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Duloxetine HCl Alleviates Asthma Symptoms by Regulating PI3K/AKT/mTOR and Nrf2/HO-1 Signaling Pathways

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Abstract

Asthma is an inflammatory disease characterized by airway hyperresponsiveness, airway remodeling, and airway inflammation. In recent years, the prevalence of asthma has been increasing steadily and the pathogenesis of asthma varies from person to person. Due to poor compliance or resistance, existing drugs cannot achieve the desired therapeutic effect. Therefore, developing or screening asthma therapeutic drugs with high curative effects, low toxicity, and strong specificity is very urgent. Duloxetine HCl (DUX) is a selective serotonin and norepinephrine reuptake inhibitor, and it was mainly used to treat depression, osteoarthritis, and neuropathic pain. It was also reported that DUX has potential anti-infection, anti-inflammation, analgesic, antioxidative, and other pharmacological effects. However, whether DUX has some effects on asthma remains unknown. In order to investigate it, a series of ex vivo and in vivo experiments, including biological tension tests, patch clamp, histopathological analysis, lung function detection, oxidative stress enzyme activity detection, and molecular biology experiments, were designed in this study. We found that DUX can not only relax high potassium or ACh precontracted tracheal smooth muscle by regulating L-type voltage-dependent Ca2+ channel (L-VDCC) and nonselective cation channel (NSCC) ion channels but also alleviate asthma symptoms through anti-inflammatory and antioxidative response regulated by PI3K/AKT/mTOR and Nrf2/HO-1 signaling pathways. Our data suggests that DUX is expected to become a potential new drug for relieving or treating asthma.

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Data Availability

All data generated and analyzed in this study are available upon reasonable request from the corresponding author.

Abbreviations

ACh:

Acetylcholine chloride

Al(OH)3 :

Aluminum hydroxide

BALF:

Bronchoalveolar lavage fluids

BSA:

Bovine serum albumin

CAT:

Catalase

DEX:

Dexamethasone

DMSO:

Dimethyl sulfoxide

DTT:

Dithiothreitol

DUX:

Duloxetine HCl

Ers:

Respiratory system elasticity

HBSS:

Hanks’ balanced salt solution

H&E:

Hematoxylin and eosin

HO-1:

Heme oxygen 1

IC50 :

Half-maximal inhibitory concentration

IC75 :

Seventy-five percent of maximal inhibitory concentration

IL-4:

Interleukin 4

IL-5:

Interleukin 5

IL-13:

Interleukin 13

IG:

Intragastrical administration

IN:

Intranasally

IP:

Intraperitoneal injections

Keap1:

Kelch-like ECH-associated protein 1

L-VDCC:

L-type voltage-dependent Ca2+ channel

MAPK:

Mitogen-activated protein kinase

MDA:

Malondialdehyde

mTOR:

Mammalian target of rapamycin

mTRs:

Mouse tracheal rings

NA:

Niflumic acid

Nrf2:

Nuclear factor-erythroid 2-related factor 2

NSCCs:

Nonselective cation channels

OVA:

Ovalbumin

PAS:

Periodic acid-Schiff

PFA:

Paraformaldehyde

PI3K:

Phosphatidylinositol-3-kinase

PSS:

Physiological salts solution

Pyr3:

Pyrazole 3

Rrs:

Respiratory system resistance

SD:

Standard deviation

SNRI:

Serotonin and norepinephrine reuptake inhibitors

SPF:

Specific pathogen-free

SOD:

Superoxide dismutase

TEA:

Tetraethylammonium chloride

TBST:

Tris-Buffered Saline Tween-20

TNF-α:

Tumor necrosis factor alpha

TRPC3:

Transient receptor potential channel 3

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Acknowledgements

We appreciate all the colleagues who work in Institute for Medical Biology for their scientific and technical support.

Funding

This project was supported by the National Natural Science Foundation of China (Grant No. 31771274) to Jinhua Shen, the Fund for Key Laboratory Construction of Hubei Province (Grant No. 2018BFC360), and “The Fundamental Research Funds for the Central Universities,” South-Central Minzu University (Grant Number: CZQ22013).

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  1. Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central Minzu University, Wuhan, 430074, China

    Changsi Peng, Lu Xue, Yanling Yue, Weiwei Chen, Wenyi Wang & Jinhua Shen

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  1. Changsi Peng
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Contributions

J.S. and L.X. conceived and designed the experiments. C.P., Y.Y., and W.C. performed the experiments. C.P. and W.W. analyzed the data and generated the figures. J.S. and L.X. wrote the manuscript.

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Correspondence to Jinhua Shen.

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All the animal experiments were approved by and performed in accordance with the guidelines of the Animal Care and Ethics Committee of South-Central Minzu University (Wuhan, China).

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Peng, C., Xue, L., Yue, Y. et al. Duloxetine HCl Alleviates Asthma Symptoms by Regulating PI3K/AKT/mTOR and Nrf2/HO-1 Signaling Pathways. Inflammation 46, 2449–2469 (2023). https://doi.org/10.1007/s10753-023-01892-5

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