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

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

Urinary and circulatory netrin-1 as biomarker in diabetes and its related complications: a systematic review and meta-analysis.

BACKGROUND: Novel biomarkers have been suggested for the diagnosis and prognosis of diabetes mellitus. The biomarker utility of netrin-1 in diabetes as an extracellular protein has been investigated. In this systematic review and meta-analysis, we reviewed the role of netrin-1 as a biomarker in prediabetes, diabetes, and complications of diabetes. METHODS: PubMed, Embase, Scopus, and Web of Science were systematically searched for studies that measured circulatory and/or urinary netrin-1 levels in diabetes and compared them with non-diabetic patients or evaluated the prognostic role of this marker. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated using random-effect meta-analysis to compare netrin-1 levels between groups. The impact of mean age, male sex percentage, sample size, mean body mass index, and publication year on the overall heterogeneity was assessed using meta-regression. RESULTS: Among 413 records from international databases, 19 original studies were included with 2061 cases (1137 diabetics, 196 prediabetics, and 728 healthy controls). Meta-analysis of eight studies measuring netrin-1 in patients with diabetes and comparing it with healthy controls showed no significant difference between the two groups (SMD 0.69, 95% CI -0.78 to 2.16, I2 = 98%, p-value = 0.36). On the other hand, a meta-analysis of netrin-1 levels in patients with prediabetes in comparison with healthy controls revealed that they had lower levels (SMD -0.51, 95% CI -0.81 to -0.21, p-value < 0.01). Diabetic patients with microalbuminuria and macroalbuminuria had significantly higher circulatory netrin-1 levels compared to normoalbuminuric group SMD 1.18, 95% CI 0.83 to 1.53, p-value < 0.01 and SMD 1.67, 95% CI 0.76 to 2.58, p-value < 0.01, respectively). Moreover, no difference in urinary netrin-1 levels was found between micro-, macro-, and normoalbuminuric groups (p-value > 0.05). CONCLUSION: Netrin-1 showed promising results as a biomarker in diabetes prognosis. However, more studies are required to confirm our findings, and higher sample size studies are needed to evaluate the diagnostic utility of this marker.

Swimming training reduced inflammation and apoptotic changes in pulmonary tissue in type 1 diabetic mice.

Background: Despite the vulnerability of pulmonary tissue to diabetic conditions, there are few reports related to the detrimental effects of hyperglycemia and therapeutic modalities on lung parenchyma. Here, the apoptotic changes were monitored in the diabetic pulmonary tissue of mice (DM1) subjected to a four‒week swimming plan. Methods: The mice were randomly allocated into Control; Control + Swimming (S); Diabetic group (D); and Diabetic + Swimming (D + S) groups (each in 8 mice). In the D and D + S groups, mice received intraperitoneally 50 mg/kg of streptozotocin (STZ). After 14 days, swimming exercise was done for four weeks. The expression of il-1ß, bcl-2, bax, and caspase-3 was investigated using real-time PCR analysis. A histological examination was performed using H&E staining. Results: DM1 significantly upregulated il-1ß, bax, and caspase-3, and down-regulated bcl-2 compared to the non-diabetic mice (p < 0.05). We noted that swimming exercises reversed the expression pattern of all genes in the diabetic mice and closed to basal levels (p < 0.05). Data indicated that swimming exercise could diminish emphysematous changes, and interstitial pneumonitis induced by STZ. Along with these changes, swimming exercise had protective effects to reduce the thickness of the inter-alveolar septum and mean alveolar area in diabetic mice. Conclusion: These data demonstrated that swimming exercises could decrease DM1-related pathologies in mouse lungs by regulating apoptosis and inflammatory response.

Co-administration of exercise training and melatonin on the function of diabetic heart tissue: a systematic review and meta-analysis of rodent models.

PURPOSE: Diabetes mellitus (DM), a hyperglycemic condition, occurs due to the failure of insulin secretion and resistance. This study investigated the combined effects of exercise training and melatonin (Mel) on the function of heart tissue in diabetic rodent models. METHODS: A systematic search was conducted in Embase, ProQuest, Cochrane library, Clinicaltrial.gov, WHO, Google Scholar, PubMed, Ovid, Scopus, Web of Science, Ongoing Trials Registers, and Conference Proceedings in July 2022 with no limit of date or language. All trials associated with the effect of Mel and exercise in diabetic rodent models were included. Of the 962 relevant publications, 58 studies met our inclusion criteria as follows; Mel and type 1 DM (16 studies), Mel and type 2 DM (6 studies), exercise and type 1 DM (24 studies), and exercise and type 2 DM (12 studies). Meta-analysis of the data was done using the Mantel Haenszel method. RESULTS: In most of these studies, antioxidant status and oxidative stress, inflammatory response, apoptosis rate, lipid profiles, and glucose levels were monitored in diabetic heart tissue. According to our findings, both Mel and exercise can improve antioxidant capacity by activating antioxidant enzymes compared to the control diabetic groups (p < 0.05). The levels of pro-inflammatory cytokines, especially TNF-α were reduced in diabetic rodents after being treated with Mel and exercise. Apoptotic changes were diminished in diabetic rodents subjected to the Mel regime and exercise in which p53 levels and the activity of Caspases reached near normal levels (p < 0.05). Based on the data, both Mel and exercise can change the lipid profile in diabetic rodents, especially rats, and close it to near-to-control levels. CONCLUSION: These data showed that exercise and Mel can reduce the harmful effects of diabetic conditions on the heart through the regulation of lipid profile, antioxidant capacity, apoptosis, and inflammation.

Putative effect of melatonin on cardiomyocyte senescence in mice with type 1 diabetes mellitus.

Background: To date, many investigators have tried to clarify the molecular mechanism of cardiovascular injuries after T1D. In present study, we evaluated the possible effects of melatonin on the levels of aging-related factors in the heart tissue of streptozotocin-induced diabetic mice. Methods: 40 male mice were enrolled in this study and randomly allocated into 4 groups (n = 10) as follows: Control group (C), Control group + melatonin (CM), Diabetic group (D), Diabetic + melatonin (DM) group. Single Streptozotocin (50 mg/kbW) was applied for the induction of T1D. 3 mg/kg melatonin was injected intraperitoneally twice a week for consequent four weeks. After the completion of this period, the animals were sacrificed and their heart tissue was obtained for histological examination (IHC analysis of vWF and α-SMA cells), aging and inflammation-related gene analysis. Result: Hematoxylin and Eosin staining indicated cardiomyocyte toxicity in T1D mice. IHC analysis of vascular tissue showed the detachment of vWF and α-SMA cells and disintegration into the vascular lumen. Additionally, real-time PCR assay showed the up-regulation of ß-galactosidase and suppression of SOX2, Klotho, and Telomerase genes in T1D mice compared to the control group (p < 0.05). We noted that melatonin administration can revert these condition and closed near-to-control levels. Along with these conditions, the levels of IL-1ß were also decreased after melatonin treatment. Conclusions: In general, one can hypothesize that modulation of different effectors associated with aging is beneficial to alleviate cardiac injuries under hypergylcemic condition. Melatonin can exert its therapeutic effects, in part, through anti-aging capacity.

Intra-tracheal delivery of mesenchymal stem cell-conditioned medium ameliorates pathological changes by inhibiting apoptosis in asthmatic rats.

BACKGROUND: Asthma, an inflammatory illness of the lungs, remains the most common long-term disease amongst children. This study tried to elaborate the status of apoptosis in asthmatic pulmonary niche after the application of rat mesenchymal stem cells (MSC-CM)-derived secretome. METHODS AND RESULTS: Here, we randomly allocated male Wistar rats into three groups (n = 8); Control animals were intratracheally given 50 µl vehicle. In control-matched sensitized rats, 50 µl normal saline was used. In the last group, 50 µl MSC-CM was applied. Two-week post-administration, transcription of T-bet, GATA-3, Bax, Bcl-2 and Caspase-3 was measured by gene expression analysis. Pathological injuries were monitored using H&E staining. The BALF level of TNF-α was measured using ELISA assay. In asthmatic rats received MSC-CM, the expression of T-bet was increased while the level of GATA-3 decreased compared to the S group (p < 0.05). Levels of BALF TNF-α were suppressed in asthmatic niche after MSC-CM administration (p < 0.05). Compared to the asthmatic group, MSC-CM had potential to alter the expression of apoptosis-related genes in which the expression of Bax and Caspase 3 was decreased and the expression of pro-survival factor, Bcl-2 increased (p < 0.05). CONCLUSION: Our data notified the potency of direct administration of MSC-CM in the alleviation of airway inflammation, presumably by down regulating apoptotic death in pulmonary niche.

Role of melatonin in the angiogenesis potential; highlights on the cardiovascular disease.

Melatonin possesses multi-organ and pleiotropic effects with potency to control angiogenesis at both molecular and cellular levels. To date, many efforts have been made to control and regulate the dynamic of angiogenesis modulators in a different milieu. The term angiogenesis or neovascularization refers to the development of de novo vascular buds from the pre-existing blood vessels. This phenomenon is tightly dependent on the balance between the pro- and anti-angiogenesis factors which alters the functional behavior of vascular cells. The promotion of angiogenesis is thought to be an effective strategy to accelerate the healing process of ischemic changes such as infarcted myocardium. Of note, most of the previous studies have focused on the anti-angiogenesis capacity of melatonin in the tumor niche. To the best of our knowledge, few experiments highlighted the melatonin angiogenesis potential and specific regulatory mechanisms in the cardiovascular system. Here, we aimed to summarize some previous experiments related to the application of melatonin in cardiovascular diseases such as ischemic injury and hypertension by focusing on the regulatory mechanisms.

Melatonin and prolonged physical activity attenuated the detrimental effects of diabetic condition on murine cardiac tissue.

In this study, the combined effects of four-week swimming training and melatonin were examined on the oxidative response, inflammation, apoptosis, and angiogenesis capacity of cardiac tissue in the mouse model of diabetes. The mice were randomly allocated into five groups (n = 10 per group) as follows: Control; Diabetic group; Diabetic + Melatonin group; Diabetic + Exercise group; and Diabetic + Exercise + Melatonin group. 50 mg/kg streptozotocin was intraperitoneally administrated. In melatonin-treated groups, melatonin was injected intraperitoneally at 3 mg/kg body weight for four weeks and twice weekly. Swimming exercises were performed for four weeks. We measured cardiac superoxide dismutase, glutathione peroxidase enzymes, malondialdehyde, and total antioxidant capacity. The expression of tumor necrosis factor-α, Caspase­3, Sirtuin1, and Connexin-43 was measured using real-time PCR analysis. The vascular density was analyzed by immunohistochemistry using CD31 and α-smooth muscle actin antibodies. The combination of melatonin and exercise elevated cardiac superoxide dismutase, glutathione peroxidase coincided with the reduction of malondialdehyde and increase of total antioxidant capacity as compared to the diabetic mice (p < 0.05). In Diabetic + Exercise + Melatonin mice, tumor necrosis factor-α, Caspase­3 was significantly down-regulated compared to the Diabetic group (p < 0.05). Melatonin and exercise suppressed the expression of Connexin-43 and Sirtuin1 in diabetic mice in comparison with the control mice (p < 0.05). H & E staining showed necrosis and focal hyperemia reduction in the Diabetic + Exercise + Melatonin group compared to the Diabetic group. Data showed a decrease of CD31+ and α-smooth muscle actin+ vessels in the Diabetic group as compared to the normal samples (p < 0.05). The number of CD31+ vessels, but not α-smooth muscle actin+ type, increased in the Diabetic + Exercise + Melatonin group compared to the Diabetic mice. These data demonstrated that exercise along with melatonin administration could diminish the detrimental effects of diabetes on cardiac tissue via using different mechanisms.