Melatonin modulates airway smooth muscle cell phenotype by targeting the STAT3/Akt/GSK-3β pathway in experimental asthma

Yu, Qijun; Yu, Xiaowei; Zhong, Xiu-hua; Ma, Yuan; Wang, Yan; Bian, Tao; Huang, Mao; Zeng, Xianlu

doi:10.1007/s00441-019-03148-x

Cited by 17 publications

(7 citation statements)

References 47 publications

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“…Overall, these results suggest that melatonin plays a key role in regulating cell proliferation and development. However, the downstream signaling pathway triggered by melatonin that promotes cell proliferation depends on the cell state and type [20,21]. Thus, an investigation into whether melatonin promotes bursa B-lymphocyte proliferation through its membrane receptor and related intracellular signaling pathways is still required.…”

Section: Introductionmentioning

confidence: 99%

A Green and Blue Monochromatic Light Combination Therapy Reduces Oxidative Stress and Enhances B‐Lymphocyte Proliferation through Promoting Melatonin Secretion

Zhang

Wang

Cao

et al. 2021

Oxidative Medicine and Cellular Longevity

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Artificial illumination may interfere with biological rhythms and distort physiological homeostasis in avian. Our previous study demonstrated that 660 nm red light exacerbates oxidative stress, but a combination of green and blue lights (G→B) can improve the antibody titer in chickens compared with single monochromatic light. Melatonin acts as an antioxidant which is a critical signaling to the coordination between external light stimulation and the cellular response from the body. This study further clarifies the potential role of melatonin in monochromatic light combination-induced bursa B-lymphocyte proliferation in chickens. A total of 192 chicks were exposed to a single monochromatic light (red (R), green (G), blue (B), or white (W) lights) or various monochromatic light combinations (B→G, G→B, and R→B) from P0 to P42. We used qRT-PCR, MTT, western blotting, immunohistochemistry, and Elisa to explore the effect of a combination of monochromatic light on bursa B-lymphocytes and its intracellular signal pathways. With consistency in the upregulation in melatonin level of plasma and antioxidant enzyme ability, we observed increases in organ index, follicle area, lymphocyte density, B-lymphocyte proliferation, PCNA-positive cells, and cyclin D1 expression in bursa of the G→B group compared with other light-treated groups. Melatonin bound to Mel1a and Mel1c and upregulated p-AKT, p-PKC, and p-ERK expression, thereby activating PI3K/AKT and PKC/ERK signaling and inducing B-lymphocyte proliferation. Overall, these findings suggested that melatonin modulates a combination of green and blue light-induced B-lymphocyte proliferation in chickens by reducing oxidative stress and activating the Mel1a/PI3K/AKT and Mel1c/PKC/ERK pathways.

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Section: Introductionmentioning

confidence: 99%

A Green and Blue Monochromatic Light Combination Therapy Reduces Oxidative Stress and Enhances B‐Lymphocyte Proliferation through Promoting Melatonin Secretion

Zhang

Wang

Cao

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Airway remodeling is the primary pathological foundation of irreversible airflow obstruction and pulmonary function decline in asthma, and one of its important pathological features is abnormal ASMC proliferation and migration. 22,24 TGF-β1 is considered an important modulator of asthmatic airway remodeling, and it can promote ASMC proliferation and induce the production of ECM proteins (such as fibronectin, collagen I, and collagen III), thus aggravating airway remodeling. 18,25 This study unveiled that TGF-β1 stimulation enhanced ASMC proliferation and migration abilities.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA ANRIL up‐regulates CCND1 via sponging miR‐98‐5p to promote TGF‐β1‐induced human airway smooth muscle cell proliferation, migration, and extracellular matrix deposition

Zhong

Dong

Guo

et al. 2022

The Kaohsiung J of Med Scie

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Excessive proliferation and migration of airway smooth muscle cell (ASMC) contribute to asthma pathogenesis. Long noncoding RNAs (lncRNAs) are reported to take part in asthma pathogenesis. This study is targeted at deciphering the role of the lncRNA antisense noncoding RNA in the INK4 locus (ANRIL) in ASMC proliferation, migration and extracellular matrix (ECM) deposition. qRT-PCR was performed to determine ANRIL, miR-98-5p, and cyclin D1 (CCND1) mRNA expression levels in transforming growth factor-β1 (TGF-β1)-treated ASMCs. CCK-8 and Transwell assays were employed to examine ASMC proliferation and migration, respectively. Dualluciferase reporter gene assay and RNA immunoprecipitation assay were carried out for analyzing the targeted relationship of miR-98-5p with ANRIL or CCND1 mRNA 3 0 -UTR. The levels of CCND1 and ECM proteins (such as fibronectin, COL3A1, and COL1A2) in ASMCs were detected through Western blot. In this work, we found that ANRIL and CCND1 were up-regulated in TGF-β1-treated ASMCs, whereas miR-98-5p was down-regulated. ANRIL overexpression facilitated the proliferation, ECM deposition and migration of TGF-β1-induced ASMCs, while knocking down ANRIL had the opposite effect. Furthermore, ANRIL targeted miR-98-5p directly, and CCND1 was miR-98-5p's downstream target. ANRIL indirectly increased CCND1 expression in ASMCs via competitively binding to miR-98-5p. MiR-98-5p inhibition or CCND1 overexpression counteracted the inhibiting effect that ANRIL knockdown had on TGF-β1-stimulated ASMC proliferation, migration and ECM deposition. In conclusion, ANRIL indirectly up-regulates CCND1 expression by targeting miR-98-5p to promote ASMC proliferation, migration and ECM deposition, thus facilitating the pathogenesis of asthma.Zhao-Gang Zhong and Chun-Ping Dong are considered as co-first authors.

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“…Proliferative/synthetic ASM cells appear hypertrophy with aberrantly increased cytoplasm, organelles and microfilaments ( Jones et al, 2014 ). Abnormal hypertrophy of ASM cells cause cell dysfunction in contraction, which determines the development and persistence of AHR in asthma ( Wang J et al, 2018 ; Yu et al, 2020 ). Our TEM results revealed that TGF-β1 or H 2 O 2 induced ASM cells to a proliferative/synthetic state, resulting in numerous cytoplasmic processes with increased profiles of organelles, such as mitochondria, highly developed Golgi cisternae and rough endoplasmic reticulum.…”

Section: Discussionmentioning

confidence: 99%

Chloroquine Attenuates Asthma Development by Restoring Airway Smooth Muscle Cell Phenotype Via the ROS-AKT Pathway

et al. 2022

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Switching of airway smooth muscle (ASM) cell phenotype from differentiated-contractile to dedifferentiated-proliferative/synthetic state often occurs in asthmatic subjects with airway dysfunction. Evidence has been provided that chloroquine (an agonist of bitter taste receptors) presented benefits to ASM cell function implicated in asthma. However, the underlying mechanism is unclear. House dust mite (HDM)-sensitized mice were administered with chloroquine or dexamethasone before challenge. BALF and lung tissue were obtained for cell counting, histological analysis or ELISA. Primary cultured ASM cells were stimulated with transforming growth factor (TGF)-β1 or H2O2. Cells and supernatant were collected for the detection of ASM phenotype, ROS level, and proinflammatory cytokine production. In HDM-sensitized mice, chloroquine attenuated airway hyperresponsiveness (AHR), inflammation and remodeling with an inhibition of immunoglobulin E, IL-4/-13, and TGF-β1 in BALF. ASM cell proliferation (PCNA), hypertrophy (α-SMA), and parasecretion (MMP-9 and MMP-13) were strongly suppressed by chloroquine, hinting the rebalance of the heterogeneous ASM populations in asthmatic airway. Our data in vitro indicated that chloroquine markedly restrained maladaptive alteration in ASM phenotype in concert with a remission of ROS. Using H2O2 and PI3K inhibitor (LY294002), we found that the inhibition of oxidative stress level and ROS-AKT signal by chloroquine may serve as a potential mechanism that dedicates to the restoration of the phenotypic imbalance in ASM cells. Overall, the present findings suggested that chloroquine improves asthmatic airway function by controlling ASM cell phenotype shift, sketching a novel profile of chloroquine as a new therapeutic candidate for airway remodeling.

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Melatonin modulates airway smooth muscle cell phenotype by targeting the STAT3/Akt/GSK-3β pathway in experimental asthma

Cited by 17 publications

References 47 publications

A Green and Blue Monochromatic Light Combination Therapy Reduces Oxidative Stress and Enhances B‐Lymphocyte Proliferation through Promoting Melatonin Secretion

A Green and Blue Monochromatic Light Combination Therapy Reduces Oxidative Stress and Enhances B‐Lymphocyte Proliferation through Promoting Melatonin Secretion

Long noncoding RNA ANRIL up‐regulates CCND1 via sponging miR‐98‐5p to promote TGF‐β1‐induced human airway smooth muscle cell proliferation, migration, and extracellular matrix deposition

Chloroquine Attenuates Asthma Development by Restoring Airway Smooth Muscle Cell Phenotype Via the ROS-AKT Pathway

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