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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
Urinary Tract Infections (UTI)
Published in Manit Arya, Taimur T. Shah, Jas S. Kalsi, Herman S. Fernando, Iqbal S. Shergill, Asif Muneer, Hashim U. Ahmed, MCQs for the FRCS(Urol) and Postgraduate Urology Examinations, 2020
Nish Bedi, Ali Omar, Jas S. Kalsi
Pathogen recognition receptors Toll-like receptor (TLR) 4 and TLR5 appear the most important receptors for endotoxins, with TLR4 recognising lipopolysaccharide (LPS), as the major component of the cell wall in Gram-negative bacteria.
Daphnetin alleviates neuropathic pain in chronic constrictive injury rats via regulating the NF-κB dependent CXCL1/CXCR2 signaling pathway
Published in Pharmaceutical Biology, 2023
Tianrui Zhang, Wulin Liang, Wenjing Ou, Mingqian Zhang, Shuang Cui, Shuofeng Zhang
To explore how daphnetin interferes with the expression of NF-κB, we used western blot technology to explore the upstream and downstream related proteins of NF-κB. Toll-like receptor 4 (TLR4) is a pattern recognition receptor belonging to the toll-like receptor (TLR) family that contains an extracellular domain and an intracellular domain (Medzhitov et al. 1997). β-Arrestins, such as IKBα, can interact with TLR4 signaling molecules and mediate NF-κB activity (Zhang et al. 2020). We measured the protein expression of TLR4, IKBα, and p-IKBα by western blot technology and calculated the p-IKBα/IKBα protein ratio. Compared with the Sham group, the expression of TLR4 and p-IKBα and the ratio of p-IKBα/IKBα protein in the Model group were significantly increased (p < 0.01). After the injection of daphnetin, the expression of TLR4 and p-IKBα and the ratio of p-IKBα/IKBα protein were significantly downregulated (p < 0.01). The above experimental data proved that daphnetin regulates the protein expression of NF-κB in the spinal cord astrocytes of CCI rats by downregulating TLR4 and inhibiting the phosphorylation of IKBα (Figure 3).
Indole derivative XCR-5a alleviates LPS-induced inflammation in vitro and in vivo
Published in Immunopharmacology and Immunotoxicology, 2022
Jiajing Zhao, Prasanta Roy, Haimei Tang, Xingyu Ma, Qianqian Di, Jiazheng Quan, Yonghong Guan, Xiaoli Li, Weilie Xiao, Weilin Chen
The pathogen-associated molecular patterns (PAMPs), most of which are pathogen-related elements, can be recognized by innate immune cells via binding to the pattern-recognition receptors (PRRs) [4]. Among them, the toll-like receptor 4 (TLR4) related signaling pathway plays a significant role in the activation of the innate immune response. Furthermore, bacterial endotoxin activation of the TLR4 signaling pathway is a major cause of chronic and acute inflammatory illnesses [5]. In response to LPS stimulation, TLR4 gathers lipid rafts and interacts with its adjacent connector molecules [6]. LPS is a bioactive endotoxin on the membrane of Gram-negative bacterium that can stimulate macrophages to produce inflammatory cytokines. In addition, LPS activates cells by binding to TLR4 on the membrane, which causes downstream signal transmission, leading to the release of inflammatory mediators via two signaling pathways: nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs).
Neuroprotective role of camphor against ciprofloxacin induced depression in rats: modulation of Nrf-2 and TLR4
Published in Immunopharmacology and Immunotoxicology, 2021
Abeer Salama, Hend Abd-AlHakim Mahmoud, Mohamed Ahmed Kandeil, Marwa Mahmoud Khalaf
The pathophysiology of depression had been recorded to be linked with neuroinflammation [50]. The severity of depression is associated with increased cytokines levels in the brain [51]. These cytokines as IL-6, and TNF-α are considered as depression progression contributors [52]. Toll-like receptor 4 is responsible for inflammatory disorders and plays an essential key in the innate immune response initiation [53]. TLR4 induces the pro-inflammatory cytokines synthesis like TNF-α [54] that affected the neuron function [55]. The current results clarified an elevation of brain contents of TNF-α and TLR4 after 21 days of depression induction, indicating a potential inflammatory response upon administration of ciprofloxacin. An increase in TNF-α after ciprofloxacin administration in male Wistar rats was also observed [9]. Treatment with both doses of camphor concurrently with ciprofloxacin significantly decreased brain content of TNF-α and TLR4, indicating a potential anti-inflammatory effect of camphor. Camphor was previously reported to have anti-inflammatory activity by reducing leukocyte migration and chemotactic mediators [17] and through inhibiting TNF-α and IL-1β produced from macrophage cells [18]. C. camphora displayed anti-inflammatory action because of the modulation of cytokine, NO, and PGE2 production and oxidative stress [18]. Moreover, Cinnamomum cinnamaldehyde inhibited TLR4 signaling pathway [56].