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Probiotics Modulate Cell Signaling Pathway and Innate Cytokine Responses to Oral HRV Vaccine in HGM-Transplanted Gn Pigs
Published in Lijuan Yuan, Vaccine Efficacy Evaluation, 2022
TLR4 recognizes lipopolysaccharide from gram-negative bacteria. In this study, the level of TLR4 mRNA in AttHRV+LGG9X pigs was slightly but statistically higher than that in the non-LGG-fed AttHRV pigs. The effect of LGG on TLR4 mRNA levels can only be indirect since LGG does not contain TLR4 ligands. In general, the TLR4 level is down-regulated by anti-inflammatory probiotics (Villena and Kitazawa, 2014). In the present study, the increase in TLR4 mRNA levels is consistent with the increased pro-inflammatory cytokine responses in the AttHRV+LGG9X pigs. The possible reasons for the upregulated TLR4 can be the increased richness and diversity of microbiota in the AttHRV+LGG9X pigs and that certain bacterial species in the microbiota promoted TLR4 expression.
Neurodevelopmental Considerations in the Patient With Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Panagiotis Kratimenos, Frances J. Northington
Recent work highlights the role of the toll-like receptor 4 (TLR4) in NEC. TLR4, a bacterial receptor associated with gram-negative organisms (typically involved in NEC), appears to be a key factor in the mechanism of NEC-induced brain injury (57, 96, 97). Nino et al. developed a mouse model of NEC by combining rapidly advancing feeds, stool material from human neonates with NEC, and hypoxia to mice. They showed that when TRL4 knockout mice underwent this NEC induction protocol, their intestinal villi remained intact, which highlights the important role of TLR4 in the pathobiology of NEC (98). The group investigated the effect of intestinal inflammation on the brain by analyzing postmortem human brains of patients with NEC and brain regions of their mouse model of NEC. Significant neuropathological alterations, primarily involving the white matter of the frontal and temporal lobes, as well as the subcortical white matter, were noted in both human and mouse brain (96). There was a massive accumulation of reactive oxygen species (ROS) and significant microglial activation (measured as elevated ionized calcium-binding adaptor molecule 1, Iba-1), but interestingly, TLR4s were activated in the microglia secondary to the release of high mobility group protein B1 (HMGB1) from the necrotic intestinal epithelium. As expected, mice with NEC were characterized by significant neurocognitive decline (96). Administration of a nanoparticle coupled to the antioxidant N-acetyl-L-cysteine (NAC) resulted in attenuated neuropathology and neuroimaging alterations and improved neurobehavior in mice with NEC (96).
The Opioid Epidemic
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Morphine-induced hyperalgesia appears to have a distinct pathway from tolerance. Hyperalgesia requires microglia. Specifically, morphine-induced hyperalgesia requires the expression of P2X4 receptor in the microglia. Chronic exposure to morphine causes an increase in P2X4 receptor expression by a µ-receptor-dependent mechanism. P2X4 receptor stimulation results in the release of brain-derived neurotrophic factor (BDNF). BDNF through TrkB downregulates a K+-Cl− cotransporter (KCC2) expression in lamina I neurons causing an impairment in Cl− extrusion through a µ-receptor-independent mechanism. So, a µ-receptor-dependent mechanism is required to activate the microglia, but a µ-receptor-independent mechanism is responsible for the microglia-neuron signaling. Toll-like receptor 4 (TLR4) was not involved in the µ-receptor independent mechanism.28
Short-term use of ceftriaxone sodium leads to intestinal barrier disruption and ultrastructural changes of kidney in SD rats
Published in Renal Failure, 2023
Wenli Zou, Yueming Liu, Wei Zhang, Bo Lin, Wei Shen, Yiwen Li, Qiang He, Juan Jin
Interestingly, the rats in the TAK group, which also received antibiotics, showed less change in colonic ultrastructure than that in the Cef group. Recent evidence shows that TLRs recognize specific patterns of microbial components, especially those from pathogens, and regulate the activation of both innate and adaptive immunity, and participate in maintaining colonic homeostasis [26,27]. Among these TLRs, TLR4 recognizes lipopolysaccharide (LPS) in particular and is primarily involved in the control of gram-negative bacteria. Resatorvid (TAK-242), an inhibitor of TLR4 signaling, inhibits the production of LPS-induced inflammatory mediators by binding to the intracellular domain of TLR4 [28]. Because of its suppression of cytokine levels, TAK-242 is known to be a new therapeutic agent for inflammatory diseases [29,30]. Although secreted mucin is expressed constitutively by goblet cells, its production is upregulated by TLR signaling to replenish those degraded by commensals or removed by peristalsis [31]. Our results confirmed the role of TLR signaling in maintaining intestinal barrier function.
Deletion of toll-like receptor 4 ameliorates diabetic retinopathy in mice
Published in Archives of Physiology and Biochemistry, 2023
TLR4 is a transmembrane protein as well as a member of the TLR family. TLR family is a highly conserved family with structural and functional similarities, which facilitates in pathogen recognition and activation of innate immunity. They recognise some infectious pathogen and stimulate the secretion of inflammatory cytokines, which participate in the development of effective immunity. The activation of TLR4 also initiates the intracellular signalling pathway leading to the secretion of inflammatory cytokines, which results in inflammation-related physiological and pathological process (Liu et al. 2012). TLR4 is well-known for recognising lipopolysaccharide (LPS), which is expressed in many Gram-negative bacteria and select Gram-positive bacteria (Lu et al. 2008). TLR4 also recognises some vital proteins, and a wide range of endogenous proteins, including low-density lipoprotein (LDL), beta-defensins, and heat shock protein.
Disulfiram ameliorates ischemia/reperfusion-induced acute kidney injury by suppressing the caspase-11-GSDMD pathway
Published in Renal Failure, 2022
Qiaoting Cai, Zhaoxing Sun, Sujuan Xu, Xiaoyan Jiao, Shulan Guo, Yingxiang Li, Huan Wu, Xiaofang Yu
TLR4 was reported to be activated by DAMPs in kidney IR injury [35]. We measured TLR4 expression in the IR and HR models by western blotting (Figure 7a and b) and found that TLR4 protein expression was significantly upregulated in both models, while treatment with disulfiram did not reduce TLR4 expression. The TLR4 protein structure is divided into three domains: extracellular receptors, transmembrane domains, and intracellular receptors. In the presence of DAMPs, the intracellular segment of the TLR4-TIR domain dimerizes, enabling TLR4 activation and upregulating caspase-11 expression. The flexible BB loop of the TIR domain (the region between the αB chain and βB chain) may be the site of TIR dimerization, and mutations in this region could seriously affect the function of proteins containing TIR domains [36]. Therefore, it is reasonable to hypothesize that disulfiram may inhibit TLR4 activation by affecting the dimerization of the TIR domain, thus reducing the upregulation of caspase-11 expression. We established a protein model of the TIR domain by the homology modeling method. Through flexible molecular docking, we found that disulfiram could bind to the BB loop pocket of the TIR protein through hydrophobic interactions (Figure 7c and d), which may affect the conformation of the loop, thus affecting the binding of downstream proteins.