Functional Two-Way Crosstalk Between Brain and Lung: The Brain-Lung Axis.

The brain has many connections with various organs. Recent advances have demonstrated the existence of a bidirectional central nervous system (CNS) and intestinal tract, that is, the brain-gut axis. Although studies have suggested that the brain and lung can communicate with each other through many pathways, whether there is a brain-lung axis remains still unknown. Based on previous findings, we put forward a hypothesis: there is a cross-talk between the central nervous system and the lung via neuroanatomical pathway, endocrine pathway, immune pathway, metabolites and microorganism pathway, gas pathway, that is, the brain-lung axis. Beyond the regulation of the physiological state in the body, bi-directional communication between the lung and the brain is associated with a variety of disease states, including lung diseases and CNS diseases. Exploring the brain-lung axis not only helps us to understand the development of the disease from different aspects, but also provides an important target for treatment strategies.

Ripks and Neuroinflammation.

Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).

Identification of cholest-4-ene-3,6-dione as a Novel Neuroprotectant in Ischemic Stroke and Its Lipidomics.

Purpose: Stroke is a leading cause of disability and death globally. However, there are few clinical drugs for stroke therapy. Novel and effective neuroprotectants are called on the way. Methods: In this study, 93 steroids from a constructed steroidal library were randomly numbered and blindly evaluated in an L-glutamate-induced HT-22 oxidative stress model. The neuroprotective effects of 5 candidates were further investigated in potassium deprivation-induced apoptosis of cerebellar granule neurons (CGNs), D-glutamate-induced excitotoxicity of CGNs, and cortical neuron (CN) models. Results: Interestingly, unblinding revealed that cholest-4-ene-3,6-dione (78), a cholesterol derivative, was first found to have comprehensive neuroprotective effects in all cell models. 78 administration also decreased the infarction volume and improved motor function in middle cerebral artery occlusion (MCAO) model rats. Additionally, 78 treatment decreased intercellular reactive oxygen species (ROS) and NO production in the HT-22 cell model. Finally, lipidomics and molecular docking results showed that 78 may exert its neuroprotective effects by increasing platelet-activating factor (PAF) analog 1-(9Z-pentadecenoyl)-glycero-3-phosphocholine production. Conclusion: This study indicates that 78, a novel neuroprotectant, is a promising therapeutic candidate with comprehensive neuroprotective effects for the treatment of ischemic stroke by decreasing ROS/reactive nitrogen species (RNS) levels and increasing 1-(9Z-pentadecenoyl)-glycero-3-phospho-choline production.

Vanillin Attenuates Proinflammatory Factors in a tMCAO Mouse Model via Inhibition of TLR4/NF-kB Signaling Pathway.

Vanillin has been reported to reduce hippocampal neuronal death in rat models of global cerebral ischemia. However, the immunoregulatory mechanism of vanillin in ischemic stroke is still unclear. To investigate the role of vanillin in a mouse model of ischemic stroke, we administered vanillin to mice after transient middle cerebral artery occlusion (tMCAO) by tail vein injection. Vanillin reduced infarct volume and improved motor function in mice after ischemia and reperfusion. IL-1ß and TNF-α were decreased in ischemic brain tissue of tMCAO mice after vanillin treatment compared with saline treatment. Similar effects were observed using the in vitro LPS-stimulated microglia cell model. Moreover, the reduced expression of proinflammatory cytokines in the vanillin group was related to TLR4/NF-κB signaling. Taken together, the findings suggest that vanillin decreased microglial activation by inhibiting the TLR4 /NF-κB signaling pathway, which reduced expression of proinflammatory cytokines IL-1ß and TNF-α, and finally reduced the infarct volume and improved motor function in tMCAO mice.