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Anatomy of the Respiratory Neural Network
Published in Susmita Chowdhuri, M Safwan Badr, James A Rowley, Control of Breathing during Sleep, 2022
Christopher A Del Negro, Christopher G Wilson
Respiratory rhythmic activity in pFV neurons goes away with age such that in adult rodents, the pFV neurons spike tonically without evidence of respiratory rhythmicity. Instead, their firing rate is modulated by pH and CO2 (145, 149). Nevertheless, even while embryonic Phox2b-expressing pFV neurons are respiratory rhythmic, their status as a central chemoreceptor is already well established (150). The mechanism of chemosensation depends on GPR4 receptors that bind protons and then regulate TASK2-type K+ channels (151, 152). KCNQ (i.e., KV7) type K+ channels also play a role in the chemosensory function of pFV neurons (153, 154).
The N-Formylpeptide Chemotactic Receptor
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
FPR is encoded by a single copy gene ~6 kb in length (gene symbol FPR1).47,48,103 The FPR gene colocalizes on human chromosome 19q13.3 with the genes for FPRL1, FPRL2, the C5a receptor, and an orphan G protein-coupled receptor designated GPR4.103,105 FPR gene organization is fairly unusual: the entire ORF, the entire 3′ UTR and the 11 nt upstream of the ATG translation initiation codon reside on the same exon; however, the remaining 132 nt of the 5′ untranslated region (UTR) reside on two additional alternatively spliced exons (Figure 5). The start sites for transcription and translation are separated by ~5 kb. FPR1 contains three Alu repeats, one in each intron and a third in the 3′ flanking region. A major and three minor transcriptional start points have been mapped by primer extension analysis.47 The upstream sequence presumably contains the gene promoter: a nonconsensus TATA element is present 23 nt upstream from the major transcription start point. A 121 bp PvuII fragment of the FPR gene, containing 43 bp upstream of the transcription start point, exon 1 and the 5′ end of intron 1, contained promoter activity when cloned upstream of a chloramphenicol acetyltransferase reporter and transfected into COS cells. Gene regions immediately upstream from the PvuII fragment lacked activity. It will be important to confirm this result in a myeloid cell environment to begin to delineate the transcription factors responsible for expression of this gene in mature myeloid cells.
The double-edged sword of probiotic supplementation on gut microbiota structure in Helicobacter pylori management
Published in Gut Microbes, 2022
Ali Nabavi-Rad, Amir Sadeghi, Hamid Asadzadeh Aghdaei, Abbas Yadegar, Sinéad Marian Smith, Mohammad Reza Zali
The interaction between H. pylori infection and SCFA is far from being fully elucidated, yet the reduction of SCFA has been reported in the feces of H. pylori-infected mice.111 Specifically, butyrate promotes intestinal barrier function via activating AMP-activated protein kinase (AMPK) or inhibiting claudin-2 production to stimulate the expression of tight junction proteins.40 Through the G protein-coupled receptor 4 (GPR4) and mammalian target of rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, butyrate promotes AMPs expression in epithelial cells. SCFAs might lead to NLR family pyrin domain containing 3 (NLRP3) inflammasome activation by GPR4 receptor inducing IL-18 secretion from the epithelium. GPR109A is a surface receptor on DCs and macrophages that detects butyrate and further induces the development of regulatory T cells (Treg) and prevents the proliferation of T helper 17 (Th17) cells.112 Moreover, butyrate can suppress the production of iNOS, TNF-α, IL-6, MCP-1, and IFN-γ by inhibiting NF-κB activation.113 On the other hand, propionate downregulates the production of pro-inflammatory cytokines including IL-4, IL-5, and IL-17A, and stimulates Treg cells to release the anti-inflammatory cytokine IL-10. In LPS-activated monocytes, propionate is reported to inhibit TNF-α and iNOS expression.45 It is also suggested that the interaction of SCFAs with DCs elevates retinoic acid (RA) production and consequently increases IgA secretion by B cells in lamina propria.114
Lactic acid in macrophage polarization: The significant role in inflammation and cancer
Published in International Reviews of Immunology, 2022
Hai-cun Zhou, Wen-wen Yu, Xiao-qin Liang, Xiao-yan Du, Zhi-chang Liu, Jian-ping Long, Guang-hui Zhao, Hong-bin Liu
The signaling transduction function of lactic acid in extracellular space is mediated by the activation of G-protein-coupled receptor GPR [5,23–26]. In physiological environment, lactic acid binds to GPR81, thus inhibiting lipolysis in adipocytes [27]. In cancers, GPR81 is highly expressed in different cancer cell lines, including colon cancer, breast cancer, lung cancer, liver cancer, cervical cancer, and pancreatic cancer [28,29]. In vitro, the expression of GPR81 is associated with the survival, proliferation, migration, invasion and chemotherapy resistance of cancer cells, and participates in the inhibition of anti-tumor immunity by promoting the overexpression of PD-L1 in lung cancer cell lines [28]. During inflammation, lactic acid activated the GPR81-mediated pathway, inhibitted inflammation and reduced organ damage [30]. Another study revealed that high levels of lactic acid produced during childbirth acted on uterine GPR81, and down-regulated the key pro-inflammatory genes [31]. In addition, GPR4, GPR65, GPR68 and GPR132, acted as lactic acid sensors, are activated in acidic tumor microenvironment (TME) due to the low pH value of lactic acid [32]. It remains to be clarified whether the regulation of the lactic acid signaling pathway occurs directly through GPR-lactic acid interaction or through conformational modification of the receptor induced by lactic acidosis.
Identifying molecular mechanisms of acute to chronic pain transition and potential drug targets
Published in Expert Opinion on Therapeutic Targets, 2022
Kannan Aravagiri, Adam Ali, Hank C Wang, Kenneth D Candido, Nebojsa Nick Knezevic
Another target to prevent chronic pain formation involves proton-sensing receptor proteins such as ASIC and acid-sensing GPCR. As previously stated, these receptor proteins have been noted to be upregulated to help catalyze the sensitization and further priming of chronic pain, neuropathic pain, and visceral pain [33–35]. Amiloride, a potassium-sparing diuretic that is widely used in treating hypertension, has been found to inhibit ASIC, especially regarding nociceptive transmission [36]. Studies involving amiloride as a potential novel chronic pain adjuvant or treatment are limited though, with one finding benefit in pain reduction upon direct injury and inflammation in animal studies and another, a phase 2 clinical trial, on the effects of amiloride in the setting of optic neuritis that has completed recruitment (Table 1) [36,37]. GPCR have also been noted to participate in peripheral and central chronic pain priming/sensitization [38]. As Retamal et al. has discussed thoroughly, there are many types of GPCR (nearly 40 and counting) that are involved in the pain sensitization/priming process [38]. However, discriminating between whether GPCR are anti- or pro-nociceptive or whether they play a significant role in the pain transmission process has proven challenging. Thus, focusing on GPCR proven to be involved in the conduction of nociceptive information such as proton-sensing GPCR may serve as a more optimal means in preventing CPSP than focusing on the breadth of GPCR already discovered to participate in the process. Some therapeutic mechanisms in preventing GPCR activation include either competitively inhibiting GPCR with the use of monoclonal antibodies or using pepducins, peptides that can act intracellularly, to alter the course of the intracellular actions of GCPRs, thereby impeding the priming process required in acute to chronic transition [39]. Additionally, four specific proton-sensing GPCR (GPR4, TDAG8, OGR1, and G2A) have been shown to be expressed in DRG and are suggested to play a role in inflammatory and neuropathic pain [40]. Thus, these GPCR could be the targets of therapeutic intervention with regard to CPSP as well. However, like ASIC, the use of GPCR targeting with regard to the management or even prevention of CPSP is relatively new and to date has been understudied so further research is required in order to truly clarify their effectiveness in chronic pain prevention.