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Melatonin was initially extracted from the pineal gland and was thought to be produced exclusively by this organ. Subsequently it was shown that melatonin is also produced in other tissues including the gastrointestinal tract, retina and cells of the immune system. Melatonin is believed to be an important regulator of circadian and seasonal rhythms. Over the last thirty years, a great number of reports have documented a relationship between melatonin/pineal gland and the immune system in various species, including humans. In this review, current knowledge about the role of melatonin in the regulation of immune responses will be discussed.
Department of Human Developmental Biology, Jagiellonian University College of Medicine,
Kraków, Poland
Melatonin was initially extracted from the pineal gland and was thought to be
produced exclusively by this organ. Subsequently it was shown that melatonin is also
produced in other tissues including the gastrointestinal tract, retina and cells of the
immune system. Melatonin is believed to be an important regulator of circadian and
seasonal rhythms. Over the last thirty years, a great number of reports have
documented a relationship between melatonin/pineal gland and the immune system
in various species, including humans. In this review, current knowledge about the
role of melatonin in the regulation of immune responses will be discussed.
Key words: melatonin, immunoregulation, inflammation, innate immune response,
adaptive immune response.
Our bodies are constantly exposed to different microorganisms that are
present in the environment. However, contact with pathogenic microorganisms
rarely results in infection. This is because our bodies are protected by both innate
and adaptive immune mechanisms.
The innate immune system consists of many cells, such as macrophages,
dendritic cells, mast cells, neutrophils, eosinophils and natural killer (NK) cells.
These become activated during inflammation, which is virtually always a sign of
infection with pathogenic microbes (1). The main goal of these cells is to
eliminate the infection. It is worthy to underline that innate responses depend on
host recognition of highly conserved structures present on microorganisms called
"pathogen-associated molecular patterns" (PAMPs) (2). PAMPs are recognized by
"pathogen recognition receptors" (PRR) (2). The two major currently recognized
groups of PRRs in humans are toll-like receptors (TLRs) and nucleotide-binding
oligomerization domain (NOD)-containing proteins (3). Whereas TLRs are
associated with the plasma membrane or, in some case, with lysosomal and/or
endosomal vesicles, both NOD1 and NOD2 are present in the cytosol (4).
However, in certain types of infection, the innate immune system is not able
to deal with the infection and then an adaptive immune response is required. In
such infections, the innate immune system can instruct the adaptive immune
system regarding the nature of the pathogen through the expression of CD80 and
CD86 costimulatory molecules on dendritic cells and by producing cytokines to
direct the response.
There are two major classes of adaptive immune responses. The first, the so-
called "cellular response", is mediated by MHC II restricted, Th1 CD4
T cells
which drive delayed type hypersensitivity (DTH) responses, or MHC class I
restricted CD8
T cells which mediate direct cytotoxicity. The cellular response
is principally directed against intracellular pathogens (5). During the effector
phase of DTH, Th1 lymphocytes release proinflammatory cytokines like IFN-γ,
which induce local tissue cells to produce chemokines that recruit and activate an
infiltrate of bone marrow-derived leukocytes (6). CD8
T cytotoxic (Tc) cells kill
infected host cells via released perforin and granzymes and by triggering FasL
dependent apoptosis.
The second type of adaptive immune response is the humoral immune
response and is mediated by antibodies produced by B lymphocytes (1). In this
type of immune response, B cells receive support from Th2 T cells that produce
IL-4, IL-5, IL-6 and IL-13. The main function of the humoral response is to
destroy extracellular microorganisms and prevent the spread of infection. The
health of an organism is dependent on the ability of all of these branches of the
immune system to function together to protect from and control pathogenic
organisms as well as cancerous tissue. At the same time there must be
mechanisms to protect the organism from developing inappropriate immune
responses that are harmful to self (allergy, autoimmunity) as well as to control and
resolve inflammatory responses after clearance of the pathogen. This
demonstrates the importance of the balance of the immune response and its strict
control by regulatory mechanisms.
The immune response is negatively regulated by the action of T suppressor
(Ts) cells, which are also called T regulatory (Treg) cells. It is becoming
increasingly clear that there are multiple populations of T cells with regulatory
activity and that these can use different mechanisms, including direct cell-to-cell
contact and production of anti-inflammatory cytokines, to dampen the immune
response (7-9). Additionally, there is a body of evidence that the nervous and
endocrine systems can also interact with the immune system to modulate its
function (10). Indeed, it has been shown that many neurotransmitters,
neuroendocrine factors and hormones can dramatically alter immune function and
that, conversely, cytokines released by immune cells can affect the central
nervous system (11). It is also believed that environmental signals can regulate
many immune processes in different species including humans. It has been
demonstrated that light is one of the environmental signals that can modulate the
immune system. Although most of the light energy received by the retina is
relayed to the visual cortex for vision, an alternative pathway from the retina
relays a small part to the suprachiasmatic nucleus, which is part of the
hypothalamic region in the brain (12, 13). The suprachiasmatic nucleus is thought
to direct circadian rhythm and therefore controls many processes in the body such
as temperature, appetite, and mood (12). The pituitary and pineal glands are also
involved in light-induced neuroendocrine changes. The neuroendocrine
hormones that are sensitive to modifications in circadian rhythm are growth
hormone, thyroid hormones, thyroid-stimulating hormone, plasma cortisol and
melatonin (12, 14).
Over the last thirty years, a great number of reports have documented a
relationship between melatonin from the pineal gland and the immune system in
various species including humans (15, 16). Current knowledge about the role of
melatonin in the regulation of immune mechanisms will be discussed further below.
It is important to note that melatonin is produced not only by pineal gland, but
also in the retina, kidneys and digestive tract (17). This suggests that the immune
system might be affected by melatonin originating from different organs of the
body. Additionally it was found that human peripheral blood mononuclear cells
synthesize biologically relevant amounts of melatonin (18). This indicates a
potential intracrine and paracrine role of melatonin in immune regulation.
It is believed that melatonin influences cells of the immune system via
melatonin receptors. Both membrane and nuclear melatonin receptors have been
identified on leukocytes. Membrane receptors were found mostly on CD4
lymphocytes, but also on CD8 T and B cells (19-21). Through these receptors,
melatonin modulates the proliferative response of stimulated lymphocytes. On
the other hand, melatonin induces cytokine production by human peripheral
blood mononuclear cells via the nuclear melatonin receptor (22).
The immunoregulatory activity of melatonin was determined with the use of
following experimental models: surgical or functional pinealectomy, in vivo
treatment with melatonin or in vitro treatment of immune cells with melatonin.
Some studies demonstrated an immunoenhancing activity for melatonin. Daily
afternoon injections of melatonin induced an increase in thymus weight in the
gerbil (23) and spleen hypertrophy in the Syrian hamster (24). Treatment with
melatonin also increased the mitogenic response of mouse spleen cells to
concanavalin A and lipopolysaccharide (LPS) (25, 26). The mechanism by which
melatonin acts to enhance the immune response is not fully understood. It is
believed that, in part, it may act to increase phagocytosis and antigen presentation
(20). Indeed it was shown that treatment with melatonin enhanced antigen
presentation by splenic macrophages to T cells with a concurrent increase in
MHC class II expression and synthesis of the proinflammatory cytokines IL-1
and TNF-β (27). Additionally, melatonin was observed to induce IL-12
production to drive T cell differentiation towards the Th1 phenotype (28). The
activating effect of melatonin on the immune system is also mediated through the
regulation of gene expression of cytokines in the spleen, thymus, lymph nodes
and bone marrow. It was shown gene expression of M-CSF, TNF-α, TGF-β and
SCF was increased in peritoneal macrophages, while IL-1β, IFN-γ, M-CSF, TNF-
α and SCF was increased in spleen cells of mice treated with melatonin (29).
Other studies have shown that melatonin administration increases NK cell
activity in humans (30). Similar observations were made in mice where
treatment with melatonin increased antibody dependent cellular cytotoxicity
(ADCC) (31, 32). Aside from activation of immune cells by melatonin, this
hormone also enhances production of NK cells and monocytes in the bone
marrow of mice (33). Melatonin seems also to promote the survival of precursor
B cells in mouse bone marrow (34).
To summarize, melatonin is considered as a modulator of haemopoiesis and of
immune cell production and function. Melatonin has been demonstrated to
stimulate cytokine production, enhanced phagocytosis, increased NK cell activity
and skewing of the immune response toward a helper T cell type 1 profile. The
activating effect of melatonin on the immune system is presented in Fig. 1.
Melatonin has been shown to aggravate Th1 dependent inflammatory response
in animal models of multiple sclerosis (35) and rheumatoid arthritis (36).
Additionally, it was found in rats that melatonin is important in controlling cell
recruitment from the bone marrow and their subsequent migration to the lung. It
may suggest that melatonin is involved in allergic lung inflammation (37). This
observation is in line with human studies showing that elevated serum melatonin
is associated with the nocturnal worsening of asthma (38). Moreover, it is
suggested that melatonin may play a role in the etiology and treatment of several
dermatoses e.g. atopic eczema, psoriasis and malignant melanoma (39, 40).
Importantly, while many studies have implicated melatonin as a positive
regulator of immune responses, a number of other reports have suggested that
melatonin may act as an anti-inflammatory agent, inhibiting immune responses in
some cases. It is believed that the anti-inflammatory action of melatonin is at least
partly due to the induction of Th2 lymphocytes that produce IL-4, thereby
inhibiting the function of Th1 cells (41). Indeed, melatonin has been shown to be
protective in septic shock (42), an animal model of ulcerative colitis (43) and
experimental pancreatitis (44, 45).
Inflammation begins when cells within the infected tissue, whether they be
epithelial or stromal cells, tissue resident mast cells or dendritic cells, recognize
an inflammatory stimulus. These signals lead to the recruitment and activation of
effector cells of the immune system. As mentioned in Introduction, PRR (e.g.
TLR and NOD) play a crucial role in sensing microbial invaders by recognition
of PAMPS (46, 47). PRR ligation leads to the transcription of nuclear factor-
kappa B (NF-κB)-dependent genes, many of which encode for proinflammatory
cytokines and chemokines (48). Additionally, recognition of PAMPS by PRR
results in NF-κB-dependent expression of defensins that possess strong
bactericidal activity (49). NF-κB is also important for the synthesis of the
enzymes that generate prostaglandins and reactive oxygen species (e.g. COX and
iNOS), substances that are also involved in inflammation (48). Furthermore, the
expression of adhesion molecules on circulating leukocytes and endothelium
involved in leukocyte migration are also regulated by NF-κB (50, 51).
naive CD4
T cells
Th1 cells
Fig. 1. The activating effect of melatonin on the immune system.
Melatonin activates both innate (antigen presenting cells (APC), natural killer (NK) cells) and adaptive
immune responses (CD4
T lymphocytes).
Because NF-κB regulates a large number of genes involved in the immune
response and inflammation, this pathway is a likely target to silence chronic
inflammation that occurs in various diseases e.g. autoimmunity. Recently,
melatonin has been found to reduce NF-κB binding to DNA, probably by
preventing its translocation to the nucleus (52). This, in turn, reduced the
production of proinflammatory cytokines and chemokines. Additionally, because
melatonin has been shown to reduce adhesion of leukocytes to endothelium as
well as transendothelial migration, it may also suppress the expression of NF-κB-
regulated adhesion molecules (53). Finally, melatonin has been shown to reduce
recruitment of neutrophils to the site of inflammation (54, 55). The anti-
inflammatory effect of melatonin is presented in Fig. 2.
Septic shock caused by systemic bacterial infection is a form of
uncontrolled acute inflammatory response. This syndrome is characterized by
hypotension, inadequate perfusion, vascular damage and disseminated
intravascular coagulation leading to multiple organ failure and death (56). It is
known that many of the pathological symptoms of septic shock to Gram-
negative bacteria are attributable to (LPS) present in bacterial membranes.
Nitric oxide (NO) produced in response to LPS has been shown to be
responsible for LPS-induced hypotension and vascular hyporesponsiveness,
suggesting that excessive production of NO plays an important role in septic
adhesion molecules
Fig. 2. The anti-inflammatory effect
of melatonin.
Melatonin inhibits NF-κB binding to
DNA and prevents its translocation
to the nucleus. This, in turn, reduces
the production of proinflammatory
cytokines and chemokines.
Additionally, melatonin inhibits
expression of adhesion molecules
and suppresses synthesis of the
enzymes that generate
prostaglandins and reactive oxygen
species (e.g. COX and iNOS).
shock (57, 58). Importantly, melatonin has been shown to regulate NO
synthesis. Following on from these studies, Maestroni et al. investigated
whether melatonin could influence the pathology of septic shock (20). Indeed,
melatonin-treated mice were protected from LPS-induced shock and reduced
mortality correlated with reduced NO synthesis (59). It has been recently
reported that melatonin inhibits expression of iNOS in murine macrophages
via suppression of NF-κ B (60).
To summarize, melatonin is both a positive regulator of immune responses and
a negative regulator of inflammation.
Acknowledgements: This work was supported by grants from the Polish Committee of Scientific
research (KBN, Warsaw) No. 2 PO 5A 157 28, 2PO 5A 208 29 and the grant from the Polish
Committee of Scientific research (KBN, Warsaw) No. N N401 3553 33 to MS. The author is
indebted to Dr. S. Kerfoot for critical comments on the manuscript.
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Received: September 12, 2007
Accepted: November 14, 2007
Authors address: Marian Szczepanik, Department of Human Developmental Biology,
Jagiellonian University College of Medicine, ul. Kopernika 7, 31-034 Kraków, Poland; tel/fax: +48
12 422 99 49; e-mail:
... For example, the presence of these receptors in bone marrow stem cells (BMSC) (29,30) indicates an important role in the maintenance and recovery of the haematopoietic system. Its central role in influencing the immune response has gained importance in a variety of research areas for the treatment of several diseases (31,32). Radiation-induced injuries are due to an increase in free radical burden, inflammation, and pathogenesis in sensitive organs, if not intervened, can lead to syndromes. ...
... Due to this importance, a large number of radiomitigators are under investigation in rodents (Table I). Because melatonin has multiple properties, and its role as an "immunological buffer", a large number of studies have already been undertaken for different disease models in small animals (31,32). The range of indications includes inflammation, immune dysfunction, infections, cancer, and metabolic disorders. ...
Full-text available
Background/aim: Melatonin (N-acetyl-5-methoxytryptamine), a chief secretory molecule of the pineal gland, has multiple properties, and numerous clinical investigations regarding its actions are in progress. This study investigated the radiomitigative role of melatonin in C57BL/6 mice. Materials and methods: Melatonin (100 mg/kg) was orally administered once daily starting at 1 h on day 1 and subsequently every 24 h until day 7 after whole-body irradiation (WBI) and survival was monitored for 30 days. The bone marrow, spleen, and intestine were studied to evaluate the mitigative potential of melatonin after radiation-induced damage. Results: Melatonin significantly improved the survival upto 60% and 90% after 9 Gy (lethal) and 7.5 Gy (sub-lethal) WBI, respectively. Melatonin alleviated WBI-induced myelosuppression and pancytopenia, and increased white blood cell, red blood cell, platelet, and lymphocyte (CD4+ and CD8+) counts in peripheral blood. Bone marrow and spleen cellularity were restored through enhanced haematopoiesis. Melatonin ameliorated the damage in the small intestine, and promoted recovery of villi length, crypts number, and goblet cell count. Conclusion: Melatonin mitigates the radiation-induced injury in the gastrointestinal and haematopoietic systems. The observed radiomitigative properties of melatonin can also be useful in the context of adjuvant therapy for cancer and radiotherapy.
... It has been stated that melatonin activates the innate immunity and the adaptive immunity. In contrast, melatonin can reduce the inflammation via the prevention of nuclear factor Kappa B binding to DNA and the inhibition of its translocation to the nucleus, these effects decrease cytokines and chemokines production (23). ...
Full-text available
Melatonin, a hormone synthesized mainly by the pineal gland, has been found in extra-pineal organs as well. It’s known as an organizer of circadian rhythms and more recently as an anti-oxidant. In addition to its role in maintaining immunity, pathophysiology of cardiovascular and neurological diseases, and as an anti-cancer agent, evidence has demonstrated that melatonin exerts a positive impact on male and female fertility primarily through oxygen scavenging effects. In In Vitro Fertilization (IVF) programs, supplementation of melatonin may be associated with better outcomes in terms of sperm quality, oocyte quality, embryo quality and pregnancy rates. This review summarizes various actions of melatonin on the body focusing on male and female fecundity.
... The neurohormone melatonin exerts its neuroprotective effects as an antioxidant against oxidative and nitrosative stress, 20 an immunomodulator, 21 and a modulator for angiogenesis and neurogenesis. 22,23 Additionally, melatonin pretreatment decreases neutrophil myeloperoxidase activity to reduce inflammation after brain ischemia. ...
Objectives: Post-ischemic inflammation leads to apoptosis as an indirect cause of functional disabilities after the stroke. Melatonin may be a good candidate for the stroke recovery because of its anti-inflammatory effects. Therefore, we investigated the effect of melatonin on inflammation in the functional recovery of brain by evaluating ipsilesional and contralesional alterations. Materials and methods: Melatonin (4 mg/kg/day) was intraperitoneally administered into the mice from the 3rd to the 55th day of the post-ischemia after 30 min of middle cerebral artery occlusion. Results: Melatonin produced a functional recovery by reducing the emigration of the circulatory leukocytes and the local microglial activation within the ischemic brain. Overall, the expression of the inflammation-related genes reduced upon melatonin treatment in the ischemic hemisphere. On the other hand, the expression level of the inflammatory cytokine genes raised in the contralateral hemisphere at the 55th day of the post-ischemia. Furthermore, melatonin triggers an increase in the iNOS expression and a decrease in the nNOS expression in the ipsilateral hemisphere at the earlier times in the post-ischemic recovery. At the 55th day of the post-ischemic recovery, melatonin administration enhanced the eNOS and nNOS protein expressions. Conclusions: The present molecular, biological, and histological data have revealed broad anti-inflammatory effects of melatonin in both hemispheres with distinct temporal and spatial patterns at different phases of post-stroke recovery. These outcomes also established that melatonin act recruitment of contralesional rather than of ipsilesional.
... Melatonin is a direct actor in immune system response through the stimulation of T-Lymphocytes, interleukin-2 and -6, and natural killer cells (Cherry, 2002;Peña et al., 2007;Szczepanik, 2007). The role of melatonin levels on immune system outcomes is thought to be modulated by cytokines. ...
It has been hypothesized that solar and geomagnetic activity can affect the function of the autonomic nervous system (ANS) and melatonin secretion, which both may influence immune response. We investigated the association between solar geomagnetic activity and white blood cell counts in the Normative Aging Study (NAS) Cohort between 2000 and 2013. Linear mixed effects models with moving day averages ranging from 0 to 28 days were used to evaluate the effects of solar activity measures, Interplanetary Magnetic Field (IMF), and Sunspot Number (SSN), and a measure of geomagnetic activity, Kp Index (Kp), on total white blood cell (WBC), neutrophil, monocytes, lymphocyte, eosinophil, and basophil concentrations. Even after adjusting for demographic and health related factors, there were consistent significant associations between IMF, SSN, and Kp index, with reduced total WBC, neutrophils, and basophil counts that were stronger with longer moving averages. The associations were similar after adjusting for ambient air particulate pollution. Our findings suggest that periods of increased solar and geomagnetic activity result in lower WBC, neutrophil and basophil counts that may contribute to slight immune suppression.
IntroductionIn this study, it was aimed to compare the effects of both melatonin and 25-hydroxyvitamin D3, defined as an immune modulator, on laboratory diagnostic criteria parameters and disease activity in patients with systemic lupus erythematosus (SLE).Methods The study included 56 women with SLE and 40 healthy women (control group). Melatonin and 25-hydroxyvitamin D3 levels of patients and healthy individuals included in the study were examined. In addition, leukocytes, lymphocytes, platelets, C3, C4, anti-double-stranded DNA (Anti-dsDNA), antinuclear antibody, and SLE disease activity index (SLEDAI) were analyzed in women with SLE. Patients were divided into four subgroups according to SLEDAI.ResultsMelatonin and 25-hydroxyvitamin D3 levels of women with SLE were lower than healthy women (p < 0.001). Both melatonin and 25-hydroxyvitamin D3 levels were not correlated with laboratory diagnostic criteria parameters. Only 25-hydroxyvitamin D3 levels were correlated with leukocyte levels (p < 0.01). There was no significant difference between the melatonin levels of the subgroups. The 25-hydroxyvitamin D3 levels of the subgroup without disease activity were higher than levels of the subgroups with disease activity (p < 0.05). There was a negative correlation between SLEDAI score and 25-hydroxyvitamin D3 levels (p < 0.05).Conclusion Women with SLE had lower melatonin and 25-hydroxyvitamin D3 levels than healthy women. On the other hand, parameters of laboratory diagnostic criteria of SLE disease were not related. Only 25-hydroxyvitamin D3 levels were inversely related leukocyte levels. SLE disease activity was not correlated with melatonin levels but negatively correlated with 25-hydroxyvitamin D3 levels. Key Points • Women with SLE have low levels of melatonin and 25-hydroxyvitamin D3. • Melatonin and 25-hydroxyvitamin D3 levels are not related to the laboratory diagnostic criteria parameters for SLE disease. • Low levels of melatonin and 25-hydroxyvitamin D3 may be a factor in the unbalanced immune system of SLE. • Supplementation of melatonin and 25-hydroxyvitamin D3 may be recommended for women patients with SLE.
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Melatonin is an indole-like neuroendocrine hormone. A large number of studies have shown that melatonin can improve production performance of ewes, but it is not clear in lambs. In this study, the growth and development of the 2-month-old lambs implanted with melatonin were monitored for 60 days. The results showed that the growth rate of body weight and body skew length of lambs with melatonin treatment were significantly improved compared to the controls. The similar results were also observed in red blood cell count, hematocrit, red blood cell volume distribution width, the levels of growth hormone, testosterone, immunoglobulin A, immunoglobulin M and albumin. In addition, the cross sectional area of muscle fibers and adipose cells of lambs with melatonin implantation were also significantly increased compared to the controls (P<0.05). To further explore the potential mechanisms, the muscle and adipose tissue were selected for transcriptome sequencing. KEGG enrichment results showed that melatonin regulated the expression of genes related to apoptotic signaling pathway in muscle and adipocytes. Since the intestinal microbiota are involved in the nutritional balance and animal growth, the 16SrRNA sequencing related to the intestinal microbiota was also performed. The data indicated that the structural differences of fecal microflora mainly occur in the pathways of Cardiovascular disease, Excretory system and Signaling molecules and interaction. In brief, melatonin promotes the growth and development of lambs. The potential mechanisms may be that melatonin increased the growth hormone and testosterone mediated apoptosis signaling pathway and regulated intestinal microbial flora. Our results provide valuable information for melatonin to improve the production of sheep husbandry in the future.
Neurorehabilitation after spinal cord injury (SCI) is a complicated medical process that involves profound neurological disorders and severe disability. Although recent advances in the management of SCI have improved significantly, there has been little progress in treatment options for improving secondary injury following SCI. There is accumulating evidence that melatonin (MT) protects neural tissues from secondary injury after SCI. After SCI, MT can reduce oxidative stress, decrease inflammation, and regulate autophagy, among other functions. In this chapter, we will explore the promising molecular mechanisms of MT intervention for the management of SCI-induced secondary injury. We also discuss strategies of MT combined with exercise to attenuate secondary injury after SCI. Low levels of endogenous MT significantly disrupt sleep in SCI patients, leading to further worsening of secondary injury. Finally, we examine the crucial role of endogenous MT, which may influence the recovery process after SCI.
Gestational diabetes mellitus (GDM) promotes changes in the placenta and fetuses, due to oxidative stress. Antioxidants can reduce oxidative stress in the placenta. We tested the hypothesis that melatonin (Mel) can prevent these effects in the placenta and fetuses, analyzing their histology, histochemistry, morphometry, and immunohistochemistry. Thirty albino rats were used, divided into groups: CG—pregnant non-diabetic rats; GD—pregnant diabetic rats; GD + Mel—pregnant diabetic rats treated with melatonin. Diabetes was induced by streptozotocin at a dosage of 50 mg/kg i.p. Melatonin was administered in daily injections of 0.8 mg/kg i.p. Melatonin prevented the placental weight and fetal weight and length from increasing, in addition to histomoformetric, histochemical, and immunohistochemical changes in the placentas, compared to the placentas of diabetic females (GD). Thus, we conclude that melatonin has a great potential to prevent placental changes due to GDM.
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In the present study, tryptophan was evaluated for its hepatoprotective effects against carbontetrachloride-induced hepatocellular injury in rats. Hepatotoxicity was induced in male Sprague-Dawley rats by intraperitoneal injection of CCl 4 (4ml/kg) in olive oil (1:1). Tryptophan at doses of 100mg/kg and 200mg/kg was administered orally for 28 days. The hepatoprotective effect of tryptophan was evaluated by the assay of biochemical parameters viz.: alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), alkaline phosphatase (ALP), total protein, albumin and lipid peroxidation. Tryptophan produced a dose-dependent significant increase (p<0.001) in serum ALP (41% & 60%), a dose-dependent decrease (p<0.001) in serum Malondialdehyde (61% & 65%), and a significant increase (p<0.001) in levels of serum protein and serum albumin, in CCl 4 induced hepatotoxic rats, following administration of 100 mg/kg bwand 200 mg/kg bw, respectively. The toxic effect of CCl 4 in tryptophan treated groups was controlled significantly by restoration of the levels of enzymes, total protein and albumin as compared to the CCl 4 treated groups. The results suggest that tryptophan is able to significantly alleviate the hepatotoxicity induced by CCl 4 and may be attributed to the antioxidant property of tryptophan.
One of the host risk factors involved in aging-related diseases is coupled with the reduction of endogenous melatonin (MLT) synthesis in the pineal gland. MLT is considered a well-known pleiotropic regulatory hormone to modulate a multitude of biological processes such as the regulation of circadian rhythm attended by potent anti-oxidant, anti-inflammatory, and anti-cancer properties. It has also been established that the microRNAs family, as non-coding mRNAs regulating post-transcriptional processes, also serve a crucial role to promote MLT-related advantageous effects in both experimental and clinical settings. Moreover, the anti-aging impact of MLT and miRNAs participation jointly are of particular interest, recently. In this review, we aimed to scrutinize recent advances concerning the therapeutic implications of MLT, particularly in the brain tissue in the face of aging. We also assessed the possible interplay between microRNAs and MLT, which could be considered a therapeutic strategy to slow down the aging process in the nervous system.
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Asthma is an inflammatory lung disease characterized by cell migration, bronchoconstriction and hyperresponsiveness, and can be induced, as an experimental model, by ovalbumin sensitization followed by a challenge. In addition to the well-known immunostimulatory effects of melatonin, research has identified some of its anti-inflammatory properties. In this study, we evaluated the influence of pinealectomy and melatonin administration on cell migration in an experimental model of allergic airway inflammation. We evaluated, in pinealectomized rats treated or not with melatonin, cell migration into the bronchoalveolar fluid, the number of cells and their proliferative activity in the bone marrow, and plasma corticosterone levels. Pinealectomy reduces, 24 hr after the challenge, the total cell number count in the lung and bone marrow cell proliferation, without changing the number of cells in the bone marrow or in the peripheral blood. This fact suggests that melatonin is important in the control of cell recruitment from the bone marrow and the migration of those cells to the lung. Melatonin administration to pinealectomized rats seems to restore the ability of cells to migrate from the bone marrow to the bronchoalveolar fluid. So, the development of specific inhibitors of melatonin would benefit patients with asthma.
There is now overwhelming evidence that cytokines, peptide hormones and neurotransmitters, as well as their receptors, are endogenous to the brain, endocrine and immune systems. Here, Edwin Blalock discusses how these shared ligands and receptors are used as a common chemical language for communication within and between the immune and neuroendocrine systems. Such communication suggests an immunoregulatory role for the brain and a sensory function for the immune system. A clearer understanding of this circuitry is dramatically altering our understanding of physiology and may profoundly affect the treatment of human disease.
Inhibition of synthesis of the pineal neurohormone melatonin (MEL) in mice, by administration of propranolol (PRO) in the evening, and daily injections of p-chlorophenylalanine (PCPA), resulted in a significant depression of the primary antibody response to sheep red blood cells (SRBC). Spleen cells from these mice showed a reduced reactivity against antigens in the autologous mixed lymphocyte reaction (AMLR). In contrast, alloreactivity remained normal. Reconstitution of the night-time peak of plasma MEL by evening injections to the mice completely reversed the suppression of the humoral response and the AMLR. MEL administration was able to antagonize the depression of antibody production induced by corticosterone in vivo. These results suggest that the pineal gland has important immunomodulatory functions through its cyclic, circadian release of MEL.
Paneth cells in mouse small intestinal crypts secrete granules rich in microbicidal peptides when exposed to bacteria or bacterial antigens. The dose-dependent secretion occurs within minutes and α-defensins, or cryptdins, account for 70% of the released bactericidal peptide activity. Gram-negative bacteria, Gram-positive bacteria, lipopolysaccharide, lipoteichoic acid, lipid A and muramyl dipeptide elicit cryptdin secretion. Live fungi and protozoa, however, do not stimulate degranulation. Thus intestinal Paneth cells contribute to innate immunity by sensing bacteria and bacterial antigens, and discharge microbicidal peptides at effective concentrations accordingly.
The pineal secretory product, melatonin, exerts a variety of effects on the immune system. Administration of melatonin stimulates cell-mediated immunity, particularly by inhibiting apoptosis among T lymphocytes in the thymus and inducing production of T-cell-derived cytokines. However, its possible effects on the humoral immune system are unclear. In the present study, we have examined whether melatonin may influence the in vivo development of B lymphocytes in mouse bone marrow, a process in which apoptosis is normally a prominent feature. Double immunofluorescence labeling and flow cytometry were used to quantitate phenotypically defined precursor B-cell and mature B-cell populations and their apoptotic rates in bone marrow of mice fed either melatonin-containing or control diet for 16 days from 9 wk of age. In short-term bone marrow cultures, the incidence of apoptosis among large pre-B cells, including cells expressing the Λ5 component of pre-B-cell receptor, was markedly reduced in melatonin-treated mice, associated with an increase in the absolute number of large pre-B cells in bone marrow. In contrast, apoptosis of earlier precursor B cells and mature B lymphocytes did not differ from control values. The results indicate that orally administered melatonin can substantially promote the survival of precursor B cells in mouse bone marrow. Melatonin treatment may thus boost the survival of newly formed B cells mediating humoral immunity.
Melatonin (N-acetyl-5-methoxytryptamine) was initially thought to be produced exclusively in the pineal gland. Subsequently its synthesis was demonstrated in other organs, for example, the retinas, and very high concentrations of melatonin are found at other sites, for example, bone marrow cells and bile. The origin of the high level of melatonin in these locations has not been definitively established, but it is likely not exclusively of pineal origin. Melatonin has been shown to possess anti-inflammatory effects, among a number of actions. Melatonin reduces tissue destruction during inflammatory reactions by a number of means. Thus melatonin, by virtue of its ability to directly scavenge toxic free radicals, reduces macromolecular damage in all organs. The free radicals and reactive oxygen and nitrogen species known to be scavenged by melatonin include the highly toxic hydroxyl radical (·OH), peroxynitrite anion (ONOO−), and hypochlorous acid (HOCl), among others. These agents all contribute to the inflammatory response and associated tissue destruction. Additionally, melatonin has other means to lower the damage resulting from inflammation. Thus, it prevents the translocation of nuclear factor-kappa B (NF-κB) to the nucleus and its binding to DNA, thereby reducing the upregulation of a variety of proinflammatory cytokines, for example, interleukins and tumor neurosis factor-alpha. Finally, there is indirect evidence that melatonin inhibits the production of adhesion molecules that promote the sticking of leukocytes to endothelial cells. By this means melatonin attenuates transendothelial cell migration and edema, which contribute to tissue damage.
Male and female gerbils were implanted s.c. with a pellet containing 2 mg melatonin/23 mg beeswax every 2 weeks for a total of 3 implants. A significant depression of ovarian and uterine weight was noted in female gerbils receiving melatonin implants. In the melatonin-treated male gerbils, growth of the accessory organs was significantly inhibited although testis size was not depressed.