|Year : 2023 | Volume
| Issue : 5 | Page : 351-358
Reducing myocardial infarction by combination of irisin and Dendrobium nobile Lindl through inhibiting nod-like receptor protein-3-related pyroptosis and activating PINK1/Parkin-mitophagy during aging
Chen Ding1, Chaofeng Zhang2
1 Department of Pharmacy, The Nuclear Industry 417 Hospital, Xi'an, China
2 Department of Cardiovascular Medicine, XD Group Hospital, Xi'an, China
|Date of Submission||03-Mar-2023|
|Date of Decision||13-Jul-2023|
|Date of Acceptance||16-Jul-2023|
|Date of Web Publication||26-Oct-2023|
Dr. Chaofeng Zhang
Department of Cardiovascular Medicine, XD Group Hospital, Xi'an 710077
Source of Support: None, Conflict of Interest: None
Aging, a crucial risk factor for ischemic heart disease, has negative impacts on cardioprotective mechanisms. As such, there is still an unmet requirement to explore potential therapies for improving the outcomes of myocardial ischemia/reperfusion (IR) injury in elderly subjects. Here, we aimed to confirm the cardioprotective function of irisin/Dendrobium nobile Lindl (DNL) combination therapy against myocardial IR injury in aged rats, with a focus on the involvement of pyroptosis and mitophagy. Male aged Wistar rats (22–24 months old, 400–450 g; n = 54) underwent myocardial IR or sham surgery. Before IR operation, rats were pretreated with irisin (0.5 mg/kg, intraperitoneally) and/or DNL (80 mg/kg, orally) for 1 or 4 weeks, respectively, at corresponding groups. Cardiac function, lactate dehydrogenase (LDH) and cardiac-specific isoform of troponin-I (cTn-I) levels, the expression of proteins involved in pyroptosis (nod-like receptor protein-3 (NLRP3), apoptosis-associated speck-like protein, c-caspase-1, and GSDMD-N) and mitophagy (PINK1 and Parkin), and pro-inflammatory cytokines levels were evaluated after 24 h of reperfusion. Irisin/DNL combined therapy significantly restored cardiac function and decreased LDH and cTn-I levels. It also downregulated pyroptosis-related proteins, upregulated PINK1 and Parkin, and decreased pro-inflammatory cytokines secretion. Pretreatment with Mdivi-1, as mitophagy inhibitor, abolished the cardioprotective action of dual therapy. This study revealed the cardioprotective effects of irisin/DNL combination therapy against IR-induced myocardial injury in aged rats, and also showed that the mechanism might be associated with suppression of NLRP3-related pyroptosis through enhancing the activity of the PINK1/Parkin mitophagy. This combination therapy is worthy of further detailed studies due to its potential to alleviate myocardial IR injury upon aging.
Keywords: Aging, Dendrobium nobile Lindl, irisin, mitophagy, myocardial ischemia/reperfusion injury, pyroptosis
|How to cite this article:|
Ding C, Zhang C. Reducing myocardial infarction by combination of irisin and Dendrobium nobile Lindl through inhibiting nod-like receptor protein-3-related pyroptosis and activating PINK1/Parkin-mitophagy during aging. Chin J Physiol 2023;66:351-8
|How to cite this URL:|
Ding C, Zhang C. Reducing myocardial infarction by combination of irisin and Dendrobium nobile Lindl through inhibiting nod-like receptor protein-3-related pyroptosis and activating PINK1/Parkin-mitophagy during aging. Chin J Physiol [serial online] 2023 [cited 2023 Dec 4];66:351-8. Available from: https://www.cjphysiology.org/text.asp?2023/66/5/351/388467
| Introduction|| |
Ischemic heart diseases (IHD) are one of the leading causes of hospitalization and death worldwide. Although reperfusion therapy diminishes the infarct size and improves the survival of IHD patients, it also causes myocardial ischemia/reperfusion (IR) injury due to a spike of further cell death that contributes to cardiac dysfunction and eventually heart failure., IHD patients enrolled in cardioprotection studies are of advanced age, a condition that has not been appropriately mimicked in the young animals used for research purposes. Aging attenuates endogenous cardioprotective targets and pathways in cardiomyocytes and renders the heart more resistant to powerful cardioprotective approaches. Due to the poor prognosis of IHD in elderly patients, developing novel therapeutic strategies for preventing cardiomyocyte death and limiting myocardial damage has been the focus of extensive studies.
Pyroptosis and mitophagy play critical roles in determining myocardial infarct size during aging, making them as important therapeutic targets for improving outcomes following myocardial IR injury.,, Pyroptosis, a newly discovered type of pro-inflammatory programmed cell death, is a critical event for maintaining and developing inflammatory responses during myocardial IR injury. A major cause of pyroptosis is activation of the nod-like receptor protein-3 (NLRP3) inflammasome, which consists of NLRP3, apoptosis-associated speck-like protein (ASC), and procaspase-1. NLRP3 inflammasome causes autocleavage of procaspase-1 into cleaved-caspase-1 (c-caspase-1), resulting in the maturation of pro-inflammatory cytokines interleukin (IL)-18/IL-1β and pyroptosis executor gasdermin D (GSDMD) and promotion of pyroptotic cell death., Mitophagy is an important mechanism involved in regulating mitochondrial quantity and quality control and protecting mitochondrial function following myocardial IR injury. PINK1 and Parkin have been identified as the main regulators of mitophagy in cardiomyocytes. Following the accumulation of full-length PINK1 on the mitochondrial surface, Parkin is recruited from the cytoplasm to the mitochondria which leads to the recruitment of autophagosomes to mitochondria by interaction with microtubule-associated protein 1 light chain 3., The activation of the PINK1/Parkin-mitophagy diminishes infarct size and preserves cardiac performance; however, NLRP3-mediated pyroptosis aggravates myocardial IR injury, suggesting that modulation of mitophagy and NLRP3-related pyroptosis may be a potential therapeutic approach to suppress IR-induced myocardial injuries.
Irisin possesses beneficial effects in cardiovascular diseases through improving myocardial function and repair in infarcted hearts. At the molecular levels, irisin mitigates myocardial damage through the regulation of apoptosis, endoplasmic reticulum stress, autophagy, and mitochondrial function.,, Similarly, Dendrobium nobile Lindl (DNL) also has multiple pharmacological features such as mitochondrial protection, anti-inflammatory and anti-oxidative functions, and correcting the molecular mechanisms of aging., On the basis of several recent reports, combination therapies are considered a potential approach for protecting the myocardium against IR injuries in the presence of risk factors and co-morbidities.,, Since aging possess interfering influences on individual treatments, the administration of combined treatments may overcome the aging-associated loss of cardioprotection. Hence, we ask whether the co-administration of irisin and DNL could better mitigate myocardial injury induced by IR during aging. Considering that pyroptosis and mitophagy have important roles in myocardial IR injury, this work aimed to observe the protective impacts of combined therapy with irisin and DNL in aged rat hearts against IR injury and to verify whether NLRP3-related pyroptosis and PINK1/Parkin-mitophagy modifications could interpret the beneficial influences of this combinational approach.
| Materials and Methods|| |
Aged male Wistar rats (22–24 months old, weighing 400–450 g; n = 54) were purchased from the animal center and housed under standard conditions (temperature: 20°C–24°C; humidity: 55%) with a 12:12 h light-dark cycles and free access to standard rat food and water ad libitum. All studies on animals followed the National Institutes of Health guidelines for the use of laboratory animals (8th Edition, revised 2011) and approved by the local ethical committee (Ethics approval number: No. 2021-4-140).
Grouping and administration
Aged rats were randomly separated into five experimental groups in the first protocol (for measuring serum levels of lactate dehydrogenase (LDH) and cardiac-specific isoform of troponin-I (cTn-I) and evaluation of cardiac function; n = 6/group), and four experimental groups in the second protocol (for biochemical and molecular assessments; n = 6/group). The first protocol's grouping is as follows: (1) Sham: rats underwent sham operation; (2) IR: rats underwent IR intervention; (3) IR + Iri: rats were administered 0.5 mg/kg/day recombinant irisin (Cloud Clone, China) by intraperitoneal injection for 1 week followed by IR intervention; (4) IR + DNL: rats were pretreated with 80 mg/kg/day DNL (Natural Products Laboratory, Academia of China) by intragastric gavage for 4 weeks followed by IR intervention; and (5) IR + Iri + DNL: the irisin/DNL-pretreated rats underwent IR intervention. The second protocol's grouping is as follows: (1) IR: similar to group 2 in the first protocol; (2) IR + Iri/DNL: similar to group 5 in the first protocol; (3) IR + Mdivi: rats were pretreated with 1 mg/kg/day mitochondrial division inhibitor 1 (Mdivi-1) (MedChemExpress, USA), a well-known mitophagy inhibitor, by intraperitoneal injection for 4 weeks followed by IR intervention; and (4) IR + Mdivi + Iri/DNL: the IR-treated rats received both Mdivi-1 and irisin/DNL combination therapy at their corresponding time points.
Establishment of regional myocardial IR model in vivo
A classical myocardial IR model was generated in rats in line with a previous report. Briefly, rats were anesthetized using the combination of xylazine and ketamine (10:60 mg/kg) through intraperitoneal injection. The corresponding groups underwent left anterior descending coronary artery ligation for 30 min and ligature loosening for 24 h; however, the sham-operated group was threaded without ligation. An immediate regional paleness or cyanosis of the anterior wall of the left ventricle below the ligation place and elevation of ST-segment on the ECG lead II were considered as the criteria of ischemic success.
After 24 h reperfusion, the rats were re-anesthetized and underwent invasive arterial catheterization of the right carotid artery. One end of the catheter was connected to the pressure amplifier and data acquisition system (ADInstruments, Australia). The other end of the catheter was carefully advanced into the left ventricle to enable the measurement of various hemodynamic parameters, including left ventricular end-diastolic pressure (LVEDP, measured in mmHg), left ventricular end-systolic pressure (LVESP, in mmHg), left ventricular developed pressure (LVDP, in mmHg), maximal ascending rate of left ventricular pressure (+dp/dt, in mmHg/s), maximal descending rate of the left ventricular pressure (-dp/dt, in mmHg/s), and heart rates (HRs, in beats per minute). LVDP was calculated by determining the difference between LVEDP and LVESP.
Serum biochemical measurements
For assessing myocardial injury in rats, cardiac blood samples were obtained following hemodynamic measurements and sera were separated to measure the levels of LDH and cTn-I by using specific kits from Life Diagnostics, Inc. (West Chester, PA, USA), as instructions by manufacturer. LDH and cTn-I levels were reported as IU/l and mg/dl, respectively.
To extract the total proteins of myocardial tissues, a lysis buffer containing 1% protease inhibitor (Roche, Switzerland) was used. For normalizing the protein concentration in the tissue lysates, the bicinchoninic acid method was carried out. After subjection of proteins samples to sodium dodecyl sulfate-polyacrylamide gel electrophoresis, they were electrotransferred into polyvinylidene difluoride membranes (Millipore, USA) followed by blocking with 5% skim milk solution. Next, membranes were incubated with primary antibodies against NLRP3 (1:1000, Abcam, UK), ASC (1:500, Santa Cruz Biotechnology, USA), c-caspase-1 (1:2000, Thermo Fisher Scientific, USA), GSDMD (1:1000, Cell Signaling Technology, USA), PINK1 (1:1000, Abcam, UK), Parkin (1:2000, Abcam, UK), and β-actin (1:10000, Abcam, UK) overnight at 4°C. Following washing, membranes were incubated with the corresponding horseradish peroxidase-labeled secondary antibody (1:5000, Abcam, USA) at room temperature for 1 h. After washing membranes, the antigen-antibody complexes were visualized with enhanced chemiluminescence solution (Bio-Rad Laboratories, USA) and quantified by ImageJ software (National Institutes of Health, Bethesda, MD, USA).
Enzyme-linked immunosorbent assay
For detecting protein levels of IL-18 and IL-1β in the supernatant, commercially available kits (Bioscience, Germany) were employed based on the protocols given by the manufacturer. The samples were compared to the standard curve generated by the kits for determining IL-18 and IL-1β protein levels.
Using SPSS statistical software (SPSS V25.0, Chicago, IL, USA), all statistical analyses were performed. All the results are reported as mean ± standard deviation. Data were compared to a normal distribution using one-way analysis of variance and Tukey post hoc test. P < 0.05 reached statistical significance.
| Results|| |
Combination therapy improved cardiac function following myocardial IR injury in the aged rats
[Figure 1]a shows representative trace of hemodynamic parameters in different groups. The results showed that there was no statistical difference in the HRs among experimental groups [Figure 1]b. LVEDP was significantly increased (P < 0.001), whereas LVDP and ±dp/dt were significantly decreased (P < 0.001) in the IR group than in the sham group. The irisin-pretreated group showed decreased LVEDP and increased LVDP and ±dp/dt compared with the IR group (P < 0.05). The cardioprotection of the DNL-pretreated group was similar to that of irisin-pretreated group, except for the LVEDP and LVDP. Notably, irisin/DNL combined therapy more potently improved the above-mentioned parameters as compared with that of the IR group (P < 0.01) [Figure 1]c, [Figure 1]d, [Figure 1]e, [Figure 1]f.
|Figure 1: Combination therapy improved cardiac function following myocardial IR injury in the aged rats. Cardiac parameters assessed by cardiac catheter: representative trace of hemodynamic parameters (a), heart rates (b), left ventricular end-diastolic pressure (c), left ventricular developed pressure (d), maximal ascending rate of left ventricular pressure (+dp/dt) (e), and maximal descending rate of left ventricular pressure (–dp/dt) (f).(n = 6/group). The data were expressed as mean ± standard deviation. ***P < 0.001 vs. Sham group, #P < 0.05 and ##P < 0.01 vs. IR group, +P < 0.05 vs. IR + Iri group, $P < 0.05 vs. IR + DNL group. IR: Ischemia/reperfusion, Iri: Irisin, DNL: Dendrobium nobile Lindl.|
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Combination therapy alleviated IR injury in the aged myocardium
[Figure 2] shows the levels of LDH and cTn-I in different groups. The IR group exhibited increased serum levels of LDH and cTn-I as compared with that of the Sham group (P < 0.001 for both). However, when the IR group was pretreated with irisin, the levels of LDH and cTn-I were significantly decreased (P < 0.05 for both), and, DNL-pretreatment exerted a similar effect on LDH level (P < 0.05) without having such an effect on cTn-I level compared with the IR group. When the rats were pretreated with both irisin and DNL, the levels of LDH and cTn-I were further decreased in comparison with the IR group (P < 0.01).
|Figure 2: Combination therapy alleviated Ischemia/reperfusion injury in the aged myocardium. Serum lactate dehydrogenase (a) and cardiac-specific isoform of troponin-I (b) levels. (n = 6/group). The data were expressed as mean ± standard deviation. ***P < 0.001 vs. Sham group, #P < 0.05 and ##P < 0.01 vs. IR group, +P < 0.05 vs. IR + Iri group, $P < 0.05 vs. IR + DNL group. IR: Ischemia/reperfusion, Iri: Irisin, DNL: Dendrobium nobile Lindl.|
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Combination therapy inhibited pyroptosis in the aged IR myocardium
[Figure 3] shows the effects of irisin/DNL combination therapy on pyroptosis markers and their reversal by Mdivi-1. Western blotting revealed that the levels of pyroptosis-related proteins including NLRP3, ASC, c-caspase-1, and GSDMD-N were significantly decreased following co-application of irisin and DNL as compared with that of the IR group (P < 0.01 to P < 0.001) [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d, [Figure 3]e. In addition, the co-application of irisin and DNL significantly decreased the levels of pro-inflammatory factors including IL-18 and IL-1β as compared with that of the IR group (P < 0.001 and P < 0.01, respectively) [Figure 3]f and [Figure 3]g. The positive impacts of irisin/DNL co-administration on the levels of pyroptosis-related proteins and pro-inflammatory factors were markedly reversed following Mdivi-1 administration (P < 0.05 to P < 0.01).
|Figure 3: Combination therapy inhibited pyroptosis in the aged IR myocardium. Representative immunoblot bands (a) and analysis of nod-like receptor protein-3 (b), apoptosis-associated speck-like protein (c), cleaved-caspase-1 (d), and pyroptosis executor gasdermin D-N terminal (e) correlated to the β-actin band. Enzyme-linked immunosorbent assay of interleukin (IL)-18 (f) and IL-1β (g) protein levels. (n = 6/group). The data were expressed as mean ± standard deviation. **P < 0.01 and ***P < 0.001 vs. IR group, #P < 0.05 and ##P < 0.01 vs. IR + Iri/DNL group. IR: Ischemia/reperfusion, Iri/DNL: Irisin plus Dendrobium nobile Lindl, Mdivi: Mitochondrial division inhibitor 1.|
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Combination therapy activated mitophagy in the aged IR myocardium
[Figure 4]a, [Figure 4]b, and [Figure 4]c shows effects of irisin/DNL combination therapy on mitophagy markers and their reversal by Mdivi-1. Western blotting revealed that the expression levels of PINK1 and Parkin were significantly increased following co-application of irisin and DNL as compared with that of the IR group (P < 0.001). However, Mdivi-1 administration prevented the positive impacts of irisin/DNL co-administration on the expression levels of PINK1 and Parkin (P < 0.01).
|Figure 4: Combination therapy activated mitophagy in the aged IR myocardium. Representative immunoblot bands (a) and analysis of PINK1 (b) and Parkin (c) correlated to the β-actin band. (n = 6/group). The data were expressed as mean ± standard deviation. ***P < 0.001 vs. IR group, ##P < 0.01 vs. IR + Iri/DNL group. IR: Ischemia/reperfusion, Iri/DNL: Irisin plus Dendrobium nobile Lindl, Mdivi: Mitochondrial division inhibitor 1.|
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| Discussion|| |
The present investigation was designed for exploring the cardioprotective impact of combination therapy with irisin and DNL following IR injury in aged rats, and the underlying mechanisms. The results presented here showed that combined conditioning with irisin and DNL markedly improved cardiac function and decreased myocardial injury markers following IR during aging. These preconditioning modalities were found to prevent NLRP3 inflammasome-induced myocardial pyroptosis. The anti-pyroptotic impact of this combined therapy was partially dependent on the enhanced activity of the PINK1/Parkin-mediated mitophagy.
Previous experimental studies have reported that aging eliminates or modifies the cardioprotection induced by therapeutic interventions which exert protective effects in young animals., In the current work, a combination therapy approach was administered in aged rats with myocardial IR injury for enhancing the efficacy and potency of their single use during aging. The cardioprotective functions of irisin as well as DNL following IR damage in young animals have been revealed in previous works;,, however, we observed that single use of irisin or DNL failed to induce full cardioprotection in aged IR hearts as evaluated by hemodynamic measurements and the levels of myocardial injury markers. As expected, it seems that aging diminishes the efficiency of single therapy with irisin or DNL. Interestingly, irisin/DNL combined therapy was able to exert full cardioprotection against IR injury in aged rats, which was confirmed by improvement of myocardial function and reduction of LDH and cTn-I levels. Our findings are in line with the previous studies reporting that combination therapy can induce superior cardioprotection against IR injury in the presence of risk factors and comorbidities., Nevertheless, it is unclear whether the maximal cardioprotection by irisin/DNL combination therapy against myocardial IR injury during aging is attributable to its anti-pyroptotic action.
Pyroptosis, a mode of inflammatory programmed cell death that is initiated by caspase-1 activation, participates in the pathological event of myocardial IR injury. The processing of pro-caspase-1 into active caspase-1 causes cleavage of GSDMD into N-terminal fragment oligomers within the cell membrane, formation of large pores and membrane rupture, promotion of pro-inflammatory cytokines, and subsequent pyroptotic cell death. On myocardial IR injury condition, the activated NLRP3 inflammasome, an initiator of pyroptosis, causes activation of caspase 1 and GSDMD-N-dependent plasma membrane disruption, in which aggravates the inflammatory response through cleavage of pro-IL-18 and pro-IL-1β and formation of mature, biologically active IL-18 and IL-1β and their secretion., Conversely, the suppression of the NLRP3 inflammasome signaling pathway preserves normal cardiac function and diminishes infarct size by mitigating pyroptosis following IR injury., In line with these reported findings that inhibition of NLRP3 has protective impacts against IR injury, the results of the current study showed that the cardioprotection by irisin/DNL was related to the inhibition of pyroptotic cell death in aged IR hearts. Immunoblotting analyses showed that pretreatment with irisin and DNL decreased the levels of pyroptosis-related proteins including NLRP3, ASC, c-caspase-1, and GSDMD-N in IR-treated aged rats. Besides, the co-application of irisin and DNL decreased the inflammatory cytokines IL-18 and IL-1β releasing. Our data provided evidence that irisin/DNL combination therapy possesses cardioprotective function during aging via suppression of NLRP3-related pyroptosis and inflammatory response.
For exploring the mechanisms by which irisin/DNL combination therapy inhibited NLRP3-related pyroptosis following myocardial IR injury in aged rats, their combinational effects on mitophagy were assessed. Furthermore, the effect of this combination therapy in the presence of Mdivi-1 as a mitophagy inhibitor was examined. Mitophagy removes excess and damaged mitochondria in cardiomyocytes. PINK1/Parkin signaling pathway is the most well-known pathway leading to mitophagy. IR-induced myocardial injuries are accompanied by impaired mitochondrial quality control, decreased mitophagy, and accumulation of dysfunctional mitochondria in cardiomyocytes. As expected, the activation of PINK1/Parkin signaling pathway and damaged mitochondria removal protects the cardiomyocytes against IR injuries during aging.,, In agreement with this view, our results indicated that the co-administration of irisin and DNL upregulated PINK1 and Parkin proteins. In addition, pretreatment with Mdivi-1 partially reversed the protective effects of irisin/DNL combination therapy. This finding implied that anti-pyroptotic action and greater cardioprotection by irisin/DNL was associated with mitophagy activation. Together, these observations enlightened us that whether the maximal cardioprotection by combined application of irisin/DNL during aging was dependent on the attenuation of NLRP3 inflammasome-mediated pyroptosis, which can likely be ascribed in part to the activation of PINK1/Parkin-mediated mitophagy. However, along with mitophagy activation by irisin/DNL combined therapy, other possible candidates may also suppress the NLRP3 inflammasome-mediated pyroptosis, which encourages further studies.
As a final point, our study primarily focused on evaluating the effects of irisin/DNL combination therapy on cardiac function and injury markers LDH and cTn-I as the main endpoints; however, additional evidence to support our findings such as infarct size assay are needed in the ongoing research. In addition, we aimed to explore the changes and outcomes associated with aging in the context of our research objectives. It is worth noting that studying young animals is also important, particularly for investigating early disease mechanisms or developmental aspects of cardioprotection. However, studying aged animals provides crucial insights into age-related changes and their impact on cardiovascular health, ultimately aiding the development of effective cardioprotective strategies for the aging population.
| Conclusion|| |
Irisin/DNL combination therapy possessed maximal cardioprotection through the downregulation of pyroptosis-related proteins NLRP3, ASC, c-caspase-1, and GSDMD-N and attenuation of inflammatory cytokines IL-18 and IL-1β releasing. The anti-pyroptotic impact of these preconditioning modalities was mediated to some extent by enhancing the activity of the PINK1/Parkin-mediated mitophagy [Figure 5]. Our findings demonstrate that irisin/DNL combination therapy merits further detailed research due to its beneficial properties for the treatment of IR injury during aging as well as diseases associated with NLRP3 inflammasome-mediated pyroptosis.
|Figure 5: A signaling pathway diagram of irisin/DNL combination therapy action. Irisin/DNL combination therapy downregulated pyroptosis-related proteins and attenuated inflammatory cytokines releasing by enhancing the activity of the PINK1/Parkin-mediated mitophagy. GSDMD: Pyroptosis executor gasdermin D, IL: Interleukin, IR: Ischemia/reperfusion, Iri + DNL: Irisin plus Dendrobium nobile Lindl, NLRP3: Nod-like receptor protein-3, ROS: Reactive oxygen species.|
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Data availability statement
The authors confirm that the data supporting the findings of this study are available upon reasonable request.
All authors designed the project, performed the experimentations, and analyzed and interpreted the data. All authors read and approved the final manuscript.
Financial support and sponsorship
This study was funded by the Department of Cardiovascular Medicine, XD Group Hospital, Xi'an, 710077, China and Department of Pharmacy, the Nuclear Industry 417 Hospital, Xi'an, 710699, China.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]