Role for IRAK-4 and p38 in Neutrophil Signaling in Response to Bacterial Lipoproteins from Staphylococcus aureus.

被引量：- 发表：1970

Low-Protein Diet Inhibits the Synovial Tissue Macrophage Pro-Inflammatory Polarization Via NRF2/SIRT3/SOD2/ROS Pathway in K/BxN Rheumatoid Arthritis Mice.

被引量：- 发表：1970

Functional Upregulation of TRPM3 Channels Contributes to Acute Pancreatitis-associated Pain and Inflammation.

Transient receptor potential melastatin M3 (TRPM3) channels have been recognized as a pain transducer in dorsal root ganglion (DRG) neurons in recent years. TRPM3 activation initiates neurogenic inflammation and is required for the development of inflammatory hyperalgesia. We aimed to evaluate the role of TRPM3 in pancreas sensory afferents in pancreatic nociception, neurogenic inflammation, and acute pancreatitis (AP)-associated pain. AP was induced by intraperitoneal (i.p.) injection of L-arginine in rats. TRPM3 expression in pancreatic DRG neurons, spontaneous or mechanical-stimulation-evoked pain behaviors, and the extent of inflammation were evaluated. We found that TRPM3 channels were expressed on pancreatic primary afferent nerve terminals containing calcitonin gene-related peptide (CGRP). Activation of TRPM3 in the pancreas by injection of its specific agonist CIM0216 (10 μM) induced pain, CGRP and substance P release, and neurogenic inflammation, as evidenced by edema, plasma extravasation, and inflammatory cell accumulation in the pancreas. Increased TRPM3 functional expression was detected in pancreatic DRG neurons from AP rats, and blocking TRPM3 activity with its antagonist (Primidone, 5 mg/kg, i.p.) attenuated AP-associated pain behaviors and pancreatic inflammation. Pre-incubation of pancreatic DRG neurons with nerve growth factor (NGF) enhanced the increase in intracellular Ca2+ induced by the TRPM3 agonist (CIM0216, 1 μM). Our findings indicate that, in addition to TRPV1 and TRPA1 channels, TRPM3 is another pain channel that has a critical role in pancreatic nociception, neurogenic inflammation, and AP-associated pain behaviors. TRPM3 may be a promising pharmaceutical target for AP pain treatment.

被引量：- 发表：1970

Phosphorylation of Serine 536 of p65(RelA) Downregulates Inflammatory Responses.

Nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of various genes involved in inflammatory diseases and immune responses. Recently, a novel transcriptional regulatory mechanism of NF-κB involving the phosphorylation of serine 536 (534 in mice; S534) of its p65 subunit was reported; however, further research is required to elucidate the physiological role of S534 phosphorylation. Therefore, we generated S534A knock-in (KI) mice, in which the S534 of p65 was substituted with alanine. Similar to the wild-type (WT) mice, S534A KI mice developed normally. After stimulation with tumor necrosis factor α (TNFα), mouse embryonic fibroblasts (MEFs) derived from S534A KI mice exhibited increased target gene expression compared with that in the WT MEFs, which was induced by long-term binding of p65 to DNA. According to comprehensive gene expression analysis after stimulation with TNFα, the expression of genes p65ted to inflammatory and immune responses was increased, and the expression of genes p65ted to lipolysis was decreased in S534A KI MEFs. Analyses of a periodontal disease model established using WT and S534A KI mice revealed that alveolar bone resorption was enhanced in S534A KI mice owing to an increase in the number of osteoclasts, which was not attributed to the differentiation of osteoclast precursor cells but to an increased expression of interleukin-1β and receptor activator of NF-κB ligand in the periodontal tissue. Hence, phosphorylation of S536 negatively regulates inflammatory responses in vitro and in vivo.

被引量：- 发表：1970

The Neuroprotective Effects of Agmatine on Parkinson's Disease: Focus on Oxidative Stress, Inflammation and Molecular Mechanisms.

Agmatine (AGM), a naturally occurring polyamine derived from L-arginine, has shown significant potential for neuroprotection in Parkinson's Disease (PD) due to its multifaceted biological activities, including antioxidant, anti-inflammatory, and anti-apoptotic effects. This review explores the therapeutic potential of AGM in treating PD, focusing on its neuroprotective mechanisms and evidence from preclinical studies. AGM has been demonstrated to mitigate the neurotoxic effects of rotenone (ROT) by improving motor function, reducing oxidative stress markers, and decreasing levels of pro-inflammatory cytokines in animal models. Additionally, AGM protects against the loss of TH + neurons, crucial for dopamine synthesis. The neuroprotective properties of AGM are attributed to its ability to modulate several key pathways implicated in PD pathogenesis, such as inhibition of NMDA receptors, activation of Nrf2, and suppression of the HMGB1/ RAGE/ TLR4/ MyD88/ NF-κB signaling cascade. Furthermore, the potential of agmatine to promote neurorestoration is highlighted by its role in enhancing neuroplasticity elements such as CREB, BDNF, and ERK1/2. This review highlights agmatine's promising therapeutic potential in PD management, suggesting that it could offer both symptomatic relief and neuroprotective benefits, thereby modifying the disease course and improving the quality of life for patients. Further research is warranted to translate these preclinical findings into clinical applications.

被引量：- 发表：1970