Silicosis is a systemic disease marked by diffuse pulmonary fibrosis resulting from prolonged inhalation of crystalline silica (CS) dust. This study aimed to examine the effects of anisodamine (ANI) on pulmonary inflammation and fibrosis in silicosis, as well as to elucidate the underlying molecular mechanisms. Animal experiments demonstrated that ANI significantly reduced alveolar structure damage and the formation of silicosis nodules in affected mice, as confirmed by pathological slides. ANI inhibited the expression of tumor necrosis factor (TNF-α) in bronchoalveolar lavage fluid (BALF) while promoting the secretion of interleukin-4 (IL-4) and interleukin-10 (IL-10). Further molecular investigations indicated a strong link between pulmonary inflammation and fibrosis, showing decreased levels of α7nAChR and increased expression of phosphorylated Janus kinase 2 (JAK2) and phosphorylated transcription factor 3 (STAT3) in the lung tissues of mice exposed to CS. The relevant molecular alterations in the lung tissue of the model group of mice were reversed by ANI. Methyllycaconitine(MLA, α7nAChR inhibitor) and RO8191 (JAK2/STAT3 agonist) could reverse the therapeutic effect of ANI in silicosis and related molecular mechanisms. The results suggest that ANI may alleviate silicosis by inhibiting pulmonary inflammation and fibrosis through modulation of the JAK2/STAT3 signaling pathway, which is mediated by α7nAChR. Coal workers can utilize ANI early on to treat and prevent silicosis.

2024-12-01·ANESTHESIOLOGY

Activation of α7 Nicotinic Acetylcholine Receptors Inhibits Hepatic Necroptosis and Ameliorates Acute Liver Injury in Mice

Article

作者: Xu, Fang-Fang ; Zhang, Wen-Jing ; Shen, Fu-Ming ; Fu, Hui ; Li, Dong-Jie ; Meng, Hong-Bo ; Li, Zi-Chen ; Li, Qiao

Background:

Acute liver injury is a disease characterized by severe liver dysfunction, caused by significant infiltration of immune cells and extensive cell death with a high mortality. Previous studies demonstrated that the α7 nicotinic acetylcholine receptor (α7nAChR) played a crucial role in various liver diseases. The hypothesis of this study was that activating α7nAChR could alleviate acute liver injury and investigate its possible mechanisms.

Methods:

Acute liver injury was induced by intraperitoneal injection of lipopolysaccharide (LPS)/D-galactosamine (D-Gal) in wild type, α7nAChR knockout (α7nAChR-/-) and stimulator of interferon gene (STING) mutation (Sting gt /gt ) mice in the presence or absence of a pharmacologic selective α7nAChR agonist (PNU-282987). The effects of α7nAChR on hepatic injury, inflammatory response, mitochondrial damage, necroptosis, and infiltration of immune cells during acute liver injury were assessed.

Results:

The expression of α7nAChR in liver tissue was increased in LPS/D-Gal–induced acute liver injury mice. Compared to the age-matched wild-type mice, α7nAChR deficiency decreased the survival rate, exacerbated the hepatic injury accompanied with enhanced inflammatory response and oxidative stress, and aggravated hepatic mitochondrial damage and necroptosis. Conversely, pharmacologic activation of α7nAChR by PNU-282987 displayed the opposite trends. Furthermore, PNU-282987 significantly reduced the proportion of infiltrating monocyte-derived macrophages (CD45+CD11bhiF4/80int), M1 macrophages (CD45+CD11b+F4/80+CD86hiCD163low), and Ly6Chi monocytes (CD45+CD11b+MHC [major histocompatibility complex] ⅡlowLy6Chi), but increased the resident Kupffer cells (CD45+CD11bintF4/80hiTIM4hi) in the damaged hepatic tissues caused by LPS/D-Gal. Interestingly, α7nAChR deficiency promoted the STING signaling pathway under LPS/D-Gal stimulation, while PNU-282987 treatment significantly prevented its activation. Finally, it was found that Sting mutation abolished the protective effects against hepatic injury by activating α7nAChR.

Conclusions:

The authors' study revealed that activating α7nAChR could protect against LPS/D-Gal–induced acute liver injury by inhibiting hepatic inflammation and necroptosis possibly via regulating immune cells infiltration and inhibiting STING signaling pathway.

Editor’s Perspective:

What We Already Know about This Topic:

What This Article Tells Us That Is New:

2024-12-01·PHYTOMEDICINE

Liang–Ge–San protects against viral infection-induced acute lung injury through inhibiting α7nAChR-mediated mitophagy

Article

作者: Ou, Jinying ; Chen, Bing ; Yu, Linzhong ; Yu, Jingtao ; Cao, Huihui ; He, Xuemei ; Peng, Gefei ; Li, Yuhua ; Ma, Qinhai ; Liu, Junshan ; Lu, Zibin ; Zhao, Wei

BACKGROUND:

Acute lung injury (ALI) is the main cause of death in clinical respiratory virus infection. Liang-Ge-San (LGS), a famous traditional Chinese formula, has been proved to be effective in treating ALI caused by lipopolysaccharide. However, the effects of LGS on ALI induced by viral infections remain uncertain.

PURPOSE:

To investigate the effect and mechanism of action of LGS on viral infection-induced ALI.

METHODS:

The inhibitory effects of LGS on virus-induced inflammation in vitro were evaluated by qRT-PCR and ELISA. The protein expression of α7nAChR was examined by Western blotting. α7nAChR was inhibited by the transfection of siRNA or methyllycaconitine citrate (MLA, an α7nAChR inhibitor) to investigate the role of α7nAChR in the anti-inflammatory effect of LGS. Adoptive culture and co-culture systems of macrophages RAW264.7 and alveolar epithelial cells MLE-12 were established to mimic their interaction. Western blotting, immunofluorescence, flow cytometry and transmission electron microscopy were used to examine the effects of LGS on mitophagy inhibition. In vivo, ALI mouse models induced by SARS-CoV-2, H1N1 or Poly(I:C) infection were established to explore the therapeutic effect and mechanism of LGS.

RESULTS:

LGS reduced the release of IL-6, TNF-α and IL-1β and increased the expression of α7nAChR in virus-infected RAW264.7 cells. The blockage of α7nAChR counteracted the anti-inflammatory effect of LGS. Moreover, LGS significantly inhibited autophagy in MLE-12 cells induced by Poly(I:C) in adoptive culture and co-culture systems of RAW264.7 and MLE-12 cells, which could be attenuated after the inhibition of α7nAChR in RAW264.7 cells by decreasing the secretion of IL-6, TNF-α and IL-1β. Further study showed that LGS suppressed TNF-α-induced mitochondrial damage and mitophagy by inhibiting the generation of ROS in MLE-12 cells. In vivo, LGS significantly prolonged the survival time, alleviated pathological injury and acute inflammation of ALI mice induced by SARS-CoV-2, H1N1 or Poly(I:C) infection which were associated with the inhibition of α7nAChR-mediated mitophagy.

CONCLUSION:

This study first demonstrates that LGS inhibits virus infection-induced inflammation in RAW246.7 cells by increasing the expression of α7nAChR, thereby inhibiting mitophagy induction in MLE-12 cells to alleviate ALI. This work indicates that LGS may serve as a candidate drug for treating ALI/ARDS caused by viral infection.

100 项与 α7nAChR Program(180 Life Sciences) 相关的药物交易

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