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Fulltext An immunohistochemical study of Toll-like receptors 2 and 4 in placenta with and without infection

Hayati AR, Mohamed AE, Tan GC

Malays J Pathol, 2010 Jun;32(1):13-9.
PMID: 20614721 MyJurnal

The placenta constitutes a physical and immunological barrier against infectious agents. Toll-like receptors (TLRs) are essential components for the induction of innate immunity responses in different human tissues including the placenta. We investigated the expressions of TLR2 and TLR4 in the decidua and amniotic cells in non-inflamed placenta and placenta with infection.

Matched MeSH terms: Toll-Like Receptor 4/biosynthesis*; Toll-Like Receptor 4/immunology
An in silico approach towards the identification of novel inhibitors of the TLR-4 signaling pathway

Mahita J, Harini K, Rao Pichika M, Sowdhamini R

J Biomol Struct Dyn, 2016 Jun;34(6):1345-62.
PMID: 26264972 DOI: 10.1080/07391102.2015.1079243

Precise functioning and fine-tuning of Toll-like receptor 4 (TLR4) signaling is a critical requirement for the smooth functioning of the innate immune system, since aberrant TLR4 activation causes excessive production of pro-inflammatory cytokines and interferons. This can result in life threatening conditions such as septic shock and other inflammatory disorders. The TRIF-related adaptor molecule (TRAM) adaptor protein is unique to the TLR4 signaling pathway and abrogation of TRAM-mediated TLR4 signaling is a promising strategy for developing therapeutics aimed at disrupting TRAM interactions with other components of the TLR4 signaling complex. The VIPER motif from the vaccinia virus-producing protein, A46 has been reported to disrupt TRAM-TLR4 interactions. We have exploited this information, in combination with homology modeling and docking approaches, to identify a potential binding site on TRAM lined by the BB loop and αC helix. Virtual screening of commercially available small molecules targeting the binding site enabled to short-list 12 small molecules to abrogate TRAM-mediated TLR4 signaling. Molecular dynamics and molecular mechanics calculations have been performed for the analysis of these receptor-ligand interactions.

Matched MeSH terms: Toll-Like Receptor 4/antagonists & inhibitors; Toll-Like Receptor 4/metabolism; Toll-Like Receptor 4/chemistry*
Fulltext Anti-High Mobility Group Box-1 Monoclonal Antibody Attenuates Seizure-Induced Cognitive Decline by Suppressing Neuroinflammation in an Adult Zebrafish Model

Paudel YN, Othman I, Shaikh MF

Front Pharmacol, 2020;11:613009.
PMID: 33732146 DOI: 10.3389/fphar.2020.613009

Epilepsy is a chronic brain disease afflicting around 70 million global population and is characterized by persisting predisposition to generate epileptic seizures. The precise understanding of the etiopathology of seizure generation is still elusive, however, brain inflammation is considered as a major contributor to epileptogenesis. HMGB1 protein being an initiator and crucial contributor of inflammation is known to contribute significantly to seizure generation via activating its principal receptors namely RAGE and TLR4 reflecting a potential therapeutic target. Herein, we evaluated an anti-seizure and memory ameliorating potential of an anti-HMGB1 monoclonal antibody (mAb) (1, 2.5 and 5 mg/kg, I.P.) in a second hit Pentylenetetrazol (PTZ) (80 mg/kg, I.P.) induced seizure model earlier stimulated with Pilocarpine (400 mg/kg, I.P.) in adult zebrafish. Pre-treatment with anti-HMGB1 mAb dose-dependently lowered the second hit PTZ-induced seizure but does not alter the disease progression. Moreover, anti-HMGB1 mAb also attenuated the second hit Pentylenetetrazol induced memory impairment in adult zebrafish as evidenced by an increased inflection ration at 3 and 24 h trail in T-maze test. Besides, decreased level of GABA and an upregulated Glutamate level was observed in the second hit PTZ induced group, which was modulated by pre-treatment with anti-HMGB1 mAb. Inflammatory responses occurred during the progression of seizures as evidenced by upregulated mRNA expression of HMGB1, TLR4, NF-κB, and TNF-α, in a second hit PTZ group, which was in-turn downregulated upon pre-treatment with anti-HMGB1 mAb reflecting its anti-inflammatory potential. Anti-HMGB1 mAb modulates second hit PTZ induced changes in mRNA expression of CREB-1 and NPY. Our findings indicates anti-HMGB1 mAb attenuates second hit PTZ-induced seizures, ameliorates related memory impairment, and downregulates the seizure induced upregulation of inflammatory markers to possibly protect the zebrafish from the incidence of further seizures through via modulation of neuroinflammatory pathway.

Matched MeSH terms: Toll-Like Receptor 4
Arginase activity in a murine macrophage cell line (RAW264.7) stimulated with lipopolysaccharide from Actinobacillus actinomycetemcomitans

Sosroseno W, Musa M, Ravichandran M, Fikri Ibrahim M, Bird PS, Seymour GJ

Oral Microbiol. Immunol., 2006 Jun;21(3):145-50.
PMID: 16626370

The aim of the present study was to determine whether or not lipopolysaccharide from Actinobacillus actinomycetemcomitans could stimulate arginase activity in a murine macrophage cell line (RAW264.7 cells).

Matched MeSH terms: Toll-Like Receptor 4/metabolism
Fulltext Arjunolic acid modulate pancreatic dysfunction by ameliorating pattern recognition receptor and canonical Wnt pathway activation in type 2 diabetic rats

Aamir K, Sethi G, Afrin MR, Hossain CF, Jusuf PR, Sarker SD, et al.

Life Sci, 2023 Aug 15;327:121856.
PMID: 37307966 DOI: 10.1016/j.lfs.2023.121856

BACKGROUND: Arjunolic acid (AA) is a potent phytochemical with multiple therapeutics effects. In this study, AA is evaluated on type 2 diabetic (T2DM) rats to understand the mechanism of β-cell linkage with Toll-like receptor 4 (TLR-4) and canonical Wnt signaling. However, its role in modulating TLR-4 and canonical Wnt/β-catenin crosstalk on insulin signaling remains unclear during T2DM. Aim The current study is aimed to examine the potential role of AA on insulin signaling and TLR-4-Wnt crosstalk in the pancreas of type 2 diabetic rats.
METHOD: Multiple methods were used to determine molecular cognizance of AA in T2DM rats, when treated with different dosage levels. Histopathological and histomorphometry analysis was conducted using masson trichrome and H&E stains. While, protein and mRNA expressions of TLR-4/Wnt and insulin signaling were assessed using automated Western blotting (jess), immunohistochemistry, and RT-PCR.
RESULTS: Histopathological findings revealed that AA had reversed back the T2DM-induced apoptosis and necrosis caused to rats pancreas. Molecular findings exhibited prominent effects of AA in downregulating the elevated level of TLR-4, MyD88, NF-κB, p-JNK, and Wnt/β-catenin by blocking TLR-4/MyD88 and canonical Wnt signaling in diabetic pancreas, while IRS-1, PI3K, and pAkt were all upregulated by altering the NF-κB and β-catenin crosstalk during T2DM.
CONCLUSION: Overall results, indicate that AA has potential to develop as an effective therapeutic in the treatment of T2DM associated meta-inflammation. However, future preclinical research at multiple dose level in a long-term chronic T2DM disease model is warranted to understand its clinical relevance in cardiometabolic disease.

Matched MeSH terms: Toll-Like Receptor 4/metabolism
Fulltext Association of NOD1, CXCL16, STAT6 and TLR4 gene polymorphisms with Malaysian patients with Crohn's disease

Chua KH, Ng JG, Ng CC, Hilmi I, Goh KL, Kee BP

PeerJ, 2016;4:e1843.
PMID: 27069792 DOI: 10.7717/peerj.1843

Crohn's disease (CD) is a prominent type of inflammatory bowel disease (IBD) that can affect any part of the gastrointestinal tract. CD is known to have higher prevalence in the Western countries, but the number of cases has been increasing in the past decades in Asia, including Malaysia. Therefore, there is a need to investigate the underlining causes of CD that may shed light on its prevention and treatment. In this study, genetic polymorphisms in NOD1 (rs2075820), CXCL16 (rs2277680), STAT6 (rs324015) and TLR4 (rs4986791) genes were examined in a total of 335 individuals (85 CD patients and 250 healthy controls) with PCR-RFLP approach. There was no significant association observed between NOD1 rs2075820 and STAT6 rs324015 with the onset of CD in the studied cohort. However, the G allele of CXCL16 rs2277680 was found to have a weak association with CD patients (P = 0.0482; OR = 1.4310). The TLR4 rs4986791 was also significantly associated to CD. Both the homozygous C genotype (P = 0.0029; OR = 0.3611) and C allele (P = 0.0069; OR = 0.4369) were observed to confer protection against CD. On the other hand, the heterozygous C/T genotype was a risk genotype (P = 0.0015; OR = 3.1392). Further ethnic-stratified analysis showed that the significant associations in CXCL16 rs2277680 and TLR4 rs4986791 were accounted by the Malay cohort. In conclusion, the present study reported two CD-predisposing loci in the Malay CD patients. However, these loci were not associated to the onset of CD in Chinese and Indian patients.

Matched MeSH terms: Toll-Like Receptor 4
Fulltext BDMC33, A curcumin derivative suppresses inflammatory responses in macrophage-like cellular system: role of inhibition in NF-κB and MAPK signaling pathways

Lee KH, Chow YL, Sharmili V, Abas F, Alitheen NB, Shaari K, et al.

Int J Mol Sci, 2012;13(3):2985-3008.
PMID: 22489138 DOI: 10.3390/ijms13032985

Our preliminary screening has shown that curcumin derivative BDMC33 [2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone] exerted promising nitric oxide inhibitory activity in activated macrophages. However, the molecular basis and mechanism for its pharmacological action is yet to be elucidated. The aim of this study was to investigate the anti-inflammatory properties of BDMC33 and elucidate its underlying mechanism action in macrophage cells. Our current study demonstrated that BDMC33 inhibits the secretion of major pro-inflammatory mediators in stimulated macrophages, and includes NO, TNF-α and IL-1β through interference in both nuclear factor kappaB (NF-κB) and mitogen activator protein kinase (MAPK) signaling cascade in IFN-γ/LPS-stimulated macrophages. Moreover, BDMC33 also interrupted LPS signaling through inhibiting the surface expression of CD-14 accessory molecules. In addition, the inhibitory action of BDMC33 not only restricted the macrophages cell (RAW264.7), but also inhibited the secretion of NO and TNF-α in IFN-γ/LPS-challenged microglial cells (BV-2). The experimental data suggests the inflammatory action of BDMC33 on activated macrophage-like cellular systems, which could be used as a future therapeutic agent in the management of chronic inflammatory diseases.

Matched MeSH terms: Toll-Like Receptor 4/metabolism
Fulltext Brain Lipopolysaccharide Preconditioning-Induced Gene Reprogramming Mediates a Tolerance State in Electroconvulsive Shock Model of Epilepsy

Amini E, Golpich M, Farjam AS, Kamalidehghan B, Mohamed Z, Ibrahim NM, et al.

Front Pharmacol, 2018;9:416.
PMID: 29765321 DOI: 10.3389/fphar.2018.00416

There is increasing evidence pointing toward the role of inflammatory processes in epileptic seizures, and reciprocally, prolonged seizures induce more inflammation in the brain. In this regard, effective strategies to control epilepsy resulting from neuroinflammation could be targeted. Based on the available data, preconditioning (PC) with low dose lipopolysaccharide (LPS) through the regulation of the TLR4 signaling pathway provides neuroprotection against subsequent challenge with injury in the brain. To test this, we examined the effects of a single and chronic brain LPS PC, which is expected to lead to reduction of inflammation against epileptic seizures induced by electroconvulsive shock (ECS). A total of 60 male Sprague Dawley rats were randomly assigned to five groups: control, vehicle (single and chronic), and LPS PC (single and chronic). We first recorded the data regarding the behavioral and histological changes. We further investigated the alterations of gene and protein expression of important mediators in relation to TLR4 and inflammatory signaling pathways. Interestingly, significant increased presence of NFκB inhibitors [Src homology 2-containing inositol phosphatase-1 (SHIP1) and Toll interacting protein (TOLLIP)] was observed in LPS-preconditioned animals. This result was also associated with over-expression of IRF3 activity and anti-inflammatory markers, along with down-regulation of pro-inflammatory mediators. Summarizing, the analysis revealed that PC with LPS prior to seizure induction may have a neuroprotective effect possibly by reprogramming the signaling response to injury.

Matched MeSH terms: Toll-Like Receptor 4
Fulltext Cardioprotective effects of arjunolic acid in LPS-stimulated H9C2 and C2C12 myotubes via the My88-dependent TLR4 signaling pathway

Hasan MM, Madhavan P, Ahmad Noruddin NA, Lau WK, Ahmed QU, Arya A, et al.

Pharm Biol, 2023 Dec;61(1):1135-1151.
PMID: 37497554 DOI: 10.1080/13880209.2023.2230251

CONTEXT: Arjunolic acid (AA) is a triterpenoid saponin found in Terminalia arjuna (Roxb.) Wight & Arn. (Combretaceae). It exerts cardiovascular protective effects as a phytomedicine. However, it is unclear how AA exerts the effects at the molecular level.
OBJECTIVE: This study investigates the cardioprotective effects of arjunolic acid (AA) via MyD88-dependant TLR4 downstream signaling marker expression.
MATERIALS AND METHODS: The MTT viability assay was used to assess the cytotoxicity of AA. LPS induced in vitro cardiovascular disease model was developed in H9C2 and C2C12 myotubes. The treatment groups were designed such as control (untreated), LPS control, positive control (LPS + pyrrolidine dithiocarbamate (PDTC)-25 µM), and treatment groups were co-treated with LPS and three concentrations of AA (50, 75, and 100 µM) for 24 h. The changes in the expression of TLR4 downstream signaling markers were evaluated through High Content Screening (HCS) and Western Blot (WB) analysis.
RESULTS: After 24 h of co-treatment, the expression of TLR4, MyD88, MAPK, JNK, and NF-κB markers were upregulated significantly (2-6 times) in the LPS-treated groups compared to the untreated control in both HCS and WB experiments. Evidently, the HCS analysis revealed that MyD88, NF-κB, p38, and JNK were significantly downregulated in the H9C2 myotube in the AA treated groups. In HCS, the expression of NF-κB was downregulated in C2C12. Additionally, TLR4 expression was downregulated in both H9C2 and C2C12 myotubes in the WB experiment.
DISCUSSION AND CONCLUSIONS: TLR4 marker expression in H9C2 and C2C12 myotubes was subsequently decreased by AA treatment, suggesting possible cardioprotective effects of AA.

Matched MeSH terms: Toll-Like Receptor 4/metabolism
Comparative efficacy of vanilloids in inhibiting toll-like receptor-4 (TLR-4)/myeloid differentiation factor (MD-2) homodimerisation

Mai CW, Kang YB, Hamzah AS, Pichika MR

Food Funct, 2018 Jun 20;9(6):3344-3350.
PMID: 29808897 DOI: 10.1039/c8fo00136g

Vanilloid (4-hydroxy-3-methoxyphenyl benzenoid) containing foods are reported to possess many biological activities including anti-inflammatory properties. Homodimerisation of the Toll-like receptor-4 (TLR-4)/Myeloid differentiation factor 2 (MD-2) complex results in life-threatening complications in inflammatory disorders. In this study, we report activity of vanilloids in inhibition of TLR-4/MD-2 homodimersization and their molecular interactions with the receptor. The inhibitory activities of vanilloids were assessed in vitro by determining their antagonistic actions of lipopolysaccharide from Escherichia coli (LPSEc) in activation of TLR-4/MD-2 homodimerisation in TLR-4/MD-2/CD-14 transfected HEK-293 cells. The in vitro anti-inflammatory activity of vanilloids was also determined using RAW 264.7 cells. All the vanilloids were found to be active in the inhibition of TLR-4/MD-2 homodimersiation and nitric oxide production in RAW 264.7 cells. Rigid and flexible molecular docking studies were performed to gain insight into interactions between vanilloids and the binding site of the TLR-4/MD-2 complex.

Matched MeSH terms: Toll-Like Receptor 4/immunology; Toll-Like Receptor 4/chemistry*
Delayed liver regeneration in C3H/HeJ mice: possible involvement of haemodynamic and structural changes in the hepatic microcirculation

Marlini M, Mabuchi A, Mallard BL, Hairulhisyam N, Akashi-Takamura S, Harper JL, et al.

Exp Physiol, 2016 12 01;101(12):1492-1505.
PMID: 27634415 DOI: 10.1113/EP085727

NEW FINDINGS: What is the central question of this study? The liver regenerative process is complex and involves a sequence of signalling events, but the possible involvement of structural and haemodynamic changes in vivo during this process has never been explored. What is the main finding and its importance? Normal sinusoidal blood flow and velocity are crucial for a normal regenerative response, and delays in these haemodynamic events resulted in impaired liver regeneration in lipopolysaccharide-insensitive, C3H/HeJ mice. Toll-like receptor 4 signalling is required for restoration of normal liver architecture during the liver regenerative process. Liver regeneration is delayed in mice with a defective Toll-like receptor 4 (TLR4; C3H/HeJ mice) but is normal in TLR4 knockouts (TLR4-/- ). Here, we investigated the possible involvement of structural and haemodynamic changes in vivo in the underlying mechanism. In lipopolysaccharide-sensitive (C3H/HeN and C57BL/6) and lipopolysaccharide-insensitive (C3H/HeJ and TLR4-/- ) mice, a 70% partial hepatectomy (PH) was performed under inhalational anaesthesia. At days 3 and 7 after PH, the hepatic microcirculation was interrogated using intravital microscopy. Delayed liver regeneration was confirmed in C3H/HeJ, but not in C3H/HeN, C57BL/6 (WT) or TLR4-/- mice by liver weight-to-body-weight ratio, the percentage of proliferating cell nuclear antigen (PCNA)-positive cells and mitotic index data. At day 3 after PH, sinusoidal red blood cell velocity increased by 100% in C3H/HeN mice, but by only 40% in C3H/HeJ mice. Estimated sinusoidal blood flow was significantly higher at day 7 after PH in C3H/HeN than in C3H/HeJ mice. The hepatic cord width was significantly larger in C3H/HeN than in C3H/HeJ mice at day 3 and it was significantly larger in TLR4-/- than in C57BL/6 WT mice at day 7 after PH. Hepatocyte nucleus density and functional sinusoidal density was significantly reduced at days 3 and 7 after PH in all mouse strains compared with their zero-time controls. Functional sinusoidal density was significantly lower in C3H/HeJ compared with C3H/HeN mice at day 7 after PH. The present study indicates that altered sinusoidal blood flow and velocity in C3H/HeJ mice may contribute to the observed delay in the regenerative response in these mice. In addition, restoration of normal liver architecture may be delayed in TLR4-/- mice.

Matched MeSH terms: Toll-Like Receptor 4/metabolism
Fulltext Effect of ultrapure lipopolysaccharides derived from diverse bacterial species on the modulation of platelet activation

Vallance TM, Ravishankar D, Albadawi DAI, Layfield H, Sheard J, Vaiyapuri R, et al.

Sci Rep, 2019 12 03;9(1):18258.
PMID: 31796818 DOI: 10.1038/s41598-019-54617-w

Platelets are small circulating blood cells that play essential roles in the maintenance of haemostasis via blood clotting. However, they also play critical roles in the regulation of innate immune responses. Inflammatory receptors, specifically Toll-like receptor (TLR)-4, have been reported to modify platelet reactivity. A plethora of studies have reported controversial functions of TLR4 in the modulation of platelet function using various chemotypes and preparations of its ligand, lipopolysaccharide (LPS). The method of preparation of LPS may explain these discrepancies however this is not fully understood. Hence, to determine the impact of LPS on platelet activation, we used ultrapure preparations of LPS from Escherichia coli (LPSEC), Salmonella minnesota (LPSSM), and Rhodobacter sphaeroides (LPSRS) and examined their actions under diverse experimental conditions in human platelets. LPSEC did not affect platelet activation markers such as inside-out signalling to integrin αIIbβ3 or P-selectin exposure upon agonist-induced activation in platelet-rich plasma or whole blood whereas LPSSM and LPSRS inhibited platelet activation under specific conditions at supraphysiological concentrations. Overall, our data demonstrate that platelet activation is not largely influenced by any of the ultrapure LPS chemotypes used in this study on their own except under certain conditions.

Matched MeSH terms: Toll-Like Receptor 4/metabolism
Fulltext Embelin Prevents Seizure and Associated Cognitive Impairments in a Pentylenetetrazole-Induced Kindling Zebrafish Model

Kundap UP, Paudel YN, Kumari Y, Othman I, Shaikh MF

Front Pharmacol, 2019;10:315.
PMID: 31057394 DOI: 10.3389/fphar.2019.00315

Epilepsy is a neuronal disorder associated with several neurological and behavioral alterations characterized by recurrent spontaneous epileptic seizures. Despite having more than 20 anti-epileptic drugs (AEDs), they only provide a symptomatic treatment. As well as, currently available AEDs also displayed cognitive alterations in addition to retarding seizure. This leads to the need for exploring new molecules that not only retard seizure but also improve cognitive impairment. Embelin (EMB) is a benzoquinone derivative which has already demonstrated its pharmacological potentials against arrays of neurological conditions. The current study developed a chronic kindling model in adult zebrafish by using repeated administration of small doses of pentylenetetrazole (PTZ) and a single dose of Kainic acid (KA) to investigate the associated memory impairment. This has been done by using the three-axis maze which is a conventional method to test the learning ability and egocentric memory in zebrafish. As well as, the ameliorative potential of EMB has been evaluated against chronic epilepsy-related memory alterations. Moreover the expression level of pro-inflammatory genes such as C-C motif ligand 2 (CCL2), toll-like receptor-4 (TLR4), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interferon-γ (IFN-γ) were evaluated. The level of several neurotransmitters such as γ-aminobutyric acid (GABA), acetylcholine (Ach) and glutamate (Glu) was evaluated by liquid chromatography-mass spectrometry (LC-MS). The results showed that daily dose of PTZ 80 mg/kg for 10 days successfully induces a kindling effect in zebrafish, whereas the single dose of KA did not. As compared to control, the PTZ and KA group demonstrates impairment in memory as demonstrated by the three-axis maze. The PTZ group treated with a series of EMB doses (ranging from 0.156 to 0.625 mg/kg) was found to have retarded seizure as well as significantly reduces epilepsy-induced memory alteration. In addition, EMB treatment reduces the expression of inflammatory markers implicating its anti-inflammatory potential. Moreover, levels of GABA, Ach, and glutamate are increased in EMB administered group as compared to the PTZ administered group. Overall, findings demonstrate that EMB might be a potential candidate against chronic epilepsy-related cognitive dysfunction as EMB prevents the seizures, so we expect it to prevent the associated neuroinflammation and learning deficit.

Matched MeSH terms: Toll-Like Receptor 4
Fulltext Genetic polymorphisms in the CD14 gene are associated with monocyte activation and carotid intima-media thickness in HIV-infected patients on antiretroviral therapy

Yong YK, Shankar EM, Westhorpe CL, Maisa A, Spelman T, Kamarulzaman A, et al.

Medicine (Baltimore), 2016 Aug;95(31):e4477.
PMID: 27495090 DOI: 10.1097/MD.0000000000004477

HIV-infected individuals on antiretroviral therapy (ART) are at increased risk of cardiovascular disease (CVD). Given the relationship between innate immune activation and CVD, we investigated the association of single-nucleotide polymorphisms (SNPs) in TLR4 and CD14 and carotid intima-media thickness (cIMT), a surrogate measurement for CVD, in HIV-infected individuals on ART and HIV-uninfected controls as a cross-sectional, case-control study. We quantified the frequency of monocyte subsets (CD14, CD16), markers of monocyte activation (CD38, HLA-DR), and endothelial adhesion (CCR2, CX3CR1, CD11b) by flow cytometry. Plasma levels of lipopolysaccharide, sCD163, sCD14, sCX3CL1, and sCCL2, were measured by ELISA. Genotyping of TLR4 and CD14 SNPs was also performed. The TT genotype for CD14/-260SNP but not the CC/CT genotype was associated with elevated plasma sCD14, and increased frequency of CD11b+CD14+ monocytes in HIV-infected individuals. The TT genotype was associated with lower cIMT in HIV-infected patients (n = 47) but not in HIV-uninfected controls (n = 37). The AG genotype for TLR4/+896 was associated with increased CX3CR1 expression on total monocytes among HIV-infected individuals and increased sCCL2 and fibrinogen levels in HIV-uninfected controls. SNPs in CD14/-260 and TLR4/+896 were significantly associated with different markers of systemic and monocyte activation and cIMT that differed between HIV-infected participants on ART and HIV-uninfected controls. Further investigation on the relationship of these SNPs with a clinical endpoint of CVD is warranted in HIV-infected patients on ART.

Matched MeSH terms: Toll-Like Receptor 4/genetics
Genetic polymorphisms in the Toll-like receptor signalling pathway in Helicobacter pylori infection and related gastric cancer

Castaño-Rodríguez N, Kaakoush NO, Pardo AL, Goh KL, Fock KM, Mitchell HM

Hum Immunol, 2014 Aug;75(8):808-15.
PMID: 24929142 DOI: 10.1016/j.humimm.2014.06.001

Gastric cancer (GC) is a progressive process initiated by Helicobacter pylori-induced inflammation. Initial recognition of H. pylori involves Toll-like receptors (TLRs), central molecules in the host inflammatory response. Here, we investigated the association between novel polymorphisms in genes involved in the TLR signalling pathway, including TLR2, TLR4, LBP, MD-2, CD14 and TIRAP, and risk of H. pylori infection and related GC.

Matched MeSH terms: Toll-Like Receptor 4/genetics*; Toll-Like Receptor 4/immunology
Fulltext HMGB1-Mediated Neuroinflammatory Responses in Brain Injuries: Potential Mechanisms and Therapeutic Opportunities

Paudel YN, Angelopoulou E, Piperi C, Othman I, Shaikh MF

Int J Mol Sci, 2020 Jun 29;21(13).
PMID: 32610502 DOI: 10.3390/ijms21134609

Brain injuries are devastating conditions, representing a global cause of mortality and morbidity, with no effective treatment to date. Increased evidence supports the role of neuroinflammation in driving several forms of brain injuries. High mobility group box 1 (HMGB1) protein is a pro-inflammatory-like cytokine with an initiator role in neuroinflammation that has been implicated in Traumatic brain injury (TBI) as well as in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Herein, we discuss the implication of HMGB1-induced neuroinflammatory responses in these brain injuries, mediated through binding to the receptor for advanced glycation end products (RAGE), toll-like receptor4 (TLR4) and other inflammatory mediators. Moreover, we provide evidence on the biomarker potential of HMGB1 and the significance of its nucleocytoplasmic translocation during brain injuries along with the promising neuroprotective effects observed upon HMGB1 inhibition/neutralization in TBI and EBI induced by SAH. Overall, this review addresses the current advances on neuroinflammation driven by HMGB1 in brain injuries indicating a future treatment opportunity that may overcome current therapeutic gaps.

Matched MeSH terms: Toll-Like Receptor 4
Fulltext HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction

Paudel YN, Shaikh MF, Chakraborti A, Kumari Y, Aledo-Serrano Á, Aleksovska K, et al.

Front Neurosci, 2018;12:628.
PMID: 30271319 DOI: 10.3389/fnins.2018.00628

High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein released by glia and neurons upon inflammasome activation and activates receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR) 4 on the target cells. HMGB1/TLR4 axis is a key initiator of neuroinflammation. In recent days, more attention has been paid to HMGB1 due to its contribution in traumatic brain injury (TBI), neuroinflammatory conditions, epileptogenesis, and cognitive impairments and has emerged as a novel target for those conditions. Nevertheless, HMGB1 has not been portrayed as a common prognostic biomarker for these HMGB1 mediated pathologies. The current review discusses the contribution of HMGB1/TLR4/RAGE signaling in several brain injury, neuroinflammation mediated disorders, epileptogenesis and cognitive dysfunctions and in the light of available evidence, argued the possibilities of HMGB1 as a common viable biomarker of the above mentioned neurological dysfunctions. Furthermore, the review also addresses the result of preclinical studies focused on HMGB1 targeted therapy by the HMGB1 antagonist in several ranges of HMGB1 mediated conditions and noted an encouraging result. These findings suggest HMGB1 as a potential candidate to be a common biomarker of TBI, neuroinflammation, epileptogenesis, and cognitive dysfunctions which can be used for early prediction and progression of those neurological diseases. Future study should explore toward the translational implication of HMGB1 which can open the windows of opportunities for the development of innovative therapeutics that could prevent several associated HMGB1 mediated pathologies discussed herein.

Matched MeSH terms: Toll-Like Receptor 4
Fulltext Impact of HMGB1, RAGE, and TLR4 in Alzheimer's Disease (AD): From Risk Factors to Therapeutic Targeting

Paudel YN, Angelopoulou E, Piperi C, Othman I, Aamir K, Shaikh MF

Cells, 2020 02 07;9(2).
PMID: 32046119 DOI: 10.3390/cells9020383

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.

Matched MeSH terms: Toll-Like Receptor 4/metabolism*
Implication of HMGB1 signaling pathways in Amyotrophic lateral sclerosis (ALS): From molecular mechanisms to pre-clinical results

Paudel YN, Angelopoulou E, Piperi C, Othman I, Shaikh MF

Pharmacol Res, 2020 06;156:104792.
PMID: 32278047 DOI: 10.1016/j.phrs.2020.104792

Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly progressing neurodegenerative disorder with no effective disease-modifying treatment up to date. The underlying molecular mechanisms of ALS are not yet completely understood. However, the critical role of the innate immune system and neuroinflammation in ALS pathogenesis has gained increased attention. High mobility group box 1 (HMGB1) is a typical damage-associated molecular pattern (DAMP) molecule, acting as a pro-inflammatory cytokine mainly through activation of its principal receptors, the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) which are crucial components of the innate immune system. HMGB1 is an endogenous ligand for both RAGE and TLR4 that mediate its biological effects. Herein, on the ground of pre-clinical findings we unravel the underlying mechanisms behind the plausible contribution of HMGB1 and its receptors (RAGE and TLR4) in the ALS pathogenesis. Furthermore, we provide an account of the therapeutic outcomes associated with inhibition/blocking of HMGB1 receptor signalling in preventing motor neuron's death and delaying disease progression in ALS experimental models. There is strong evidence that HMGB1, RAGE and TLR4 signaling axes might present potential targets against ALS, opening a novel headway in ALS research that could plausibly bridge the current treatment gap.

Matched MeSH terms: Toll-Like Receptor 4/metabolism*
Fulltext Inducible RasGEF1B circular RNA is a positive regulator of ICAM-1 in the TLR4/LPS pathway

Ng WL, Marinov GK, Liau ES, Lam YL, Lim YY, Ea CK

RNA Biol, 2016 09;13(9):861-71.
PMID: 27362560 DOI: 10.1080/15476286.2016.1207036

Circular RNAs (circRNAs) constitute a large class of RNA species formed by the back-splicing of co-linear exons, often within protein-coding transcripts. Despite much progress in the field, it remains elusive whether the majority of circRNAs are merely aberrant splicing by-products with unknown functions, or their production is spatially and temporally regulated to carry out specific biological functions. To date, the majority of circRNAs have been cataloged in resting cells. Here, we identify an LPS-inducible circRNA: mcircRasGEF1B, which is predominantly localized in cytoplasm, shows cell-type specific expression, and has a human homolog with similar properties, hcircRasGEF1B. We show that knockdown of the expression of mcircRasGEF1B reduces LPS-induced ICAM-1 expression. Additionally, we demonstrate that mcircRasGEF1B regulates the stability of mature ICAM-1 mRNAs. These findings expand the inventory of functionally characterized circRNAs with a novel RNA species that may play a critical role in fine-tuning immune responses and protecting cells against microbial infection.

Matched MeSH terms: Toll-Like Receptor 4/metabolism*

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