The journal of pharmacology and experimental therapeutics

The blood-brain barrier (BBB) is an important physiological barrier that separates the central nervous system (CNS) from the peripheral circulation, which contains inflammatory mediators and immune cells. The BBB regulates cellular and molecular exchange between the blood vessels and brain parenchyma. Normal functioning of the BBB is crucial for the homeostasis and proper function of the brain. It has been demonstrated that peripheral inflammation can disrupt the BBB by various pathways, resulting in different CNS diseases. Recently, clinical research also showed CNS complications following SARS-CoV-2 infection and chimeric antigen receptor (CAR)-T cell therapy, which both lead to a cytokine storm in the circulation. Therefore, elucidation of the mechanisms underlying the BBB disruption induced by peripheral inflammation will provide an important basis for protecting the CNS in the context of exacerbated peripheral inflammatory diseases. In the present review, we first summarize the physiological properties of the BBB that makes the CNS an immune-privileged organ. We then discuss the relevance of peripheral inflammation-induced BBB disruption to various CNS diseases. Finally, we elaborate various factors and mechanisms of peripheral inflammation that disrupt the BBB.

Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms.

Journal of Orthopaedic and Sports Physical Therapy

Despite many years of research, no biomarkers for stroke are available to use in clinical practice. Progress in high-throughput technologies has provided new opportunities to understand the pathophysiology of this complex disease, and these studies have generated large amounts of data and information at different molecular levels. The integration of these multi-omics data means that thousands of proteins (proteomics), genes (genomics), RNAs (transcriptomics) and metabolites (metabolomics) can be studied simultaneously, revealing interaction networks between the molecular levels. Integrated analysis of multi-omics data will provide useful insight into stroke pathogenesis, identification of therapeutic targets and biomarker discovery. In this Review, we detail current knowledge on the pathology of stroke and the current status of biomarker research in stroke. We summarize how proteomics, metabolomics, transcriptomics and genomics are all contributing to the identification of new candidate biomarkers that could be developed and used in clinical stroke management. In this Review, Montaner and colleagues summarize how proteomics, genomics, transcriptomics and metabolomics are contributing to the discovery and development of biomarkers in stroke, and how bringing them together with integromics could provide new biomarkers and therapeutic opportunities.

Multilevel omics for the discovery of biomarkers and therapeutic targets for stroke.

Pharmacology and experimental therapeutics : a survey for 1941-1946

Research progress of mechanisms and drug therapy for neuropathic pain

Ischemic stroke is one of the leading health issues and the major cause of permanent disability in adults worldwide. Energy depletion and hypoxia occurring after ischemic stroke result in cell death, which activates resident glia cells and promotes the peripheral immune cells breaching into brain performing various functions even contradictory effects. The infiltration of immune cells may mediate neuron apoptosis and escalate ischemic damage, while it enhances neuron repair, differentiation, and neuroregeneration. The central nervous system (CNS) is immune-privileged site as it is separated from the peripheral immune system by the blood-brain barrier (BBB). Pathologically, the diapedesis of peripheral immune cells to CNS is controlled by BBB and regulated by immune cells/endothelial interactions. As immune responses play a key role in modulating the progression of ischemic injury development, understanding the characteristics and the contribution on regulating inflammatory responses of glia cells and peripheral immune cells may provide novel approaches for potential therapies. This review summarizes the multistep process of periphery immune cell extravasation into brain parenchyma during immunosurveillance and chronic inflammation after ischemic stroke onset. Furthermore, the review highlights promising target intervention, which may promote the development of future therapeutics for ischemic stroke.

Immune Cells After Ischemic Stroke Onset: Roles, Migration, and Target Intervention

Background: Tumor compression-induced pain (TCIP) is a complex pathological cancer pain. Spinal glial cells play a critical role in maintenance of cancer pain by releasing proinflammatory cytokines and chemokines. In this study, we verified the role of levo-corydalmine (l-CDL) on TCIP. Methods: Spontaneous pain, paw withdrawal threshold and latency were assessed using TCIP mouse model. Immunofluorescence was used to identify the reactions of glia. RT-PCR and western blot or ELISA were used to determine mRNA or protein expression of tumor necrosis factor-α (TNF-α), interlukin-1β (IL-1β), CC chemokine ligand 2 (CCL2) and chemotactic cytokine receptor 2 (CCR2) in vivo and in vitro. Results: l-CDL significantly attenuated TCIP hypersensitivity, accompanying with downregulation of TNF-α and IL-1β expression levels and declined astrocytes and microglial activation. It also significantly decreased the expression of the mRNA and protein level for CCL2 and CCR2. Further, l-CDL could suppress TNF-α-induced astrocytes activation and IL-1β expression through downregulating the CCL2/CCR2. Besides, CCL2-induced BV-microglia activation and inflammatory factors secretion were suppressed by l-CDL via CCR2. Conclusions: Suppression of CCL2/CCR2 by l-CDL may contribute to alleviate TCIP, offering an alternative medication for TCIP.

https://www.mdpi.com/1420-3049/22/6/937/pdf

Levo-Corydalmine Alleviates Neuropathic Cancer Pain Induced by Tumor Compression via the CCL2/CCR2 Pathway

1-(5-(1H-Indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (KFP-H008), a novel potassium-competitive acid blocker developed for the treatment of acid-related diseases, has been reported to inhibit gastric acid secretion effectively, while its effects on gastric ulcer have not been previously explored. The current study aimed to investigate the protective potential of KFP-H008 on ethanol-induced gastric ulcer and gastric epithelial cell damage. 0.2 ml absolute ethanol and 5% ethanol were applied to establish a gastric ulcer model in vivo and in vitro, respectively. In vivo, pre-treatment with KFP-H008 reduced ethanol-induced gastric ulcer index (gross lesions) and histopathological scores (microscopic lesions), and also decreased the expressions of malonaldehyde (MDA), NO and myeloperoxidase (MPO), along with the decline of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) or iNOS in tissues and serum. Meanwhile, the levels of superoxide dismutase (SOD) and glutathione (GSH) were both increased. Pre-treatment with KFP-H008 also effectively down-regulated the protein expression of p-p38 mitogen-activated protein kinase (MAPK) and p65 nuclear factor-κB (NF-κB) in ethanol-treated gastric tissues. In vitro, pre-treatment of KFP-H008 promoted the cell viability after challenge of 5% ethanol, and suppressed the expression of TNF-α, IL-1β, IL-6 or iNOS in cell supernatant. Furthermore, the activations of p38 MAPK and NF-κB in GES-1 cells induced by ethanol were reversed by KFP-H008. In all, KFP-H008 presented protective effects against gastric ulcer and the underlying mechanism might be associated with the antioxidant properties and anti-inflammatory status through p38 MAPK/NF-κB pathway.

/pdf/anti-ulcerogenic-effect-of-kfp-h008-against-ethanol-induced-1m18db8lxj.pdf

Anti-ulcerogenic effect of KFP-H008 against ethanol-induced gastric ulcer via p38 MAPK/NF-κB pathway

Stroke is the fifth leading cause of death worldwide and is a main cause of disability in adults. Neither currently marketed drugs nor commonly used treatments can promote nerve repair and neurogenesis after stroke, and the repair of neurons damaged by ischemia has become a research focus. This article reviews several possible mechanisms of stroke and neurogenesis and introduces novel neurogenic agents (fibroblast growth factors, brain-derived neurotrophic factor, purine nucleosides, resveratrol, S-nitrosoglutathione, osteopontin, etc.) as well as other treatments that have shown neuroprotective or neurogenesis-promoting effects.

Lin Zhou

Papers

Research progress of mechanisms and drug therapy for neuropathic pain

Immune Cells After Ischemic Stroke Onset: Roles, Migration, and Target Intervention

Levo-Corydalmine Alleviates Neuropathic Cancer Pain Induced by Tumor Compression via the CCL2/CCR2 Pathway

Anti-ulcerogenic effect of KFP-H008 against ethanol-induced gastric ulcer via p38 MAPK/NF-κB pathway

Protective Mechanism and Treatment of Neurogenesis in Cerebral Ischemia.