Magnolol exerts anti-asthmatic effects by regulating Janus kinase-signal transduction and activation of transcription and Notch signaling pathways and modulating Th1/Th2/Th17 cytokines in ovalbumin-sensitized asthmatic mice

Huang, Qibai; Han, Lele; Lv, Rong; Ling, Ling

doi:10.4196/kjpp.2019.23.4.251

Cited by 19 publications

(18 citation statements)

References 67 publications

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“…e study also found that the counts of inflammatory eosinophils, neutrophils, and lymphocytes of the BALF of asthma mice in the OVA + MDSCs group increased, and macrophages were reduced relative to the OVA group. It was similar to the Huang et al's study that neutrophils and their related inflammatory factors played an increasingly vital role in asthma, and there was also an increase in neutrophils in the asthma model [24].…”

Section: Discussionsupporting

confidence: 83%

MDSCs Aggravate the Asthmatic Progression in Children and OVA-Allergic Mice by Regulating the Th1/Th2/Th17 Responses

Lin

Peng

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. Asthma is a chronic inflammatory disease of respiratory with serious risks for children. This study explored myeloid-derived suppressor cells (MDSCs) on the pathogenesis of asthmatic children and mice. Methods. The clinical study enrolled 30 asthma, 20 pneumonia, and 20 control participants. The MDSCs, Th17 and Th1 cells percentage, and IL-4, IL-12, IL-10, and IFN-γ levels were detected by flow cytometry and ELISA. In experimental asthma, mice were divided into control, ovalbumin (OVA), and OVA + MDSCs groups. The changes in inflammatory cell count and the levels of IL-5, IL-12, and IL-10 in mice BALF and the levels of inflammatory factors, IgE, and IFN-γ in mice were detected by ELISA. The amount of ROS generation and pathological changes and the levels of caspase 1 and caspase 3 were tested by flow cytometry, HE and PAS staining, and immunohistochemistry. The expression of cleaved caspase 1/caspase 1 and cleaved caspase 3/caspase 3 was detected by western blot. Results. In clinical trials, the levels of IL-12, IFN-γ, and Th1 percentage decreased in pneumonia and asthma children’s peripheral blood, while the levels of IL-4 and IL-10 and the percentages MDSCs and Th17 increased. In asthma mice, pathological staining showed that asthma caused lung inflammation and damage, while the OVA + MDSC group was severer. Moreover, the percentages of eosinophils, neutrophils, lymphocytes, and the levels of inflammatory factors, IgE, ROS production, caspase 1, caspase 3, cleaved caspase 1/caspase 1, and cleaved caspase 3/caspase 3 increased in OVA + MDSC group, while the percentage of macrophages, IL-12, and IFN-γ levels reduced, illustrating that MDSCs exacerbated asthma. Conclusion. Our study indicated that MDSCs could aggravate asthma by regulating the Th1/Th2/Th17 response.

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Section: Discussionsupporting

confidence: 83%

MDSCs Aggravate the Asthmatic Progression in Children and OVA-Allergic Mice by Regulating the Th1/Th2/Th17 Responses

Lin

Peng

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…Moreover, we have observed that treatment with the γ-secretase inhibitor DAPT, which blocks NOTCH activation, inhibited the Th17 immune response and downstream inflammatory response in obstructed kidneys. Our findings extend to renal diseases the previous studies describing that NOTCH inhibition diminished the Th17 immune response in the experimental models of allergic asthma, 59 and autoimmune encephalomyelitis. 35 Interestingly, although in injured kidneys there is a markedly upregulation of many proinflammatory genes, only Ccl2 (encoding MCP-1) was significantly upregulated in Dlk1-null mice compared to WT mice.…”

Section: F I G U R Esupporting

confidence: 87%

Deletion of delta‐like 1 homologue accelerates renal inflammation by modulating the Th17 immune response

et al. 2020

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Preclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta‐like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms. Using a Dlk1‐null mouse model in the experimental renal damage of unilateral ureteral obstruction, we found activation of NOTCH, as shown by increased nuclear translocation of the NOTCH1 intracellular domain, and upregulation of Dlk2/hey‐1 expression compared to wild‐type (WT) littermates. NOTCH1 over‐activation in Dlk1‐null injured kidneys was associated with a higher inflammatory response, characterized by infiltration of inflammatory cells, mainly CD4/IL17A + lymphocytes, and activation of the Th17 immune response. Furthermore, pharmacological NOTCH blockade inhibited the transcription factors controlling Th17 differentiation and gene expression of the Th17 effector cytokine IL‐17A and other related‐inflammatory factors, linked to a diminution of inflammation in the injured kidneys. We propose that the non‐canonical NOTCH ligand DLK1 acts as a NOTCH antagonist in renal injury regulating the Th17‐mediated inflammatory response.

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“…Indeed, there is some evidence from other studies in OVA‑sensitized mice that inhibiting the JAK/STAT pathway may suppress Th1 and Th17 signaling. 56 , 57 Our data do not rule out the possibility that AZD0449 and AZD4604 have an effect on non-type 2 asthma phenotypes, suggesting broad applicability for selective inhaled JAK1 inhibitors, but further studies are required to explore this potential.…”

Section: Discussionmentioning

confidence: 73%

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma

Nilsson¹,

Rhedin²,

Hendrickx³

et al. 2022

DDDT

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Purpose Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation. Methods The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 μg/kg and AZD4604 at 30 µg/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]). Results Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model. Conclusion AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.

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Magnolol exerts anti-asthmatic effects by regulating Janus kinase-signal transduction and activation of transcription and Notch signaling pathways and modulating Th1/Th2/Th17 cytokines in ovalbumin-sensitized asthmatic mice

Cited by 19 publications

References 67 publications

MDSCs Aggravate the Asthmatic Progression in Children and OVA-Allergic Mice by Regulating the Th1/Th2/Th17 Responses

MDSCs Aggravate the Asthmatic Progression in Children and OVA-Allergic Mice by Regulating the Th1/Th2/Th17 Responses

Deletion of delta‐like 1 homologue accelerates renal inflammation by modulating the Th17 immune response

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma

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