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Melatonin reduces lung injury in type 1 diabetic mice by the modulation of autophagy



In recent years, the role of autophagy has been highlighted in the pathogenesis of diabetes and inflammatory lung diseases. In this study, using a diabetic model of mice, we investigated the expression of autophagy-related genes in the lung tissues following melatonin administration.


Data showed histopathological remodeling in lung tissues of the D group coincided with an elevated level of IL-6, Becline-1, LC3, and P62 compared to the control group (p < 0.05). After melatonin treatment, histopathological remodeling was improved D + Mel group. In addition, expression levels of IL-6, Becline-1, LC3, and P62 were decreased in D + Mel compared to D group (P < 0.05). Statistically significant differences were not obtained between Mel group and C group (p > 0.05).


Our results showed that melatonin injection can be effective in the amelioration of lung injury in diabetic mice presumably by modulating autophagy-related genes.

Peer Review reports


Type 1 diabetes (T1D), characterized by destroyed insulin-producing cells, is a chronic immune-mediated condition with an autoimmune reason. It is believed that a genetically sensitive person is exposed to an assumed environmental component that results in a breakdown of immune control before developing cell autoantibodies. A decrease in insulin secretion, the emergence of hyperglycemia, and ultimately the development of T1D are caused by the destruction of cells [1]. The majority of diabetes studies 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 and lessen 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 part in how it affects the pulmonary vasculature, airways, and lung parenchyma [8]. A catabolic process known as "self-eating," autophagy includes the transfer of damaged organelles or misfolded proteins from the cytoplasm to the lysosome for destruction [9]. Basal autophagy normally plays a crucial role in maintaining cellular homeostasis; nevertheless, excessive autophagy results in a particular kind of cell death that plays a role in the etiology of numerous illnesses [10, 11]. Several factors such as Becline-1, LC3, and P62 contribute to initiating and progressing 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 chronic lung diseases have been proven [14,15,16]. There is evidence that melatonin can help avoid many diabetes consequences, such as damage to the liver, kidneys, and lungs, 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).

Fig. 1
figure 1

An overview of study design

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 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 dose of 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, Sigma-Aldrich, 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 to measure 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 injecting a high dose of ketamine and xylazine, and their lung tissue was coming out and analyzed for pathology (right lung) and gene expression (left lung).

Histology of lung tissue

To examine the pathogenic impact of T1D on the pulmonary niche, formalin (10% w/v) was used to fix a sample of the right lung from each mouse. Next, samples were sliced into 5-μm thick pieces using a microtome and embedded in paraffin blocks. Hematoxylin and eosin (H&E) solution were used to stain the slides, and then monitored under a light microscope (Model: BX41; Olympus; Japan) as previously described [4]. Tissue damage including, bronchiolar epithelium degeneration and minor 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's left 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 Master Mix (Yekta Tajhiz Azma Co, Iran)were used to perform reaction. Following extraction of ct values detected by PCR machine, the relative fold changeswere calculated using the 2−ΔΔCT method after normalizing to the housekeeping gene, GAPDH. Table 1 lists the primers designed by Oligo 7 program (version 7.60).

Table 1 The list of primers used for real-time PCR analysis

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 and reported as means ± SEM. We considered a p value < 0.05 as statistically significant in GraphPad prism software (ver. 8).


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).

Fig. 2
figure 2

Measuring the blood glucose levels in 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 D groups: +  +  + ; p < 0. 001. Statistical differences between D group and D + Mel group:: +  +  + ; p < 0. 001

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) in the diabetic lung tissue (groups D, D + Mel). As shown in Fig. 3, Melatonin reduced the severity of interstitial bronchopneumonia in D group lung tissue.

Fig. 3
figure 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

Melatonin reduced the expression of the IL-6 gene within pulmonary tissue

PCR assay showed that induction of diabetes with STZ caused an increase in the expression level of IL-6 in lung tissue 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 difference between the M and C groups regarding the IL-6 gene (p > 0.05).

Fig. 4
figure 4

Measuring the transcription of IL-6 mRNA in the lung tissues 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 D groups: +  +  + ; p < 0. 001. Statistical differences between D group and D + Mel group: *; 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 up-regulate Becline-1, LC3, and P62 genes against the C group (p < 0.001; Fig. 5a, b, and c). Compared to the D group, 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 showed that systemic injection of melatonin in the D + Mel group can bring, in part, the activity of the autophagy pathway closer to normal values.

Fig. 5
figure 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


Diabetes remains the most challenging health problem in the world [18]. Oxidative stress and inflammation play a central 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 and pathological changes in the airways are the main characteristics of inflammatory lung diseases [22]. IL-6 is a proinflammatory cytokine that definitively promotes the development of insulin resistance and the pathogenesis of diabetes [23]. It seems that the vascular bed of the lung parenchyma and chronic inflammation in diabetes provide the key cause for the incidence of inflammation in the lungs and lung dysfunction [4, 7]. Therefore, these observations 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 found a decrease in interstitial pneumonia and IL-6 expression in diabetic lung tissue. Melatonin is an antioxidant and anti-inflammatory agent that removes free radicals and ROS, preventing organelle damage within cells. There is evidence to suggest that melatonin participated in improving tissue damage and lessening inflammation by removing 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 was very 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 the pro-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. showed that melatonin administration reduced hyperlipidemia, hyperglycemia, and oxidative stress. Melatonin acted as an anti-inflammatory agent that inhibited oxidative stress and 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 tissues of 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 and melatonin-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 and autophagy 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 level of 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 to decreased 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 levels of 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 melatonin promoted autophagy flux within cardiac tissues, which improved cardiac remodeling and dysfunction [40].

Overall, we observed that melatonin reduced the expression of inflammation factor, IL-6 and improved 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, whose levels were close to those of control. Therefore, in our opinion, increased autophagy during inflammation and 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 in future studies.


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 and pathological changes. Our preliminary data suggest that melatonin could be taken advantage of ameliorating T1D-associated complications, however, additional experimental investigations are desirable to confirm.

Availability of data and materials

The datasets are available from the corresponding author upon reasonable request.



Type 1 diabetes




  1. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383:69–82.

    Article  PubMed  Google Scholar 

  2. Hacioglu C, Kar F, Kara Y, Yucel E, Donmez DB, Sentürk H, Kanbak G. Comparative effects of metformin and Cistus laurifolius L. extract in streptozotocin-induced diabetic rat model: oxidative, inflammatory, apoptotic, and histopathological analyzes. Environ Sci Pollut Res. 2021;28:57888–901.

    Article  CAS  Google Scholar 

  3. Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Front Immunol. 2020;11:1582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zarafshan E, Rahbarghazi R, Rezaie J, Aslani MR, Saberianpour S, Ahmadi M, Keyhanmanesh R. Type 2 diabetes mellitus provokes rat immune cells recruitment into the pulmonary niche by up-regulation of endothelial adhesion molecules. Advanced Pharmaceutical Bulletin. 2022;12:176.

    CAS  PubMed  Google Scholar 

  5. Samarghandian S, Afshari R, Sadati A. Evaluation of lung and bronchoalveolar lavage fluid oxidative stress indices for assessing the preventing effects of safranal on respiratory distress in diabetic rats. Scientific World Journal. 2014;2014:251378.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Irfan M, Jabbar A, Haque AS, Awan S, Hussain SF. Pulmonary functions in patients with diabetes mellitus. Lung India: official organ of Indian Chest Society. 2011;28:89.

    Article  PubMed  Google Scholar 

  7. Lecube A, Simó R, Pallayova M, Punjabi NM, López-Cano C, Turino C, Hernández C, Barbé F. Pulmonary function and sleep breathing: two new targets for type 2 diabetes care. Endocr Rev. 2017;38:550–73.

    Article  PubMed  Google Scholar 

  8. Khateeb J, Fuchs E, Khamaisi M. Diabetes and lung disease: an underestimated relationship. Review of Diabetic Studies. 2019;15:1–15.

    Article  Google Scholar 

  9. Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2021;17:1–382.

  10. Bursch W. The autophagosomal–lysosomal compartment in programmed cell death. Cell Death Differ. 2001;8:569–81.

    Article  CAS  PubMed  Google Scholar 

  11. Debnath J, Baehrecke EH, Kroemer G. Does autophagy contribute to cell death? Autophagy. 2005;1:66–74.

    Article  CAS  PubMed  Google Scholar 

  12. Codogno P, Meijer AJ. Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ. 2005;12:1509–18.

    Article  CAS  PubMed  Google Scholar 

  13. Pourhanifeh MH, Hosseinzadeh A, Dehdashtian E, Hemati K, Mehrzadi S. Melatonin: new insights on its therapeutic properties in diabetic complications. Diabetol Metab Syndr. 2020;12:1–20.

    Article  Google Scholar 

  14. El-Sokkary GH, Cuzzocrea S, Reiter RJ. Effect of chronic nicotine administration on the rat lung and liver: beneficial role of melatonin. Toxicology. 2007;239:60–7.

    Article  CAS  PubMed  Google Scholar 

  15. Inci I, Inci D, Dutly A, Boehler A, Weder W. Melatonin attenuates posttransplant lung ischemia-reperfusion injury. Ann Thorac Surg. 2002;73:220–5.

    Article  PubMed  Google Scholar 

  16. Zhao X, Sun J, Su W, Shan H, Zhang B, Wang Y, Shabanova A, Shan H, Liang H. Melatonin protects against lung fibrosis by regulating the Hippo/YAP pathway. Int J Mol Sci. 2018;19:1118.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Allegra M, Reiter RJ, Tan DX, Gentile C, Tesoriere L, Livrea M. The chemistry of melatonin’s interaction with reactive species. J Pineal Res. 2003;34:1–10.

    Article  CAS  PubMed  Google Scholar 

  18. Ghasemi-Dehnoo M, Amini-Khoei H, Lorigooini Z, Rafieian-Kopaei M. Oxidative stress and antioxidants in diabetes mellitus. Asian Pac J Trop Med. 2020;13:431.

    Article  CAS  Google Scholar 

  19. Rajendiran D, Packirisamy S, Gunasekaran K. A review on role of antioxidants in diabetes. Asian J Pharm Clin Res. 2018;11:48–53.

    Article  Google Scholar 

  20. Rahbarghazi A, Siahkouhian M, Rahbarghazi R, Ahmadi M, Bolboli L, Mahdipour M, Haghighi L, Hassanpour M, Nasimi FS, Keyhanmanesh R. Melatonin and prolonged physical activity attenuated the detrimental effects of diabetic condition on murine cardiac tissue. Tissue Cell. 2021;69: 101486.

    Article  CAS  PubMed  Google Scholar 

  21. Aslani MR, Sharghi A, Boskabady MH, Ghobadi H, Keyhanmanesh R, Alipour MR, Ahmadi M, Saadat S, Naghizadeh P. Altered gene expression levels of IL-17/TRAF6/MAPK/USP25 axis and pro-inflammatory cytokine levels in lung tissue of obese ovalbumin-sensitized rats. Life Sci. 2022;296: 120425.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang W-X, Li C-C. Airway remodeling: a potential therapeutic target in asthma. World Journal of Pediatrics. 2011;7:124–8.

    Article  PubMed  Google Scholar 

  23. Kawasaki E, Fukuyama T, Uchida A, Sagara Y, Nakano Y, Tamai H, Tojikubo M, Hiromatsu Y, Koga N. Development of type 1 diabetes in a patient treated with anti-interleukin-6 receptor antibody for rheumatoid arthritis. Journal of Diabetes Investigation. 2022;13:738–40.

    Article  CAS  PubMed  Google Scholar 

  24. Talakatta G, Sarikhani M, Muhamed J, Dhanya K, Somashekar BS, Mahesh PA, Sundaresan N, Ravindra PV. Diabetes induces fibrotic changes in the lung through the activation of TGF-β signaling pathways. Sci Rep. 2018;8:11920.

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  25. Jalili-Nik M, Soukhtanloo M, Javanshir S, Jahani Yazdi A, Esmaeilizadeh M, Jafarian AH, Ghorbani A. Effects of ethanolic extract of Ferula gummosa oleo-resin in a rat model of streptozotocin-induced diabetes. Res Pharm Sci. 2019;14:138–45.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Colares JR, Hartmann RM, Schemitt EG, Fonseca SR, Brasil MS, Picada JN, Dias AS, Bueno AF, Marroni CA, Marroni NP. Melatonin prevents oxidative stress, inflammatory activity, and DNA damage in cirrhotic rats. World J Gastroenterol. 2022;28:348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Agil A, Reiter RJ, Jiménez-Aranda A, Ibán-Arias R, Navarro-Alarcón M, Marchal JA, Adem A, Fernández-Vázquez G. Melatonin ameliorates low-grade inflammation and oxidative stress in young Zucker diabetic fatty rats. J Pineal Res. 2013;54:381–8.

    Article  PubMed  Google Scholar 

  28. Farid A, Moussa P, Youssef M, Haytham M, Shamy A, Safwat G. Melatonin relieves diabetic complications and regenerates pancreatic beta cells by the reduction in NF-kB expression in streptozotocin induced diabetic rats. Saudi journal of biological sciences. 2022;29: 103313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bhutia SK, Dash R, Das SK, B Azab, Su Zz, Lee SG, Grant S, Yacoub A, Dent P, Curiel DT. Mechanism of autophagy to apoptosis switch triggered in prostate cancer cells by antitumor cytokine melanoma differentiation-associated gene 7/interleukin-24. Cancer Res. 2010;70:3667–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bianco R, Garofalo S, Rosa R, Damiano V, Gelardi T, Daniele G, Marciano R, Ciardiello F, Tortora G. Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer. 2008;98:923–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dewanjee S, Vallamkondu J, Kalra RS, John A, Reddy PH, Kandimalla R. Autophagy in the diabetic heart: a potential pharmacotherapeutic target in diabetic cardiomyopathy. Ageing Res Rev. 2021;68: 101338.

    Article  CAS  PubMed  Google Scholar 

  32. Bhattacharya D, Mukhopadhyay M, Bhattacharyya M, Karmakar P. Is autophagy associated with diabetes mellitus and its complications? A review EXCLI journal. 2018;17:709.

    PubMed  Google Scholar 

  33. Liu J-N, Suh D-H, Trinh HKT, Chwae Y-J, Park H-S, Shin YS. The role of autophagy in allergic inflammation: a new target for severe asthma. Exp Mol Med. 2016;48:e243-e.

    Article  Google Scholar 

  34. Netea-Maier RT, Plantinga TS, van de Veerdonk FL, Smit JW, Netea MG. Modulation of inflammation by autophagy: consequences for human disease. Autophagy. 2016;12:245–60.

    Article  CAS  PubMed  Google Scholar 

  35. Luo N, Wang Y, Ma Y, Liu Y, Liu Z. Melatonin alleviates renal injury in diabetic rats by regulating autophagy. Mol Med Rep. 2023;28:214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Song Z, Yan C, Zhan Y, Wang Q, Zhang Y, Jiang T. Melatonin attenuates lung ischemia-reperfusion injury through SIRT3 signaling-dependent mitophagy in type 2 diabetic rats. Exp Lung Res. 2023;49:101–15.

    Article  CAS  PubMed  Google Scholar 

  37. Xu X, Kobayashi S, Chen K, Timm D, Volden P, Huang Y, Gulick J, Yue Z, Robbins J, Epstein PN. Diminished autophagy limits cardiac injury in mouse models of type 1 diabetes. J Biol Chem. 2013;288:18077–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ding D-F, You N, Wu X-M, Xu J-R, Hu A-P, Ye X-L, Zhu Q, Jiang X-Q, Miao H, Liu C. Resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK. Am J Nephrol. 2010;31:363–74.

    Article  CAS  PubMed  Google Scholar 

  39. Xu X-H, Ding D-F, Yong H-J, Dong C-L, You N, Ye X-L, Pan M-L, Ma J-H, You Q, Lu Y-B. Resveratrol transcriptionally regulates miRNA-18a-5p expression ameliorating diabetic nephropathy via increasing autophagy. Eur Rev Med Pharm Sci. 2017;21:4952–65.

    Google Scholar 

  40. Zhang M, Lin J, Wang S, Cheng Z, Hu J, Wang T, Man W, Yin T, Guo W, Gao E. Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling. J Pineal Res. 2017;63: e12418.

    Article  Google Scholar 

  41. Ge X, Wang L, Fei A, Ye S, Zhang Q. Research progress on the relationship between autophagy and chronic complications of diabetes. Front Physiol. 2022;13: 956344.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wu J, Bai Y, Wang Y, Ma J. Melatonin and regulation of autophagy: Mechanisms and therapeutic implications. Pharmacol Res. 2021;163: 105279.

    Article  CAS  PubMed  Google Scholar 

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The authors wish to thank the personnel of the Drug Applied Research Center of Tabriz University of Medical Sciences for guidance and help.


This study was funded by Drug Applied Research Center of Tabriz University of Medical Sciences (IR.TBZMED.VCR.REC.1399.250).

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MA and JR conceived and designed the experiments. MJ and RM-H performed experiments. and SH and MA analyzed the data. NA participated in revising the manuscript. JR wrote and finally approved the text. AR prepared the figures. All authors read and approved the final manuscript.

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Correspondence to Mahdi Ahmadi.

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The animal experimental procedures were conducted according to the principles of guidelines for the ethical use of animals in applied studies and approved by the Ethics Committee on Animal Use of Tabriz University of Medical Sciences (IR.TBZMED.VCR.REC.1399.250) in compliance with the ARRIVE guidelines.

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Rezaie, J., Jahanghiri, M., Heris, R.M. et al. Melatonin reduces lung injury in type 1 diabetic mice by the modulation of autophagy. BMC Mol and Cell Biol 25, 7 (2024).

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