Therapeutic effect of phycocyanin on chronic obstructive pulmonary disease in mice

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Therapeutic effect of phycocyanin on chronic obstructive pulmonary

disease in mice

Wenjun Li

a,b,1

, Yuanyuan Li

c,d,1

, Qi Wang

a,b

, Runze Liu

, Jianing Lu

, Wenju Lu

c,d,

⇑

, Song Qin

a,b,

⇑

Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China

Shandong University of Traditional Chinese Medicine, Ji’nan 250355, China

Guangzhou Medical University, Guangzhou 510030, China

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institue of Respiratory Health, the First Afﬁliated Hospital of

Guangzhou Medical University, Guangzhou 510031, China

highlights

PC signiﬁcantly ameliorated the

pulmonary function of COPD mice

and.

PC reduced cigarette smoke induced

lung inﬂammation of COPD mice.

Molecular docking results indicate

that PCB in PC had a good binding site

in Keap1 and NOX2 proteins.

In vivo PC decreased p-Nrf2 and

NQO1 level.

In vitro PCB-PC-peptide could depress

the p-Nrf2 and NQO1 protein level in

RAW264.7 cells induced by cigarette

smoke extract.

graphical abstract

article info

Article history:

Received 26 July 2023

Revised 2 January 2024

Accepted 8 January 2024

Available online xxxx

Keywords:

Phycocyanin

Chronic obstructive pulmonary disease

Antioxidants

Anti-inﬂammatory drugs

abstract

Introduction: The prevention and treatment of chronic obstructive pulmonary disease (COPD) is closely

tied to antioxidation and anti-inﬂammation. Phycocyanin (PC) has numerous pharmacological effects,

such as antioxidation and anti-inﬂammation. However, it remains unclear whether PC can play a thera-

peutic role in COPD.

Objective: As inﬂammation and oxidative stress can aggravate COPD, this study is to explore the effect of

PC on COPD mice and its mechanisms.

Methods: The COPD mice model was established by exposing them to lipopolysaccharide (LPS) and cigar-

ette smoke (CS); PC was administrated in a concentration of 50 mg/kg for 30 days. On the last day, lung

function was measured, and bronchoalveolar lavage ﬂuid (BALF) was obtained and classiﬁed for cells.

Lung tissue pathological change was analyzed, and organ indices statistics were measured. Based on

molecular docking, the mechanism was explored with Western blotting, immunohistochemical, and

immunoﬂuorescence in vivo and in vitro.

Results: PC signiﬁcantly ameliorated the pulmonary function of COPD mice and reduced inﬂammation of

the lung (p< 0.05), and hematoxylin and eosin (H&E) staining showed PC depressed lung inﬂammatory

https://doi.org/10.1016/j.jare.2024.01.009

2090-1232/Ó2023 The Authors. Published by Elsevier B.V. on behalf of Cairo University.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abbreviations: BALF, Bronchoalveolar lavage ﬂuid; Cchord, Chord compliance; COPD, Chronic obstructive pulmonary disease; CSE, Cigarette smoke extract; CS, Cigarette

smoke; FRC, Functional residual capacity; H&E, Hematoxylin and eosin; HO-1, Heme oxygenase 1; IF, Immunoﬂuorescence; IHC, Immunohistochemical; Keap1, Kelch-like

ECH-associated protein 1; LPS, Lipopolysaccharide; FEV50%, Maximal expiratory ﬂow during exhalation of 50% of lung volume; MLI, Mean alveolar diameter; NQO1, NAD (P)

H: quinoline 1; NOX2, NADPH oxidase 2; Nrf2, NF-E2-related factor 2; PEF, Peak expiratory ﬂow; PAS, Periodic acid Schiff; PC, Phycocyanin; PCB, Phycocyanobilin; PCB-PC-

peptide, phycocyanobilin-bound phycocyanin peptide; PFT, Pulmonary function test; ROS, Reactive oxygen species.

⇑

Corresponding authors at: Guangzhou Medical University, Guangzhou 510030, China (W. Lu). Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences,

Yantai 264003, China (S. Qin)

E-mail addresses: wlu92@gzhmu.edu.cn (W. Lu), sqin@yic.an.cn (S. Qin).

Wenjun Li and Yuanyuan Li contributed equally to this study.

Journal of Advanced Research xxx (xxxx) xxx

Contents lists available at ScienceDirect

Journal of Advanced Research

journal homepage: www.elsevier.com/locate/jare

Please cite this article as: W. Li, Y. Li, Q. Wang et al., Therapeutic effect of phycocyanin on chronic obstructive pulmonary disease in micePlease review the

<b>given names and surnames</b> to make sure that we have identiﬁed them correctly and that they are presented in the desired order. Carefully verify

cell accumulation and emphysema. Periodic acid Schiff (PAS) and Masson staining revealed that PC

retarded goblet cells metaplasia and collagen deposition (p< 0.05). In addition, in vivo PC regulated

Heme oxygenase 1 (HO-1) (p< 0.05) and NAD(P)H dehydrogenase quinone 1 (NQO1) level (p< 0.01)

in the lung, as well as NOX2 level in pulmonary macrophages. Molecular docking results indicate that

phycocyanobilin (PCB) in PC had a good binding site in Keap1 and NOX2 proteins; the

phycocyanobilin-bound phycocyanin peptide (PCB-PC-peptide) was obtained for further studies. In vitro,

PCB-PC-peptide could depress the phospho-NF-E2-related factor 2 (p-Nrf2) and NQO1 protein expression

in RAW264.7 cells induced by cigarette smoke extract (CSE) (p< 0.05).

Conclusion: PC exerts beneﬁcial effects on COPD via anti-inﬂammatory and antioxidative stress, which

may be achieved through PCB.

Ó2023 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article

under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Chronic obstructive pulmonary disease (COPD) is a highly

pathological disorder of the respiratory system featuring limitation

of airﬂow. Without prompt prophylaxis and treatment, the pul-

monary function of patients with COPD will continue to deteriorate

irreversibly until death [1]. Environmental factors and individual

organism factors are the leading causes of COPD, there are

increased airway inﬂammatory response and lungs to harmful

gases or particles as in tobacco smoke, among them smoking is

the most crucial trigger [2]. Long-term stimulation of harmful

gases and particles contributes to lung peroxide production, dam-

aging immune cells or epithelial cells. Recruitment of multiple

immune cells, such as neutrophils and macrophages, as well as

the release of inﬂammatory mediators, will lead to lung parench-

yma injury, airway remodeling, and emphysema [3]. The imbal-

ance of the protease-antiprotease system increases mucus

secretion and narrows the airway wall, thus leading to obstructive

bronchitis and eventually COPD [4]. In addition, exogenous oxi-

dants in tobacco smoke and other harmful gases may directly irri-

tate the respiratory tract and lungs, inﬂicting cell and organ

damage. On the other hand, neutrophils in pulmonary circulation

are activated by exogenous oxidants, leading to a massive release

of reactive oxygen species (ROS) and accelerating the development

of COPD [5]. In recent years, the morbidity and mortality of COPD

have been on the rise worldwide, which has become a severe pub-

lic health issue in human society [6]. The traditional pharmacolog-

ical strategy is to improve the symptoms and complications of

COPD, but it is unable to cure the disease completely. The drugs

involved include bronchodilators, corticosteroids, and antibiotics,

which are usually used alone or in combination [7].

Phycocyanin (PC) is a light-harvesting pigment-protein

extracted from cyanobacteria, red algae, and some Cryptophyta

[8]. PC is composed of mainly

and bsubunits, most of which

are in the natural form of heteropolymer [9]. In addition to efﬁ-

ciently capturing light energy [10], PC can also have numerous

pharmacological effects such as anti-tumor [11], antioxidation

[12], anti-inﬂammation [13], neuroprotection [14], and so on. Li

et al 2020, reported that PC treatment improved radiation-

induced lung histopathological changes in mice, including pul-

monary edema, alveolar wall thickness, and neutrophil infusion

into the alveolar cavity[15]. In the paraquat-induced acute lung

injury model, PC improved inﬂammatory cell inﬁltration and the

release of inﬂammatory factors by restraining ROS in lung tissue,

increasing antioxidant enzyme expression, and reducing lipid per-

oxidation [16]. A recent study shows that phycocyanobilin-bound

phycocyanin peptide (PCB-PC-peptide) obtained from PC that trea-

ted with complex enzymes could inhibit inﬂammation and oxidant

stress induced by TGF-b1, thus playing a role in lung protection

[17].

Smoking and long-term exposure to dust are the leading causes

of COPD, and the accompanying pathological changes in the respi-

ratory tract and lungs, such as inﬂammation and oxidative stress,

are essential pathogenesis of COPD [5]. The prevention and treat-

ment of COPD are closely tied to antioxidation and anti-

inﬂammation, but it remains unclear whether PC can play a thera-

peutic role in COPD. As PC has antioxidant and anti-inﬂammatory

pharmacological effects, we established a COPD mouse model

through lipopolysaccharide (LPS) combined with cigarette smoke

(CS) exposure to evaluate the therapeutic efﬁcacy of PC on COPD.

As the enzymatic hydrolysis product of PC, PCB-PC-peptide can

reasonably simulate the therapeutic effect of PC after gastrointesti-

nal degradation in the human body. Therefore, we also applied the

RAW264.7 cell model treated with cigarette smoke extract (CSE) to

explore the regulatory effect of PCB-PC-peptide on oxidative stress.

These results will provide new perspectives for the clinical practice

of COPD prevention and treatment.

Materials and methods

Experimental animals

Male C57BL/6 mice (6-8 weeks in age) used in this study were

purchased from Charles River Laboratories (Beijing, China, certiﬁ-

cate number: SCXK Jing 2016–0006). All mice were fed complete

pelleted diets and pure water in 40-60 % humidity at 20-24 °C,

alternating light and dark for 12 hours daily, with access to water

and food ad libitum.

Ethics statement

Animal ethics was granted from the Postgraduate Ethics Com-

mittee of Animal Science, Guangdong Academy of Agricultural

Sciences (Ethic No.SPF2020006).

Reagents

The PC was purchased from Xindaze Spirulina Co., Ltd., and Car-

bocisteine tablets (batch number: 1190002) were purchased from

Guangzhou Baiyunshan Pharmaceutical Group Co., Ltd. Normal sal-

ine was acquired from Sichuan Kelun Pharmaceutical Co., Ltd. LPS

was obtained from Sigma Company in the United States. p-Nrf2

(No. AF1609) was purchased from Biyuntian Biotechnology Co.,

Ltd. Nrf2, HO-1, NQO1, and CD68 antibodies (No. ab31163,

ab189491, ab80588, ab955) were purchased from Abcam Com-

pany, and NOX2 (No. GB11391) was purchased from Servicebio

Biotechnology Company. The ﬂuorescent secondary antibody used

was anti-rabbit IgG (H + L) (Alexandra Fluor 555) (CST, 4413) and

anti-mouse IgG (H + L) (Alexandra Fluor 488) (CST, 4408). PBS was

purchased from Boshide Biological Engineering Co., Ltd. RMPI-1640

W. Li, Y. Li, Q. Wang et al. Journal of Advanced Research xxx (xxxx) xxx

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