Immunomodulatory Effect Of Melatonin Research Articles

Melatonin inhibits the formation of chemically induced experimental encapsulating peritoneal sclerosis through modulation of T cell differentiation by suppressing of NF-κB activation in dendritic cells

Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). Surgery is a therapeutic strategy for the treatment of complete intestinal obstruction. However, complete intestinal obstruction in long-term PD results in high mortality and morbidity rates after surgery. Immunopathogenesis participates in EPS formation: CD8, Th1, and Th17 cell numbers increased during the formation of EPS. The anti-inflammatory and immunomodulatory effects of melatonin may have beneficial effects on this EPS. In the present study, we determined that melatonin treatment significantly decreases the Th1 and Th17 cell populations in mice with EPS, decreases the production of IL-1β, TNF-α, IL-6, and IFN-γ, and increases the production of IL-10. The suppression of Th1 and Th17 cell differentiation by melatonin occurs through the inhibition of dendritic cell (DC) activation by affecting the initiation of the NF-κB signaling pathway in DCs. Our study suggests that melatonin has preventive potential against the formation of EPS in patients with PD.

Melatonin Treatment Alters Biological and Immunomodulatory Properties of Human Dental Pulp Mesenchymal Stem Cells via Augmented Transforming Growth Factor Beta Secretion

IntroductionMelatonin is an endogenous neurohormone with well-reported anti-inflammatory and antioxidant properties, but the direct biological and immunomodulatory effects of melatonin on human dental pulp stem cells (hDPSCs) has not been fully elucidated. The aim of this study was to evaluate the influence of melatonin on the cytocompatibility, proliferation, cell migration, odontogenic differentiation, mineralized nodule formation, and immunomodulatory properties of hDPSCs. MethodsTo address the melatonin biological effects on hDPSCs, the cytocompatibility, proliferation, cell migration, odontogenic differentiation, mineralized nodule formation, and immunomodulatory properties of hDPSCs after melatonin treatment were evaluated. The statistical differences were evaluated using 1-way analysis of variance with the Tukey multiple comparison test. ResultsWe found that melatonin did not alter hDPSC immunophenotype or cell viability, even at the highest concentrations used. However, using intermediate melatonin concentrations (10–300 μmol/L), a significantly higher proliferation rate (P < .05 and P < .01) and migration of hDPSCs (P < .01) were observed. Importantly, melatonin treatment (100 μmol/L) significantly increased the secretion of the anti-inflammatory cytokine transforming growth factor beta (P < .05 and P < .01) and provoked a more robust antiproliferative effect on mitogen-stimulated T cells (P < .05). Finally, and unlike previous results found with mesenchymal stem cells from other sources, melatonin fails to induce or accelerate the spontaneous osteogenic differentiation of hDPSCs. ConclusionsTogether, these findings provide key data on the bioactivity of melatonin and its effects on hPDSC biological and immunomodulatory properties.

Melatonin: A Powerful Integrative Adjunctive Agent for Oncology

Melatonin is an established hormone supplement and has been well recognized for its effect on the circadian cycle to improve sleep, REM (rapid eye movement), and aiding in jetlag recovery. The utility of melatonin extends beyond sleep aid, however. This hormone also possesses less well-known antioxidant action and even robust anticancer activity. Melatonin may be a key supplement for addressing age-related neurologic decline while serving as a valuable adjunctive cancer treatment that reduces drug resistance in tumors and downregulates angiogenesis. In immunotherapy, melatonin activates Natural Killer (NK) cells nested within tumoral tissue and does not have the side effect profile of other immunoreactive agents used for chemotherapy. Since melatonin is found in high concentrations in the brain and other hormone-linked tissues, the relevance of melatonin is increased for the treatment of estrogen-linked cancers. The immunomodulatory effect of melatonin may also help with chronic inflammation seen in patients with autoimmune disorders. All of these effects together represent a unique and versatile therapeutic agent for integrative medicine. No other commercially available drug possesses all of these therapeutic mechanisms while having a very minimal side effect profile and being considered overall to be safe to use. Currently, melatonin is underutilized in medicine, especially in the field of integrative oncology and represents a crucial supportive adjuvant to improve the lives of patients.

Melatonin Reduces GSK3β-Mediated Tau Phosphorylation, Enhances Nrf2 Nuclear Translocation and Anti-Inflammation.

Alzheimer’s disease is a neuropathological condition with abnormal accumulation of extracellular Amyloid-β plaques and intracellular neurofibrillary tangles of Microtubule-associated protein Tau (Tau) in the brain. In pathological conditions, Tau undergoes post-translational modifications such as hyperphosphorylation by the activity of cellular kinases, which eventually leads to protein aggregation in neurons. Melatonin is a neuro-hormone that is mainly secreted from the pineal gland and functions to modulate the cellular kinases. In our study, we have checked the neuroprotective function of Melatonin by MTT and LDH assay, where Melatonin inhibited the Tau aggregates-mediated cytotoxicity and membrane leakage in Neuro2A cells. The potency of Melatonin has also been studied for the quenching of intracellular reactive oxygen species level by DCFDA assay and caspase 3 activity. Melatonin was shown to reduce the GSK3β mRNA and subsequent protein level as well as the phospho-Tau level (pThr181 and pThr212-pSer214) in okadaic acid-induced Neuro2A cells, as observed by western blot and immunofluorescence assay. Further, Melatonin has increased the cellular Nrf2 level and its nuclear translocation as an oxidative stress response in Tauopathy. The Melatonin was found to induce pro- and anti-inflammatory cytokines levels in N9 microglia. The mRNA level of cellular kinases such as as-GSK3β, MAPK were also studied by qRT-PCR assay in Tau-exposed N9 and Neuro2A cells. The immunomodulatory effect of Melatonin was evident as it induced IL-10 and TGF-β cytokine levels and activated MAP3K level in Tau-exposed microglia and neurons, respectively. Melatonin also downregulated the mRNA level of pro-inflammatory markers, IL-1β and Cyclooxygenase-2 in N9 microglia. Together, these findings suggest that Melatonin remediated the cytokine profile of Tau-exposed microglia, reduced Tau hyperphosphorylation by downregulating GSK3β level, and alleviated oxidative stress via Nrf2 nuclear translocation.

Administration of melatonin for prevention of preterm birth and fetal brain injury associated with premature birth in a mouse model

Maternal inflammation leads to preterm birth and perinatal brain injury. Melatonin, through its anti-inflammatory effects, has been shown to be protective against inflammation-induced perinatal adverse effects. However, the immunomodulatory effects of melatonin on preterm birth and prematurity-related morbidity remain unknown. We wanted to investigate the effects of maternally administered melatonin on preterm birth and perinatal brain injury in a mouse model of maternal inflammation. A model of maternal inflammation employing lipopolysaccharide (LPS) was used to mimic the most common clinical scenario of preterm birth, that of maternal inflammation. Mice were randomly divided into the following groups: control, LPS, and LPS with melatonin pre-treatment. Doppler ultrasonography was used to obtain fetal and maternal hemodynamic measurements in utero. Placenta and fetal brains were harvested and analyzed for proinflammatory markers and signs of perinatal brain injury, respectively. Surviving offspring were assessed for neuromotor outcomes. Melatonin pre-treatment lowered the level of proinflammatory cytokines in the uterus and the placenta, significantly improved LPS-induced acute fetal neuroinflammation and perinatal brain injury, as well as significantly upregulated the SIRT1/Nrf2 signaling pathway to reduce LPS-induced inflammation. Melatonin also prevented adverse neuromotor outcomes in offspring exposed to maternal inflammation. Maternally administered melatonin modulated immune responses to maternal inflammation and decreased preterm birth and perinatal brain injury. These results suggest that melatonin, a safe treatment during pregnancy, may be used as an experimental therapeutic in clinical trials.

Immunomodulatory properties and anti-apoptotic effects of zinc and melatonin in an experimental model of chronic Chagas disease

The immunomodulatory effects of melatonin and zinc during chronic experimental Chagas’ disease were studied. Early and late apoptosis by Annexin V-propidium iodide staining were evaluated. The expression of CD28, CD80, CD86, CD45RA and CD4+T and CD8+T cells were also evaluated by flow cytometry analysis. The combination of zinc and melatonin notably reduced the apoptotic ratios of splenic cells in the infected and treated animals when compared to untreated rats, during early and late stages of apoptosis. The percentages of CD8+T cells in Zn, Mel or Zn and Mel treated rats were reduced when compared to infected and untreated animals. Higher percentages of CD28 expression in CD4+ and CD8+ T cell populations were observed in control and infected Zn-treated group as compared to untreated ones. Zn, Mel or the combination of both did not induce any statistically significant differences for B cells when comparing to treated control and infected groups. Zinc or Mel-treated animals presented a lower expression of CD86 when compared to untreated counterparts. According to our data, this work strongly suggest that the modulation of the immune system operated by zinc and melatonin administration affected the balance among T cell immune response, apoptosis and expression of co-stimulatory molecules during chronic Trypanosoma cruzi infection, inducing important changes in the host's immune response against the parasite. Future experiments in this field should be focused in improving our understanding of the key mechanisms underlying the involvement of melatonin and zinc in the immune response during chronic Chagas’ disease.

Immunomodulatory effect of melatonin in SK-LU-1 human lung adenocarcinoma cells co-cultured with peripheral blood mononuclear cells.

The anti-cancer potential of melatonin has been examined using a variety of experimental approaches. Melatonin immunomodulatory action was evaluated against the lung cancer cell line SK-LU-1, in co-culture with human peripheral blood mononuclear cells (PBMC). Melatonin was tested on the cell line only after 24 h incubation (direct effect), and on the co-culture system of SK-LU-1 and PBMC to investigate any indirect effect. Apoptotic induction of the cancer cells was assessed using annexin V/PI staining with flow cytometric analysis for membrane alteration. Intracellular superoxide anion (O2 (•-) ) and hydrogen peroxide (H2 O2 ) for intracellular oxidative stress and glutathione (GSH) for intracellular anti-oxidation were measured with specific fluorescence probes. DNA fractions were measured employing propidium iodide (PI) fluorescence staining. High doses of melatonin were directly toxic to SK-LU-1 cells, while PBMC-mediated indirect effect occurred after moderate doses (1 μm). Under co-culture conditions, increases in apoptotic cell death, increase in oxidative stress by reduction of GSH and cell cycle arrest in G0 /G1 in SK-LU-1 cells, were observed as the immunomodulatory effect of melatonin. Melatonin had indirect effects on lung cancer cells by enhancement of immunomodulatory effects, but further studies of mechanism(s) involved are needed.

Regression of endometrial explants in a rat model of endometriosis treated with melatonin

To determine the antioxidant, antiinflammatory, and immunomodulatory effects of melatonin on endometrial explants, the distribution of cyclooxygenase-2 (COX-2), the activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and levels of malondialdehyde (MDA) in the rat endometriosis model. Prospective, placebo-controlled experimental study. Experimental surgery laboratory in a university department. Twenty-five rats with experimentally induced endometriosis. Endometriosis was surgically induced in 25 rats by transplanting an autologous fragment of endometrial tissue onto the inner surface of the abdominal wall. Four weeks later, three rats were killed and the remaining 22 rats given second-look laparotomies to identify and measure ectopic uterine tissue in three dimensions. After the second laparotomy, 4 weeks of vehicle and melatonin treatment were administered, then all of the rats were given a third laparotomy and killed. The volume and weight of the implants were measured. The remaining rats were randomly divided into two groups. In control group (group 1; n = 11) no medication was given. To the rats in melatonin-treated group (group 2; n = 11), 10 mg/kg a day of melatonin was administered intraperitoneally. Four weeks later, after the second laparotomy, the endometrial explants were reevaluated morphologically, and COX-2 expression was evaluated immunohistochemically and histologically. In addition, endometrial explants were analyzed for the antioxidant enzymes SOD, CAT, and MDA, a marker of lipid peroxidation. A scoring system was used to evaluate expression of COX-2 and preservation of epithelia. The pretreatment and posttreatment volumes within the control group were 135.9 +/- 31.5 and 129.4 +/- 28.7, respectively. The mean explant volume was 141.4 +/- 34.4 within the melatonin group before the treatment and 42.9 +/- 14.0 after 4 weeks of treatment. There was a statistically significant difference in spherical volumes (129.4 +/- 28.7 versus 42.9 +/- 14.0 mm(3)) of explant weights (155.8 +/- 27.1 versus 49.6 +/- 19.5 mg) and COX-2 positivity (91% versus 18.1%) between groups after the third laparotomy. In the melatonin-treated group, the endometrial explant levels of MDA statistically significantly decreased and activities of SOD and CAT significantly increased when compared with the control group. The epithelia showed statistically significantly better preservation in the control group when compared with the melatonin-treated group (2.54 +/- 0.52 versus 0.63 +/- 0.50). Melatonin causes regression and atrophy of the endometriotic lesions in rats.

Photoperiod modulates the inhibitory effect of in vitro melatonin on lymphocyte proliferation in female Siberian hamsters.

In Siberian hamsters (Phodopus sungorus), short days suppress reproductive function and lymphocyte proliferation. To determine whether melatonin influences cell-mediated immunity through a direct action on lymphocyte proliferation, in vitro responsiveness to mitogens and melatonin was assessed in systemic and splenic lymphocytes from adult female Siberian hamsters housed in either long or short days for 13 weeks. Short days provoked reproductive regression and reduced lymphocyte proliferation. Physiological concentrations of melatonin (50 pg/ml) inhibited in vitro proliferation of circulating lymphocytes, whereas higher concentrations (> or = 500 pg/ml) were required to inhibit proliferation of splenic lymphocytes. Immunomodulatory effects of melatonin were restricted to lymphocytes from long-day hamsters-in vitro melatonin had no effect on circulating or splenic lymphocytes from females in short days. Responsiveness to melatonin in short-day lymphocytes may be restrained by the already expanded nightly pattern of melatonin secretion in short days. These data support the hypothesis that melatonin acts directly on lymphocytes from long-day hamsters to suppress blastogenesis.

NONRESOLVING AND SLOWLY RESOLVING PNEUMONIA: Diagnosis and Management in the Elderly Patient

The immunomodulatory effects of melatonin and zinc during chronic experimental Chagas’ disease were studied. Early and late apoptosis by Annexin V-propidium iodide staining were evaluated. The expression of CD28, CD80, CD86, CD45RA and CD4+T and CD8+T cells were also evaluated by flow cytometry analysis. The combination of zinc and melatonin notably reduced the apoptotic ratios of splenic cells in the infected and treated animals when compared to untreated rats, during early and late stages of apoptosis. The percentages of CD8+T cells in Zn, Mel or Zn and Mel treated rats were reduced when compared to infected and untreated animals. Higher percentages of CD28 expression in CD4+ and CD8+ T cell populations were observed in control and infected Zn-treated group as compared to untreated ones. Zn, Mel or the combination of both did not induce any statistically significant differences for B cells when comparing to treated control and infected groups. Zinc or Mel-treated animals presented a lower expression of CD86 when compared to untreated counterparts. According to our data, this work strongly suggest that the modulation of the immune system operated by zinc and melatonin administration affected the balance among T cell immune response, apoptosis and expression of co-stimulatory molecules during chronic Trypanosoma cruzi infection, inducing important changes in the host's immune response against the parasite. Future experiments in this field should be focused in improving our understanding of the key mechanisms underlying the involvement of melatonin and zinc in the immune response during chronic Chagas’ disease.

Constant light exposure increases 2-[125I]iodomelatonin binding sites in the guinea pig spleen.

The effect of constant light exposure on 2-[125I]iodomelatonin binding sites in the guinea pig spleen was investigated. Guinea pigs exposed to constant light for 2-3 weeks showed an increase in the number of splenic 2-[125I]iodomelatonin binding sites, without any difference in the binding affinity, in comparison to animals kept under 12 h light/12 h darkness condition, whereas the splenic indices were similar in both groups. This light dependence of the splenic 2-[125I]iodomelatonin binding sites suggests that the binding sites are melatonin receptors and that the light dependent immunomodulatory effect of melatonin is mediated via a direct action on the lymphoid tissue.