental 1group. Electron microscopy revealed that in this group several intercellular spaces appeared between spermatogenic cells and secretory granules in interstitial cells was increased. There were several vacuolated mitochondria and destroyed organelles in spermatogonial cells but in Experimental 2 group condition was similar to control group. These results indicate that the cetrorelix administration before cancer treatment may protect germinal epithelium against side effects of cisplatin.

Memantine’s action against aminoglycoside-induced ototoxicity

The objectives of this study were (1) to assess the protective role of NMDA antagonists against the ototoxic effects of aminoglycosides, (2) to provide any possible evidence between ototoxicity due to aminoglycosides and excitotoxicity. An animal experiment was conducted. Twenty-eight, 3-month-old female New Zealand rabbits, weighing 1,000-1,500g, were studied prospectively for 28days after intramuscular administration of amikacin (15mg/kg/day divided into two equal doses) for 14days. Twenty-one rabbits were categorized into three equal treatment groups and seven animals received no medication and served as the control group. The animals of A, B and C groups were injected, intramuscularly, with amikacin 15mg/kg/day, divided into two equal doses every day for 14days. Animals of group A received in parallel memantine (per os) and those of group B received p.o. the same volume of placebo solution. The rabbits of the third group (group C) received on the 15th day and every 2days for the next 2weeks, until the day 28, memantine of the same quantity as the members of group A. Differences in DPOAE amplitudes, and therefore in cochlear activity, between group A and group B were revealed. DPOAE amplitudes of group B were further reduced compared to the respective amplitudes in rabbits of group A. No improvement was observed in DPOAE measurements performed after the discontinuation of injections. The findings in group C should be examined separately. The measurements showed apparent reversal ototoxic effects in four of the animals. The development of aminoglycoside otoprotective strategies is a primary goal in ototoxicity research. The administration of NMDA antagonists has been shown to prevent, at least to some extent, toxic damage to hair cells in guinea pigs, treated with aminoglycoside antibiotics.

A potential role for sex hormone receptor antagonists in treatment of malignant salivary gland tumours, as compared to breast cancer: A review of literature

Malignant salivary gland tumours (MSGTs) account for less than 5% of all cancers of the head and neck. However, their treatment represents a challenge to oral and maxillofacial specialists. Surgical resection followed by radiation therapy represents the primary treatment of localized MSGTs. Since breast and salivary glands share similar morphologic features; similarities in the pathological processes are also expected. Adjuvant hormonal therapy is recommended for breast tumours containing hormone receptor protein. The expression of sex hormones in MSGTs, and their potential use in treatment is still controversial. This review article discusses three types of tumours arising in the breast and salivary glands; namely mucoepidermoid carcinoma, adenoid cystic carcinoma and salivary duct carcinoma. The expression of sex hormone receptor proteins and the potential use of hormone receptor antagonists in treatment are also being addressed.

Ticagrelor reduces neutrophil recruitment and lung damage in abdominal sepsis

Platelets play an important role in abdominal sepsis and P2Y12 receptor antagonists have been reported to exert anti-inflammatory effects. Herein, we assessed the impact of platelet inhibition with the P2Y12 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis. Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were treated with ticagrelor (100 mg/kg) or vehicle prior to CLP induction. Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified. Flow cytometry was used to determine expression of platelet–neutrophil aggregates, neutrophil activation and CD40L expression on platelets. CLP-induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50% in ticagrelor-treated animals. Moreover, ticagrelor abolished CLP-provoked lung edema and decreased lung damage score by 41%. Notably, ticagrelor completely inhibited formation of platelet–neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals. In addition, ticagrelor reduced platelet shedding of CD40L in septic mice. Our data indicate that ticagrelor can reduce CLP-induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists, such as ticagrelor, in the management of patients with abdominal sepsis.

The Emerging Role of Leptin Antagonist as Potential Therapeutic Option for Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic relapsing immune-mediated inflammatory disorder that affects millions of people around the world. Leptin is a satiety hormone produced primarily by adipose tissue and acts both centrally and peripherally. Leptin has been shown to play a major role in regulating metabolism, which increases during IBD progression. Leptin mediates several physiological functions including elevated blood pressure, tumorogenesis, cardiovascular pathologies and enhanced immune response in many autoimmune diseases. Recent development of a leptin mutant antagonist that blocks leptin activity raises great hope and opens up new possibilities for therapy in many autoimmune diseases including IBD. To this end, preliminary data from an ongoing study in our laboratory on pegylated leptin antagonist mutant L39A/D40A/F41A (PEG-MLA) treatment shows an inhibition of chronic colitis in IL-10−/− mice. PEG-MLA effectively attenuates the overall clinical scores, reverses colitis-associated pathogenesis including a decrease in body weight, and decreases systemic leptin level. PEG-MLA induces both central and peripheral leptin deficiency by mediating the cellular immune response. In summary, after blocking leptin activity, the correlative outcome between leptin-mediated cellular immune response, systemic leptin levels, and amount of adipose tissue together may provide new strategies for therapeutic intervention in autoimmune diseases, especially for intestinal inflammation.

Research Today

Basic research has identified the 2 major defects linked to polycystic disease: (i) the cystic cells proliferate excessively; (ii) these cells secrete fluid that enlarges the cysts. The main therapeutic strategies in autosomal dominant polycystic kidney disease (ADPKD) are the use of drugs capable of interfering with the mechanisms causing these defects. One of the strategies explored was the inhibition of the mTOR system. Unfortunately, 2 clinical trials have failed to show a protective effect of this class of drugs. Somatostatin is another molecule under intense clinical validation. At the moment, the collected data suggest a possible activity against ADPKD, but the results are still too preliminary to attain clinically meaningful conclusions. Tolvaptan is a vasopressin receptor antagonist that has been extensively studied: a clinical trial recruiting an adequate population suggested a possible positive effect of this molecule in the reduction of renal volume growth and the achievement of significant clinical targets. The near future promises new exploratory clinical trials of molecules that have already been assessed in the recent past or of completely new therapeutic strategies. For the high number of enrolled patients, the HALT study attracts the attention of the scientific community. This trial will explore the role of antagonists of the renin-angiontensin system in slowing the progression of ADPKD. Finally, a category of drugs previously unexplored is that of the inhibitors of the epidermal growth factor receptor. Clinical research in ADPKD is extraordinarily active in this period and this consideration allows a cautious optimism about the prospective therapies for this disease that for long remained orphan. A shadow on the prospect of future results in clinical research in this field comes from the observation that a considerable number of trials show a methodologically inadequate design.

Role of Toll-Like Receptor 4 in Mediating Multiorgan Dysfunction in Mice With Acetaminophen Induced Acute Liver Failure

Strategies for the prevention of multiorgan dysfunction (MOD) in acetaminophen (APAP)-induced acute liver failure (ALF) are an unmet need. Our study tested the hypothesis that sterile inflammation induced by APAP in a mouse model would activate toll-like receptor 4 (TLR4) in the liver and extrahepatic organs and lead to the progression of ALF and MOD and that the administration of the novel TLR4 antagonist STM28 (a peptide formed of 17 amino-acids) would prevent liver injury and associated MOD. ALF and, subsequently, MOD were induced in TLR4-knockout (KO) mice (B6.B10ScN-Tlr4 (lpsdel) /JthJ) and wild-type (WT) mice (C57BL/6) with APAP (500 mg/kg). A second set of experiments was conducted to evaluate the effects of a pretreatment with a novel TLR4 antagonist, STM28, on APAP-induced MOD in CD1 mice. Animals were sacrificed at the coma stage, and plasma, peripheral blood cells, liver, kidneys, and brain were collected. Biochemistry values and cytokines were measured. Liver and kidneys were studied histologically and were stained for TLR4 and activated Kupffer cells, and the expression of nuclear factor kappa B-p65 was quantified with western blotting. Brain water was measured in the frontal cortex. After APAP administration, TLR4-KO (NFkBp65) mice were relatively protected from liver necrosis and end-organ dysfunction and had significantly better survival than WT controls (P < 0.01). STM28 attenuated liver injury and necrosis, reduced creatinine levels, and delayed the time to a coma significantly. The increases in cytokines in the plasma and liver, including TLR4 expression and the activation of Kupffer cells, after APAP administration were reduced significantly in the STM28-treated animals. The increased number of circulating myeloid cells was reduced significantly after STM28 treatment. In conclusion, these data provide evidence for an important role of the TLR4 antagonist in the prevention of the progression of APAP-induced ALF and MOD.