Carbon dioxide and MAPK signalling: towards therapy for inflammation

Gałgańska, Hanna; Jarmuszkiewicz, Wieslawa; Gałgański, Łukasz

doi:10.1186/s12964-023-01306-x

Cited by 13 publications

(1 citation statement)

References 360 publications

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“…The mitogen‐activated protein kinases (MAPK) pathway is one of the most important intracellular signal transduction pathways related to inflammatory progression [21] . Upon phosphorylation activation, MAPK pathway result in significant overproduction of inflammatory factor TNF‐α [22] .…”

Section: Resultsmentioning

confidence: 99%

Osthole Activates the Cholinergic Anti‐Inflammatory Pathway via α7nAChR Upregulation to Alleviate Inflammatory Responses

Li,

Yuan

et al. 2024

Chemistry & Biodiversity

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Osthole (also known as Osthol) is the main anti‐inflammatory coumarin found in Cnidium monnieri and severs as the exclusive quality‐controlled component according the Chinese Pharmacopoeia. However, its underlying anti‐inflammatory mechanism remains unknown. In this study, we demonstrated that Osthole treatment significantly inhibited the generation of TNF‐α, but not IL‐6 in the classical LPS‐stimulated RAW264.7 macrophage model. In addition, LPS induced the activation of both MAPK and NF‐κB signalling pathways, of which the former was dose‐dependently restrained by Osthole via suppressing the phosphorylation of JNK and P38 proteins, while the phosphorylation of IκB and P65 proteins remained unaffected. Interestingly, Osthole dose‐dependently up‐regulated the expression of the key cholinergic anti‐inflammatory pathway regulator α7nAChR, and the TNF‐α inhibition effect of Osthole was also significantly alleviated by the treatment of α7nAChR antagonist methylbetaine. These results demonstrate that Osthole may regulate TNF‐α by promoting the expression of α7nAChR, thereby activate the vagus nerve‐dependent cholinergic anti‐inflammatory pathway.

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Section: Resultsmentioning

confidence: 99%

Osthole Activates the Cholinergic Anti‐Inflammatory Pathway via α7nAChR Upregulation to Alleviate Inflammatory Responses

Li,

Yuan

et al. 2024

Chemistry & Biodiversity

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A Novel Engineering Cell Therapy Platform Mimicking the Immune Thrombocytopenia‐Derived Platelets to Inhibit Cytokine Storm in Hemophagocytic Lymphohistiocytosis

Liu,

Du,

Zhou

et al. 2024

Advanced Science

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Hemophagocytic lymphohistiocytosis (HLH) is a common and highly fatal hyperinflammatory syndrome characterized by the aberrant activation of macrophages. To date, there is a lack of targeted therapies for HLH. It is validated that macrophages in HLH efficiently phagocytose anti‐CD41‐platelets (anti‐CD41‐PLTs) from immune thrombocytopenia (ITP) patients in previous research. Hence, the pathological mechanisms of ITP are mimicked and anti‐CD41‐PLTs are utilized to load the macrophage‐toxic drug VP16 to construct macrophage‐targetable engineered platelets anti‐CD41‐PLT‐VP16, which is a novel targeted therapy against HLH. Both in vitro and in vivo studies demonstrate that anti‐CD41‐PLT‐VP16 has excellent targeting and pro‐macrophage apoptotic effects. In HLH model mice, anti‐CD41‐PLT‐VP16 prevents hemophagocytosis and inhibits the cytokine storm. Mechanistic studies reveal that anti‐CD41‐PLT‐VP16 increases the cytotoxicity of VP16, facilitating precise intervention in macrophages. Furthermore, it operates as a strategic “besieger” in diminishing hyperinflammation syndrome, which can indirectly prevent the abnormal activation of T cells and NK cells and reduce the Ab‐dependent cell‐mediated cytotoxicity effect. The first platelet‐based clinical trial is ongoing. The results show that after treatment with anti‐CD41‐PLT‐VP16, HLH patients have a threefold increase in the overall response rate compared to patients receiving conventional chemotherapy. In conclusion, anti‐CD41‐PLT‐VP16 provides a general insight into hyperinflammation syndrome and offers a novel clinical therapeutic strategy for HLH.

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Nerolidol rescues hippocampal injury of diabetic rats through inhibiting NLRP3 inflammasome and regulation of MAPK/AKT pathway

Lei,

Li,

Liu

et al. 2024

BioFactors

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Despite the observation of diabetes‐induced brain tissue damage and impaired learning and memory, the underlying mechanism of damage remains elusive, and effective, targeted therapeutics are lacking. Notably, the NLRP3 inflammasome is highly expressed in the hippocampus of diabetic individuals. Nerolidol, a naturally occurring compound with anti‐inflammatory and antioxidant properties, has been identified as a potential therapeutic option for metabolic disorders. However, the ameliorative capacity of nerolidol on diabetic hippocampal injury and its underlying mechanism remain unclear. Network pharmacology and molecular docking was used to predict the signaling pathways and therapeutic targets of nerolidol for the treatment of diabetes. Then established a diabetic rat model using streptozotocin (STZ) combined with a high‐fat diet and nerolidol was administered. Morris water maze to assess spatial learning memory capacity. Hematoxylin and eosin and Nissl staining was used to detect neuronal damage in the diabetic hippocampus. Transmission electron microscopy was used to detect the extent of damage to mitochondria, endoplasmic reticulum (ER) and synapses. Immunofluorescence was used to detect GFAP, IBA1, and NLRP3 expression in the hippocampus. Western blot was used to detect apoptosis (Bcl‐2, BAX, and Cleaved‐Caspase‐3); synapses (postsynaptic densifying protein 95, SYN1, and Synaptophysin); mitochondria (DRP1, OPA1, MFN1, and MFN2); ER (GRP78, ATF6, CHOP, and caspase‐12); NLRP3 inflammasome (NLRP3, ASC, and caspase‐1); inflammatory cytokines (IL‐18, IL‐1β, and TNF‐α); AKT (P‐AKT); and mitogen‐activated protein kinase (MAPK) pathway (P‐ERK, P‐p38, and P‐JNK) related protein expression. Network pharmacology showed that nerolidol's possible mechanisms for treating diabetes are the MAPK/AKT pathway and anti‐inflammatory effects. Animal experiments demonstrated that nerolidol could improve blood glucose, blood lipids, and hippocampal neuronal damage in diabetic rats. Furthermore, nerolidol could improve synaptic, mitochondrial, and ER damage in the hippocampal ultrastructure of diabetic rats by potentially affecting synaptic, mitochondrial, and ER‐related proteins. Further studies revealed that nerolidol decreased neuroinflammation, NLRP3 and inflammatory factor expression in hippocampal tissue while also decreasing MAPK pathway expression and enhancing AKT pathway expression. However, nerolidol improves hippocampal damage in diabetic rats cannot be shown to improve cognitive function. In conclusion, our study reveals for the first time that nerolidol can ameliorate hippocampal damage, neuroinflammation, synaptic, ER, and mitochondrial damage in diabetic rats. Furthermore, we suggest that nerolidol may inhibit NLRP3 inflammasome and affected the expression of MAPK and AKT. These findings provide a new experimental basis for the use of nerolidol to ameliorate diabetes‐induced brain tissue damage and the associated disease.

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Carbon dioxide and MAPK signalling: towards therapy for inflammation

Cited by 13 publications

References 360 publications

Osthole Activates the Cholinergic Anti‐Inflammatory Pathway via α7nAChR Upregulation to Alleviate Inflammatory Responses

Osthole Activates the Cholinergic Anti‐Inflammatory Pathway via α7nAChR Upregulation to Alleviate Inflammatory Responses

A Novel Engineering Cell Therapy Platform Mimicking the Immune Thrombocytopenia‐Derived Platelets to Inhibit Cytokine Storm in Hemophagocytic Lymphohistiocytosis

Nerolidol rescues hippocampal injury of diabetic rats through inhibiting NLRP3 inflammasome and regulation of MAPK/AKT pathway

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