Rezaie et al. BMC Molecular and Cell Biology
https://doi.org/10.1186/s12860-024-00505-9(2024) 25:7

BMC Molecular andCell Biology

Open Access

RESEARCH

Melatonin reduces lung injury in type 1
diabetic mice by the modulation of autophagy
Jafar Rezaie1, Mojtaba Jahanghiri2, Reza Mosaddeghi‑ Heris3, Sina Hassannezhad3, Nima Abdyazdani4,
Afshin Rahbarghazi5 and Mahdi Ahmadi5*

Abstract
Background In recent years, the role of autophagy has been highlighted in the pathogenesis of diabetes and inflam‑
matory lung diseases. In this study, using a diabetic model of mice, we investigated the expression of autophagyrelated genes in the lung tissues following melatonin administration.
Results Data showed histopathological remodeling in lung tissues of the D group coincided with an elevated levelof IL-6, Becline-1, LC3, and P62 compared to the control group (p < 0.05). After melatonin treatment, histopathologicalremodeling was improved D + Mel group. In addition, expression levels of IL-6, Becline-1, LC3, and P62 were decreasedin D + Mel compared to D group (P < 0.05). Statistically significant differences were not obtained between Mel group
and C group (p > 0.05).
Conclusion Our results showed that melatonin injection can be effective in the amelioration of lung injury in dia‑
betic mice presumably by modulating autophagy-related genes.
Keywords Autophagy, Diabetes, Lung injury, MelatoninBackground
Type 1 diabetes (T1D), characterized by destroyed insulin-producing cells, is a chronic immune-mediated condition with an autoimmune reason. It is believed that agenetically sensitive person is exposed to an assumed
environmental component that results in a breakdown of
immune control before developing cell autoantibodies. A*Correspondence:
Mahdi Ahmadi
mahdi59866@gmail.com
1
Solid Tumor Research Center, Cellular and Molecular Medicine Institute,
Urmia University of Medical Sciences, Urmia, Iran2
Student Research Committee, Tabriz University of Medical Sciences,
Tabriz, Iran
3
Neurosciences Research Center, Tabriz University of Medical Sciences,
Tabriz, Iran4
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz,
Iran
5
Drug Applied Research Center, Tabriz University of Medical Sciences,
Tabriz, Irandecrease in insulin secretion, the emergence of hyperglycemia, and ultimately the development of T1D are causedby the destruction of cells [1]. The majority of diabetesstudies have examined the effects of diabetes complications on other body tissues, including the heart, nervous
system, and reproductive system [2, 3]. However, the precise mechanism of lung parenchymal damage in diabetes
is still not fully understood. Undoubtedly, understanding
the precise process of this damage can help manage andlessen the pulmonary difficulties that diabetic individuals experience [4, 5]. The lung parenchyma is vulnerable
to injury in diabetics due to the high levels of elastin
and collagen tissue, as well as the abundance of arterial
beds in the lung tissue, on the one hand, and the presence of chronic oxidative stress and systemic inflammation in diabetes, on the other hand [6, 7]. Hyperglycemia’s
proinflammatory, proliferative, and oxidative characteristics have been demonstrated to play a significant partin how it affects the pulmonary vasculature, airways,
and lung parenchyma [8]. A catabolic process known as© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom‑mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Rezaie et al. BMC Molecular and Cell Biology(2024) 25:7

"self-eating," autophagy includes the transfer of damaged
organelles or misfolded proteins from the cytoplasm tothe lysosome for destruction [9]. Basal autophagy normally plays a crucial role in maintaining cellular homeostasis; nevertheless, excessive autophagy results in aparticular kind of cell death that plays a role in the etiology of numerous illnesses [10, 11]. Several factors suchas Becline-1, LC3, and P62 contribute to initiating andprogressing autophagy flux [12]. Melatonin, a crucial
neuroendocrine hormone, is essential for reducing fibrosis, autophagy, mitochondrial fission, and insulin resistance in people with diabetes [13]. Today, melatonin’s
therapeutic and anti-inflammatory properties in chroniclung diseases have been proven [14–16]. There is evidence that melatonin can help avoid many diabetes
consequences, such as damage to the liver, kidneys, andlungs, as well as cardiovascular disease [17]. This project
was undertaken to design mice model of T1D and evaluate protective impact of melatonin on lung tissue histology and autophagy flux with focus on gene expression
method (Fig. 1).

Methods and Materials
Animal issues

All experimental procedures were approved by Ethics Committee of Tabriz University of Medical Sciences
according to National Institutes of Health for Laboratory

Fig. 1 An overview of study design

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Animal Care (revised 1996)with ethical number (No:IR.TBZMED.VCR.REC.1399.250).
Experimental design

In this study we used thirty-two mice (initially weighing
25–30 g). Initially, mice kept foradaptation for 10 days,
then were divided into four groups (n = 8) as follows: 1:
Control group(C): received standard food and water. 2:
Melatonin group (Mel): melatonin (Sigma-Aldrich, Steinheim, Germany)was injected intraperitoneally (3 mg/kg) for four weeks twice a week [1, 2]. 3: Diabetic group(D): received intraperitoneal injection of a single doseof streptozotocin (50 mg/kg). 4: Diabetic + Melatonin(D + Mel): two weeks after the induction of diabetes,
melatonin was administered intraperitoneally (3 mg/kg)
twice a week for four weeks(Fig. 1).
Induction of T1D

After 8 h of fasting, T1D was induced by intraperitoneal injection of 50 mg/kg streptozotocin (STZ, SigmaAldrich, Steinheim, Germany) as a single dose (Fig. 1).
In following, 72 h after the STZ injection, blood samples were obtained from the tail vein after overnight
fasting and digital glucometer (Norditalia Elettromedicali S.r.I., San Martino della Battaglia, Italy) was used tomeasure glucose levels. Mice with serum glucose levels
over 250 mg/dL were considered diabetic animals [3].
48 h after the last injection, the animals were killed by

Rezaie et al. BMC Molecular and Cell Biology(2024) 25:7

injecting a high dose of ketamine and xylazine, and theirlung tissue was coming out and analyzed for pathology(right lung) and gene expression (left lung).

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as statistically significant in GraphPad prism software(ver. 8).

Results

Histology of lung tissue

To examine the pathogenic impact of T1D on the pulmonary niche, formalin (10% w/v) was used to fix a sampleof the right lung from each mouse. Next, samples weresliced into 5-μm thick pieces using a microtome andembedded in paraffin blocks. Hematoxylin and eosin(H&E) solution were used to stain the slides, and thenmonitored under a light microscope (Model: BX41;
Olympus; Japan) as previously described [4]. Tissue damage including, bronchiolar epithelium degeneration andminor interstitial pneumonitis were evaluated.
Real‑time PCR

A quantitative real-time PCR assay was used to measure
the mRNA levels of IL-6, LC3, Beclin-1, and p62. To conduct a gene expression analysis, a portion of a mouse’sleft lung was cut out and immediately frozen in liquid
nitrogen for total RNA isolation according to the manufacturer’s instructions of the RNA extraction kit (Yekta
Tajhiz Azma Co, Iran). A Nanodrop spectrophotometer
was used to measure RNA samples (NanoDrop-1000,
USA). The cDNA Synthesis kit (Yekta Tajhiz Azma Co,
Iran)was used to convert RNA into cDNA. Real time PCR(Corbett Life Science, Australia) and SYBR Green MasterMix (Yekta Tajhiz Azma Co, Iran)were used to perform
reaction. Following extraction of ct values detected by
PCR machine, the relative fold changeswere calculatedusing the ­2−ΔΔCT method after normalizing to the housekeeping gene, GAPDH. Table 1 lists the primers designed
by Oligo 7 program (version 7.60).

Melatonin diminished blood glucose levels in diabetic
animals

Based on our results, fasting blood glucose levels
increased significantly 72 h after the STZ injection in diabetic groups compared to the C group (p < 0.001; Fig. 2).
Melatonin led to a significant decrease in the glucose
level in diabetic mice compared to the D group (p < 0.001;
Fig. 2).
Melatonin reduced pathological lesions in diabetic lungs

H & E staining revealed that induction of diabetes with
STZ caused pathological changes in the pulmonary niche(Fig. 3). The images obtained from the light field microscope showed interstitial pneumonia (red arrows) inthe diabetic lung tissue (groups D, D + Mel). As shownin Fig. 3, Melatonin reduced the severity of interstitialbronchopneumonia in D group lung tissue.
Melatonin reduced the expression of the IL‑6 genewithin pulmonary tissue

PCR assay showed that induction of diabetes with STZ
caused an increase in the expression level of IL-6 in lungtissue compared to control mice (p < 0.001; Fig. 4). Compared to the D group, we found a statistically significant
reduction in the expression of IL-6 in the D + Mel group(p < 0.05; Fig. 4). In addition, we did not find a significant

Data analysis

In the first step, the normality of the data was analyzed
using Kolmogorov–Smirnov test.
Subsequently, data was analyzed using One-WayANOVA with Tukey–Kramer post hoc analysis andreported as means ± SEM. We considered a p value < 0.05

Table 1 The list of primers used for real-time PCR analysis
Primer sequence (5’-3’) Gene Forward Reverse
LC-3

CAT​GCC​GTC​CGA​GAA​GAC​C T

GAT​GAG​CCG​GAC​ATC​T TC​CACT​P62

GAG​GCA​CCC​CGA​AAC​ATG​GACT​TAT​AGC​GAG​T TC​CCA​CCA​

Beclin-1 TTG​GCC​AAT​AAG​ATG​GGT​
CTGAA​TGT​CAG​GGA​C TC​CAG​ATA​CGA​
GTG​

IL-6

TAC​CAC​T TC​ACA​AGT​CGG​
AGGC​

CTG​CAA​GTG​CAT​CGT​TGT​TC

GAPDH

AAC​T TT​GGC​ATT​GTG​GAA​GG

ACA​CAT​TGG​GGG​TAG​GAA​CA

Fig. 2 Measuring the blood glucose levels in control animals (Cgroup), control animals received melatonin (Mel group), diabetic
animals (D group), diabetic animals received melatonin (D + Mel
group) (for each group, n = 8). Bars represent the mean ± SEM.
Statistical differences between C and D groups: +  +  + ; p < 0. 001.
Statistical differences between D group and D + Mel group:: +  +  + ;p < 0. 001

Rezaie et al. BMC Molecular and Cell Biology(2024) 25:7

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Fig. 3 H & E staining of diabetic lung tissue. Imaging showed interstitial bronchopneumonia in diabetic lungs (red arrows). Melatonin reduced
the damaging effects of diabetes on lung tissue

up-regulate Becline-1, LC3, and P62 genes against theC group (p < 0.001; Fig. 5a, b, and c). Compared to the Dgroup, melatonin reduced the expression of these genes
in the D + M group (p < 0.01 to p < 0.01; Fig. 5a, b, and c).
The expression of these genes did not change in D + Mel
compared to the C group (p > 0.05). These results showedthat systemic injection of melatonin in the D + Mel groupcan bring, in part, the activity of the autophagy pathway
closer to normal values.

Fig. 4 Measuring the transcription of IL-6 mRNA in the lungtissues of control animals (C group), control animals received
melatonin (Mel group), diabetic animals (D group), diabetic animals
received melatonin (D + Mel group) (for each group, n = 8). Bars
represent the mean ± SEM. Statistical differences between C and Dgroups: +  +  + ; p < 0. 001. Statistical differences between D group
and D + Mel group: *; p < 0.05

difference between the M and C groups regarding theIL-6 gene (p > 0.05).
Melatonin modulated autophagy status in DM1 mice

We also monitored the autophagy-related genes including Becline-1, LC3, and P62 in diabetic lungs (Fig. 5).
Data indicated that the induction of diabetes could

Discussion
Diabetes remains the most challenging health problem in
the world [18]. Oxidative stress and inflammation play acentral role in the diabetes. Therefore, this study set out
with the aim of assessing the importance of melatonin in
the treatment of complications associated with as melatonin showed antioxidants and anti-inflammatory properties [19, 20]. We measured the impact of melatonin on
autophagy genes in the lung tissue of T1D mice.
As shown in Fig. 2, we observed interstitial pneumonia in lung samples of diabetic rats, which confirms histological changes in diabetic lung tissue. Furthermore,
we found that the expression of IL-6 was up-regulated
in lung tissues, indicating an inflammatory condition.
Similarly, Aslani et al. showed that the expression of the
IL-6 gene was elevated in the lung tissue of male rats
suffering from allergic asthma [21]. Inflammation andpathological changes in the airways are the main characteristics of inflammatory lung diseases [22]. IL-6 is a

Rezaie et al. BMC Molecular and Cell Biology(2024) 25:7

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Fig. 5 Measuring the transcription of Beclin-1 (a), P62 (b) and LC3 (c) mRNA in the lung tissues of different groups by real-time PCR. Bars represent
the mean ± SEM. Statistical differences between C and D groups: +  +  + ; p < 0. 001. Statistical differences between D group and D + Mel group: *;p < 0.05 and **; p < 0.001

proinflammatory cytokine that definitively promotes thedevelopment of insulin resistance and the pathogenesisof diabetes [23]. It seems that the vascular bed of thelung parenchyma and chronic inflammation in diabetes
provide the key cause for the incidence of inflammationin the lungs and lung dysfunction [4, 7]. Therefore, theseobservations are a line with the previous studies confirming inflammation and pathological changes in lung tissues of diabetic animals [24, 25].
In keeping, after treatment with melatonin, we founda decrease in interstitial pneumonia and IL-6 expression
in diabetic lung tissue. Melatonin is an antioxidant andanti-inflammatory agent that removes free radicals and
ROS, preventing organelle damage within cells. Thereis evidence to suggest that melatonin participated in
improving tissue damage and lessening inflammation byremoving oxidative stress caused by diabetic conditions[26]. In our recent research, we found that intraperitoneal
injection of melatonin for 4 weeks improved the heart
function of Syrian mice model of diabetes [20]. Accordingly, confirmed that the serum level of melatonin hormone is low in people with diabetes and melatonin wasvery effective in improving the complications of diabetic
patients, which may correlate with the anti-inflammatory
and antioxidant activities of melatonin [13, 20].
In an experimental model of type 2 diabetes, it was
found that administration of melatonin prevented thepro-inflammatory cytokines production including, IL-6,
TNF-α, and CRP, inflammation as well as oxidative stress[27]. In STZ-induced diabetic rats, Farid et al. showedthat melatonin administration reduced hyperlipidemia,
hyperglycemia, and oxidative stress. Melatonin acted as
an anti-inflammatory agent that inhibited oxidative stressand pro-inflammatory cytokines (IL-1β and IL-12) [28].
Generally, our results are well matched with the previous
findings proposing that melatonin reduces tissue damage and inflammation in diabetic conditions. Furthermore, we evaluated the autophagy flux in lung tissuesof different rats by analyzing autophagy-related genes
and found that mRNA levels of LC3, Becline-1, and P62
in diabetic rats were higher than those of control andmelatonin-treated rats. In other words, when diabetic
rats received melatonin, the expression of these genes
was inhibited, suggesting an inhibitory effect of Melatonin on autophagy flux. The activity of these genes andautophagy flux can be affected by several factors such as
diet, high-fat foods, and metabolic stress such as oxidative stress [29, 30]. Autophagy plays a vital function in
the complications of diabetes [31]. We know that, under
diabetic conditions, metabolic inflammation is correlated with autophagy induced by oxidative stress [32],in addition, during inflammatory lung diseases, the levelof autophagy is increased, thus lessening autophagy flux
helps diseases improvement and reducing complications[33, 34]. More recently, Luo et al. reported that Melatonin improved renal injury in diabetic rats by regulating autophagy. They showed that Melatonin also reduced
the protein expression levels of LC3II, P62 and COL-IV
while the phosphorylation of AMPK was significantly
augmented both in vivo and in vitro [35]. In addition,in type 2 diabetic rats, it was demonstrated that Melatonin lessened lung ischemia–reperfusion injury through
SIRT3 signaling-dependent mitophagy [36]. In a study,
it was demonstrated that diminished autophagy led todecreased cardiac injury in an animal model of type 1
diabetes [37]. It has previously been described that in
STZ-induced type 1 diabetes or high glucose conditions,the autophagic activity of podocytes (kidney cells) is
reduced, accompanied by a reduction in expression levelsof autophagy-related proteins such as ATG12-5, Beclin-1,
and LC3 [38, 39]. However, in a model of mice with diabetic cardiomyopathy, the administration of melatoninpromoted autophagy flux within cardiac tissues, which
improved cardiac remodeling and dysfunction [40].
Overall, we observed that melatonin reduced theexpression of inflammation factor, IL-6 and improved

Rezaie et al. BMC Molecular and Cell Biology(2024) 25:7

pathological condition within lung tissues, which coincided with a reduced autophagic gene expression. Melatonin treatment resulted in a decrease in the expression
level of autophagic genes in diabetic animals, whoselevels were close to those of control. Therefore, in our
opinion, increased autophagy during inflammationand tissue damage in diabetic animals was reduced
after melatonin administration, confirming the antioxidant and anti-inflammatory impacts of melatonin [41,42]. This study has gone some way towards enhancing our understanding of the function of melatonin in
improving T1D lungs, and we hope that further works
will prove our theory by measuring molecular signaling pathways behind crosstalk between inflammation
responses and autophagy flux in T1D lungs. To be honest, the current study faces some limitations.. Here,
we did not western blot analysis of autophagy-related
markers. It is also recommended to evaluate the protein
levels of factors related to apoptosis to better understand the mechanism of melatonin’s effects in reducing
pulmonary complications under diabetic conditions infuture studies.

Conclusion
The evidence from this study suggests that melatonin
could ameliorate inflammation and pathological lesions
in the lung tissues of T1D mice. At the same time, melatonin could reduce expression levels of autophagic
genes and close them to those of control mice, indicating a correlation to diminished inflammation andpathological changes. Our preliminary data suggestthat melatonin could be taken advantage of ameliorating T1D-associated complications, however, additional
experimental investigations are desirable to confirm.
Abbreviations
T1D	Type 1 diabetes
STZ	Streptozotocin
Acknowledgements
The authors wish to thank the personnel of the Drug Applied Research Centerof Tabriz University of Medical Sciences for guidance and help.
Authors’ contributions
MA and JR conceived and designed the experiments. MJ and RM-H performedexperiments. and SH and MA analyzed the data. NA participated in revising
the manuscript. JR wrote and finally approved the text. AR prepared thefigures. All authors read and approved the final manuscript.
Funding
This study was funded by Drug Applied Research Center of Tabriz University of
Medical Sciences (IR.TBZMED.VCR.REC.1399.250).
Availability of data and materials
The datasets are available from the corresponding author upon reasonable
request.

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Declarations
Ethics approval and consent to participate
The animal experimental procedures were conducted according to theprinciples of guidelines for the ethical use of animals in applied studies andapproved by the Ethics Committee on Animal Use of Tabriz University of Medi‑
cal Sciences (IR.TBZMED.VCR.REC.1399.250) in compliance with the ARRIVE
guidelines.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 19 August 2023 Accepted: 6 March 2024

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