Melatonin, an Antitumor Necrosis Factor Therapy

Journal of Pineal Research REVIEW Melatonin, an Antitumor Necrosis Factor Therapy Ana Isabel Álvarez‐López 1,2 | Ivan Cruz‐Chamorro 1,2 | Patricia Judith Lardone 1,2 | Ignacio Bejarano 1,2 | Karla Aspiazu‐Hinostroza 1,3 | Eduardo Ponce‐España 1,2 | Guillermo Santos‐Sánchez 1,2 | Nuria Álvarez‐Sánchez 1 | Antonio Carrillo‐Vico 1,2 1 Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain | 2 Departamento de Bioquímica Médica y Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain | 3 Universidad Católica de Cuenca, Research Department, Cuenca‐Azuay, Ecuador Correspondence: Nuria Álvarez‐Sánchez ([email protected]) | Antonio Carrillo‐Vico ([email protected]) Received: 13 June 2024 | Revised: 22 October 2024 | Accepted: 10 December 2024 Funding: This work was supported by the Andalusian Government Ministry of Health PC‐0019‐2017, PI‐0015‐2018 and PEMP‐0085‐2020 (co‐financed with FEDER funds, call Resolution of 7 July 2021 of the General Secretary for Research, Development and Innovation in Health, which calls for grants to finance research, development and innovation in biomedicine and health sciences in Andalusia by 2021), the PAIDI Program from the Andalusian Government (CTS160) and Regional Ministry of Economy and Knowledge of Andalusia (US‐1263804) into the European Regional Development Fund Operational Programme 2014 to 2020. A.I.A.L. was supported by grants US‐1263804 and PEMP‐0085‐2020. I.C.C. was supported by a postdoctoral fellowship from the Andalusian Government Ministry of Economy, Knowledge, Business, and University (DOC_00587/2020). I.B. and E.P.E were supported by the VI Program of Inner Initiative for Research and Transfer of the University of Seville [VI PPIT‐US]. G.S.S. was supported by a FPU grant from the Spanish Ministerio de Educación, Cultura y Deporte (FPU16/02339). N.A.‐S. was supported by a fellowship from the Andalusian Regional Ministry of Health (PC‐0111‐2016‐0111). Keywords: anti‐TNF therapy | chronic inflammation | humans | immunomodulation | inflammatory disease | melatonin | TNF ABSTRACT Tumor necrosis factor (TNF) is a biomarker of inflammation whose levels are elevated in patients with several diseases associated with dysregulation of the immune response. The main limitations of currently used anti‐TNF therapies are the induction of immunodepression, which in many cases leads to serious adverse effects such as infection and cancer, and the inability to cross the blood‐brain barrier in neuroinflammatory conditions. Melatonin, in addition to being a chronobiotic compound, is widely known for its antioxidant and immunomodulatory capacity to control inflammatory processes in different pathological contexts. The aim of the present review is to address human‐based studies that describe the effect of melatonin on TNF production. The review includes all the articles published in PubMed databases until April 15, 2024. After depuration, 45 studies were finally included in the review, 23 related to the in vitro action of melatonin in human cells and 22 in vivo studies in humans. Most of the data reviewed support the idea that melatonin has an immunosuppressive effect on TNF levels, which, together with its low toxicity profile, low cost, and ability to cross the blood‐brain barrier, points to melatonin as a potential anti‐ TNF therapy. Therefore, improving our knowledge of the action of melatonin in regulating TNF through appropriate clinical trials would reveal the true potential of this molecule as a possible anti‐TNF therapy. 1 | Introduction Tumor necrosis factor (TNF) is one of the major cytokines involved in the acute phase of inflammatory processes. TNF exerts pro‐inflammatory and immunomodulatory cytokine functions during immune responses in a wide range of physiopathological inflammatory, infectious and malignant conditions [1]. TNF is synthesized as a type II homotrimeric transmembrane protein mainly by immune cells, such as activated macrophages, dendritic cells, T and B lymphocytes, neutrophils, or mast cells. Transmembrane TNF (mTNF) is cleaved at the cell surface by the metalloproteinase TNF‐converting enzyme (TACE), also known as ADAMS 17, and released as a soluble homotrimeric TNF (sTNF) [2, 3]. Both mTNF and sTNF can exert their function by binding to This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. © 2024 The Author(s). Journal of Pineal Research published by John Wiley & Sons Ltd. 1of20Journal of Pineal Research, 2025; 77:e70025 https://doi.org/10.1111/jpi.70025 type I (TNFR1) and/or type II (TNFR2) TNF transmembrane receptors. TNFR2 is typically located in the plasma membrane and is expressed in certain populations of lymphocytes, neurons, and endothelial cells [4, 5]. TNFR1, which is ubiquitously expressed in the lymphoid system and in almost all cells of the body [6], is originally located in the Golgi apparatus [7]andismobilizedtothe cell surface when required. Alternatively, it can be released proteolytically, also by TACE, as a soluble receptor (sTNFR), neutralizing TNF in the circulation [8]. In this way, sTNFR modulates sTNF activity and prevents adverse pathological effects caused by increased systemic levels of sTNF [9, 10](Figure1). Serum levels of both sTNF and sTNFR increase dramatically in certain inflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease, and systemic scleroderma [11]. Although the affinities of TNFR1 and TNFR2 for sTNF are similar, mTNF preferentially binds to TNFR2, resulting in a more potent response than sTNF. This makes TNFR2 a potential molecular target for the development of drugs against inflammatory diseases associated with increased TNF. Overall, TNF signaling, via TNFR1 or TNFR2, activates the downstream nuclear factor‐kB (NF‐κB), which promotes cell survival. TNFR1 is also capable of inducing apoptosis, which is why the specific activation of TNFR1 (but not TNFR2) by exogenous TNF is systemically toxic [12, 13]. Although there is some overlap in the functions of these receptors and some antagonism effects, the modulation of TNFRs depends on physiological circumstances. Although there is evidence of close crosstalk between TNFR1 and TNFR2 to modulate their complementary functions, these mechanisms are not fully understood [14]. One of the main functions of TNF is to induce the host immune response against bacterial, viral, and parasitic infections. In particular, TNF is essential for the formation and maintenance of granulomas that prevent the spread of bacterial infections throughout the body [15, 16]. Increased TNF levels is the normal host response to Plasmodium falciparum infection [17]or to viral infections such as the Crimean‐Congo hemorrhagic fever virus [18]. The tumoricidal effects of TNF, as well as other pro‐inflammatory cytokines, contribute to the fight against carcinogenesis by inhibiting tumor cell proliferation, invasion, and metastasis [19, 20]. TNF is also involved in the pathogenesis of several autoimmune diseases. All these pathologies share an immune dysregulation characterized by an increase in TNF expression that culminates in chronic inflammation, tissue destruction, and disability. In this context, both rheumatoid arthritis (RA) [21, 22] and ankylosing spondylitis [23] have been reported to exhibit a chronic increase in TNF levels and chronic joint inflammation with its consequent stiffness. In both cases, TNF plays an important role in the development of fibrosis; the inflammatory damage induced in cartilage favors the influx of synovial cells, facilitating the adhesion of inflammatory cells to the endothelium of synovial vessels, and bone erosion [24, 25]. Local synthesis of TNF has also been reported to play an important role in the pathogenesis of systemic lupus erythematosus (SLE), more particularly in the kidney [26]. This cytokine is involved not only in the synthesis of other pro‐inflammatory cytokines, but also induces the gene expression of cell adhesion molecules and antibodies, such as double‐stranded DNA, antinuclear and anticardiolipin (SLE features) [27]. In Graves' disease (GD) [28], TNF is produced by thyroid follicular cells and inflammatory cells in the thyroid gland during activation of local inflammatory and autoimmune responses in the thyroid, although the full role of TNF in this disease remains unknown [29]. Another TNF‐related autoimmune disease that affects millions of people is insulin‐dependent diabetes mellitus or type 1 diabetes (T1DM) [30]. TNF‐producing macrophages and dendritic cells infiltrate the pancreatic islets of patients with T1DM, where this cytokine plays a critical cytotoxic role in inflammation and subsequent apoptosis of pancreatic β‐cells compromising the insulin synthesis [31, 32]. In Crohn's disease, most of the cells recruited into the intestinal mucosa are macrophages, and TNF‐induced inflammation and enterocyte apoptosis significantly increase mucosal permeability, especially when TNF acts synergistically with interferon (IFN‐γ), due to its cytostatic effects [33, 34]. Regarding autoimmune diseases of the central nervous system (CNS), multiple sclerosis (MS) is a chronic neuroinflammatory FIGURE 1 | Posttranslational processing of TNF and TNF receptor (A) and different interaction models between them (B). mTNF, membrane TNF; sTNF, soluble TNF; sTNFR1/2, soluble TNF receptor 1/2; TNF, tumor necrosis factor; TNFR1/2, TNF receptor 1/2. 2of20 Journal of Pineal Research, 2025 1600079x, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jpi.70025 by Readcube (Labtiva Inc.), Wiley Online Library on [11/06/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License disease [35] in which TNF is involved in the deterioration of the blood‐brain barrier (BBB), neuroinflammation, demyelination, and neuronal death, all leading to increased disease progression and disability [36, 37]. Thus, TNF has both homeostatic and pathophysiological roles in the CNS [38], depending on the context. In a healthy CNS, TNF has regulatory functions in crucial physiological processes such as synaptic plasticity [39], learning, and memory [40, 41]. However, under pathological conditions, astrocytes and especially microglia produce large amounts of TNF, triggering a neuroinflammatory response associated with neurological disorders [42, 43] such as ischemic stroke [44], Alzheimer's disease (AD) [45, 46], Parkinson's disease (PD) [47, 48], amyotrophic lateral sclerosis (ALS) [49, 50], and MS [51–53]. Given that TNF plays a key role as a regulator in the onset and development of inflammation‐mediated diseases, neutralizing TNF activity has been shown to be an effective therapy. To achieve this goal, the Food and Drug Administration (FDA) has adopted and approved two strategies: anti‐TNF monoclonal antibodies (mAbs), such as adalimumab, certolizumab pegol, golimumab and infliximab, and soluble receptors (sTNFR) such as etanercept, which is based on a fusion protein that mimics sTNFR [54]. Although the anti‐inflammatory mechanism of TNF inhibitors appears to be selective and specific, these agents are often associated with immunosuppressive states with adverse effects such as infections or cancer [55, 56]. Currently, anti‐TNF therapies have been shown to be ineffective in a significant number of cases [57–59], as shown in Table 1. Recently, it has been estimated that one‐third of patients treated with anti‐TNF therapies are nonresponders, and only less than half of the responders achieve complete remission [60–63]. An additional disadvantage of anti‐TNF therapies is their high cost, ranging from $14 838 to $28 519 per patient per year worldwide [64]. Apparently, one of the major problems with anti‐TNF therapies for neuroinflammatory diseases is their inability to cross the BBB and reach their target [91, 92]. Although several strategies have been proposed to allow these drugs to reach the CNS [93], further research is needed to extrapolate these findings to humans. Therefore, the development of treatments capable of modulating TNF without compromising its protective role in host defense remains a major challenge. Melatonin, chemically known as N‐acetyl‐5‐methoxytryptamine, is an indolamine produced primarily by the pineal gland and released into the bloodstream to exert systemic control over circadian rhythms [94]. It is also produced extrapineally by various tissues, including the immune system, for different purposes [95–97]. In this way, it can act as a paracrine or autocrine regulator, where it reaches concentrations higher (mM) than systemic melatonin levels (pM), mainly preventing oxidative and inflammatory damage [95]. There are a large number of studies that describe the immunomodulatory role of melatonin. In this context, melatonin has been shown to stimulate the immune response under basal or immunosuppressive conditions, while inhibiting exacerbated immune responses, leading our group to propose the term “immune buffer”for this molecule [98–100]. Several studies TABLE 1 | Analysis of the efficacy of anti‐TNF therapies in different diseases. Disease Etanercept Infliximab Golimumab Adalimumab Certolizumab pegol Rheumatoid arthritis Effective [65] Effective [65] Effective [66] Effective [65] Effective [67] Ankylosing spondylitis Effective [68] Effective [68] Effective [69] Effective [68] Effective [70] Ulcerative colitis No Effective [71] Effective [72] Effective [73] Effective [74] Effective [74] Wegener's granulomatosis No Effective [75] No Effective [75] No Effective [59] No Effective [76] No tested Sarcoidosis No Effective [77] Effective [60] No Effective [78] No Effective [79] No Effective [80] Psoriasis Effective [81] Effective [82] Effective [83] Effective [84] Effective [85] Psoriatic arthritis Effective [81] Effective [86] Effective [87] Effective [84] Effective [85] Crohn's disease No Effective [88] Effective [88] No Effective [89] Effective [74] Effective [74] Multiple sclerosis No Effective [90] No Effective [90] No tested No Effective [90] No tested 3of20 1600079x, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jpi.70025 by Readcube (Labtiva Inc.), Wiley Online Library on [11/06/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License have described that melatonin reduces Pro‐inflammatory Th1 and Th17 responses and decreases cytokine levels, such as IFN‐ γ, TNF, IL‐1β,IL‐6, and IL‐17, while increasing the antiinflammatory Treg response and the production of the cytokine IL‐10 [101–106]. In fact, many studies have reported a decrease in TNF levels after melatonin administration in various approaches such as animal models of brain death [107]orMS [101], in patients with from Duchenne muscular dystrophy [108], and also in in vitro studies carried out with human lymphocytes from inflammatory pathologies [104, 109]. Melatonin can act by binding to both membrane and intracellular receptors. At the membrane level, two high‐affinity receptors coupled to G‐proteins have been identified, called MT 1 and MT 2 . Both receptors can be expressed individually or together depending on the tissue type, including the immune system [110–112]. Later, MT 3 was described in hamsters as quinone reductase 2, although no cytosolic MT receptor has been identified in humans. MT 3 has a low affinity for melatonin and is thought to protect against oxidative stress [113]. Melatonin also acts through the retinoid orphan receptor‐α(ROR‐α), which is involved in the transcriptional regulation of certain genes [114, 115]. Although ROR‐αis expressed in a variety of tissues, including testis, kidney, adipose and liver, it is most highly expressed in the brain [116]. Given its ability to cross the BBB [117], the high safety profile at high doses [118, 119] and the immunomodulatory capacity, melatonin could be a promising anti‐TNF agent. Therefore, the objective of the present study is to review the efficacy and limitations of melatonin as an anti‐TNF therapy. 2 | Materials and Methods An electronic search was carried out in the PubMed databases (www.ncbi.nlm.nih.gov) to identify research related to melatonin as a possible anti‐TNF therapy. Keywords “Melatonin”and “TNF” or “Melatonin”and “TNF‐alpha”were used. The search included articles from the start date of each source until April 15, 2024. After the removal of duplicate articles, review of titles and selection of abstracts, full‐text articles were used to verify that the content of the article was relevant. The inclusion criteria were studies conducted in vitro in human cells or in vivo in humans andmustbeinEnglish.Wehavenotconsideredbibliographicor systematic reviews and meta‐analyses on melatonin and TNF. 3 | Results We identified 121 articles with “Melatonin”and “TNF”/“TNF‐ alpha”as keywords, of which 45 were finally incorporated into the study; 23 of them were in vitro studies using human cells and 22 in vivo studies in humans (Figure 2). 3.1 | In Vitro Effects of Melatonin on TNF Production Experimental evidence shows that melatonin inhibits the increase in TNF levels in a wide variety of in vitro cultured human cells in response to various insults, such as hydrogen peroxide (H 2 O 2 )[120–122], lipopolysaccharide (LPS) [123–127], methamphetamine (METH) [128], amyloid beta (Aβ)[129], pyocyanin [130], chlorpyrifos [131], hypoxia/reoxygenation (H/R) [132–134], inflammation associated with rheumatoid arthritis [135], endothelial dysfunction in systemic lupus erythematosus (SLE) [136], hepatocellular carcinoma‐derived exosomes [137], desmoplastic reaction [138] or polarization of colostrum macrophages in breast cancer [139], and immune dysfunction in Down syndrome [140] (Table 2). Silva and colleagues reported that melatonin abolished TNF and IL‐8 production by neutrophils stimulated with LPS, whereas peripheral blood mononuclear cells (PBMCs) remained unaffected [126]. These differences found in the effect of melatonin may be due to the use of LPS, a typical stimulus for monocytes/macrophages and neutrophils [141, 142]. In line with this, previous studies from our group and others have shown that melatonin decreases TNF in ex vivo cultured PBMCs collected from healthy individuals [104, 109] and patients with MS or myasthenia gravis (MG) stimulated with the mitogen phytohemagglutinin (PHA), a more appropriate stimulus for lymphocytes [109, 143]. In addition, a study carried out in whole blood showed that LPS‐induced TNF levels were significantly reduced when cells were treated with melatonin [127]. Considering that neutrophils make up about 65% of leukocytes, it is possible that a large part of the decrease in TNF in whole blood is due to the direct effect of melatonin on neutrophils. Studies carried out in vitro with THP‐1 cells stimulated with exosomes from tumor cells are contradictory regarding the effect of melatonin to reduce the production of TNF by THP‐1 cells. Chen and colleagues pretreated tumor cells with melatonin and then collected the exosomes produced by them to add them to THP‐1 cells in culture [137]. Instead, Wang and colleagues co‐cultured THP‐1 cells with tumor cells using Transwell system for 24 h and then added melatonin [144]. To our knowledge, the fact that melatonin is present in the medium at the same time that the immune cells receive the stimulus is crucial for their activation and production of cytokines. In an in vivo study carried out in the animal model of MS, when melatonin treatment is administered from the same day that the animals are immunized, they achieve half the disability than when treatment is started from the beginning of the manifestation of clinical signs, that is, when an immune activation process has already begun [101]. Therefore, CD4 + cells infiltrating the CNS from mice treated with melatonin from the day of immunization produced significantly lower levels of TNF than cells from mice treated with melatonin from the onset of symptoms [101]. 3.2 | In Vivo Effects of Melatonin on TNF Production Randomized placebo‐controlled studies have provided in vivo evidence for the modulatory role of melatonin in TNF‐related inflammatory processes such as obesity [145], polycystic ovary syndrome [146], NAFLD [147], strenuous physical exercise [148], patients undergoing coronary artery bypass grafting [149], Charcot‐Marie‐Tooth neuropathy [150], relapsingremitting multiple sclerosis [151], Parkinson's disease [152], 4of20 Journal of Pineal Research, 2025 1600079x, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jpi.70025 by Readcube (Labtiva Inc.), Wiley Online Library on [11/06/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Chronic lung disease [153], and bronchopulmonary dysplasia [154] in premature newborns, surgical neonates [155], neoplastic cachexia [156], generalized chronic periodontitis after scaling and root planning in insomniac individuals [157], COVID‐19 patients [158], chronic kidney disease with low hemoglobin levels [159], and renal ischemia‐reperfusion injury in renal transplant patients [160] (Table 3). In these patients, melatonin showed a significant reduction in TNF levels and oxidative stress, which attenuates both the onset of oxidative stress‐induced inflammatory processes and inflammationtriggered oxidative damage. However, in patients with rheumatoid arthritis (RA) or MS, melatonin treatment did not modulate TNF levels. In the study in RA patients, Forrest and colleagues considered the fact that, for ethical medical reasons, the patients resumed the antirheumatic treatment established for more than 6 months of active disease. This could be the reason for the ineffectiveness of melatonin, since plasma TNF levels in patients had already been reduced by previous anti‐ TNF treatment (nonsteroidal anti‐inflammatory drugs, anti‐ TNF drugs or steroids), as shown by the gradual decrease in TNF levels over the 6 months of the study, even in the placebo group [161]. This may also be the reason why MS patients did not show changes in serum TNF levels after melatonin treatment, as these were patients treated with Interferon‐β [162], an immunomodulatory drug that is widely used in the treatment of MS and its ability to reduce TNF levels has been described [163–165]. Consistent with this suggestion, in a study of patients with relapsing‐remitting MS who had not been previously medicated, treatment with 25 mg of melatonin daily for 6 months reduced TNF levels [151]. In addition, the dose of melatonin administered could be another reason for the differences observed in the studies with MS patients, as patients on co‐medication took 3 mg/day and those without immunomodulators took 25 mg/day. In the same line, the dose (10 mg/day) could also be the reason for the ineffectiveness of melatonin in TNF levels in patients with RA [161]. Interestingly, in vitro administration of melatonin reduced TNF levels in synovial fibroblasts of RA patients in a dose‐dependent manner [135], suggesting that there is still room to deepen the beneficial effect of melatonin as a treatment or a co‐treatment in RA. Consistent with this, the data from our laboratory also show a dual effect of melatonin on the production of pro‐inflammatory cytokines such as TNF. Although melatonin reduced PHA‐ induced TNF production in healthy PBMCs, no inhibitory role of melatonin on pro‐inflammatory cytokine production was observed in PMBCs from SLE patients treated with antimalarial, FIGURE 2 | The flow diagram of study selection process. 5of20 1600079x, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jpi.70025 by Readcube (Labtiva Inc.), Wiley Online Library on [11/06/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License TABLE 2 | Representation of the results of the in vitro studies using human cells. Model Type of cell Experimental groups Melatonin dose Effects on TNF References Inflammation by hydrogen peroxide CHON‐001 chondrocyte cell ‐CTRL ‐H 2 O 2 ‐H 2 O 2 + MLT 43 nM ↓TNF Lim et al. [120] Inflammation by hydrogen peroxide SH‐SY5Y neuroblastoma cells ‐CTRL ‐MLT ‐H 2 O 2 ‐H 2 O 2 + MLT 1µM ↓TNF Nopparat et al. [122] Toxicity induced by hydrogen peroxide Bone‐marrow derived mesenchymal stem cells (BM‐MSCs) ‐CTRL ‐H 2 O 2 ‐H 2 O 2 + MLT ‐MLT 100 µM ↓TNF Mehrzadi et al. [121] Production of TNF stimulated by LPS THP‐1‐derived monocytes ‐CTRL (LPS) ‐LPS + MLT 0–400 µM ↓TNF Perianayagam et al. [124] Inflammation by LPS Whole blood ‐CTRL (LPS) ‐LPS + MLT ‐LPS + PMA + MLT 0–430 pM ↓TNF Fjaerli et al. [127] Inflammation by LPS Neutrophils ‐CTRL (LPS) ‐LPS + MLT 0.001–1mM ↓TNF Silva et al. [126] Inflammation by LPS PBMCs ‐CTRL (LPS) ‐LPS + MLT 0.001–1 mM = TNF Silva et al. [126] Inflammation by LPS Aorta coronary vascular smooth muscle (VSM) cell line CRL1999 ‐CTRL (LPS) ‐LPS + MLT 0.1–2.0 mM ↓TNF Shi et al. [125] Inflammation by LPS Human meibomian gland epithelial cells (HMGECs) ‐CTRL (LPS) ‐LPS + MLT 100 µM ↓TNF Liu et al. [123] Pro‐inflammatory mediators induced by methamphetamine SH‐SY5Y neuroblastoma cells ‐CTRL ‐MLT ‐METH ‐METH + MLT 100 nM ↓TNF Permpoonputtana and Govitrapong [128] Amyloid beta (Aβ)‐ induced inflammation SH‐SY5Y neuroblastoma cells ‐CTRL (pretreatment with Aβ) ‐Pretreatment with Aβ+ MLT 1 and 10 µM ↓TNF Nopparat et al. [129] Inflammation and ROS generation by pyocyanin Human globet‐like cells (LS174T) ‐CTRL (pyocyanin) ‐Pyocyanin + MLT 100 µM ↓TNF Cai et al. [130] Toxicity induced by chlorpyrifos Lymphocytes ‐CTRL ‐CP ‐CP + MLT 720 µM ↓TNF Ghayomi et al. [131] Autophagy, inflammation, and apoptosis induced by hypoxia‐reoxygenation Villous cytotrophoblasts ‐CTRL (Normoxia) ‐CTRL (H/R) ‐MLT (Normoxia) ‐MLT (H/R) 1mM ↓TNF Sagrillo‐Fagundes et al. [133] Oxidative stress induced by hypoxia‐reoxygenation and apoptosis Villous trophoblasts ‐CTRL (Normoxia) ‐Normoxia + MLT ‐H/R ‐H/R + MLT 1mM ↓TNF Lanoix et al. [132] (Continues) 6of20 Journal of Pineal Research, 2025 1600079x, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jpi.70025 by Readcube (Labtiva Inc.), Wiley Online Library on [11/06/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License anti‐inflammatory and/or immunosuppressive drugs [104], which have been reported to inhibit TNF production in human monocytes and T cells [166]. Melatonin supplementation in people with Parkinson's disease (PD) significantly reduced the Unified Parkinson's Disease Rating Scale (UPDRS) compared to placebo treatment and reduced TNF expression levels in PBMCs of these patients [152]. Beyond the control of inflammatory processes, the beneficial role of melatonin in PD has been demonstrated in several studies. Kunz and Mahlberg [171] found that melatonin improved sleep behavior in PD patients, while Dowling and colleagues reported that melatonin administration improved nonmotor disturbances in PD patients [172]. The potential of melatonin has also been evaluated in other neurodegenerative diseases, such as Alzheimer's disease (AD) or MS, as mentioned above. Wade and colleagues demonstrated that melatonin administration effectively improved cognitive performance in patients diagnosed with mild to moderate AD [173]. Moreover, a recent publication showed that melatonin treatment significantly increased lamina cribrosa thickness (LCT) and hippocampal volume compared to the placebo group, suggesting that melatonin therapy may have a beneficial effect on mild cognitive impairment patients with LCT changes [174]. However, limited studies have evaluated the role of melatonin in molecular mechanisms and clinical symptoms in neurodegenerative diseases. In view of the above results, melatonin is a potential candidate for the treatment of neuroinflammatory diseases that are the subject of many studies. In addition to the central role that TNF plays in neuroinflammatory diseases, an excess of TNF induces glutamate to reach toxic levels, altering the synaptic excitatory/ inhibitory balance and increasing neurotoxicity [175]. This fact TABLE 2 | (Continued) Model Type of cell Experimental groups Melatonin dose Effects on TNF References Oxidative stress, inflammation, and apoptosis induced by oxygen‐glucose deprivation/ reoxygenation SH‐SY5Y neuroblastoma cells ‐CTRL ‐MLT 1mM ↓TNF Zhi et al. [134] Inflammation in rheumatoid arthritis Human RA synovial fibroblasts ‐CTRL ‐MLT 0.2–1mM ↓TNF Huang et al. [135] Endothelial dysfunction in systemic lupus erythematosus (SLE) Human umbilical vein endothelial cells (HUVECs) ‐Control medium + vehicle ‐SLE medium + vehicle ‐SLE medium + MLT 10 µM ↓TNF Huang et al. [136] Immunosuppression by exosomes of hepatocellular carcinoma cells Human monocytic THP‐1 ‐Blank (without exosomes) ‐Exo‐CTRL ‐Exo‐MLT 0.1 mM ↓TNF Cheng et al. [137] Modulation of the exosomes derived from gastric cancer cells THP‐1 cells in coculture with exosomes from gastric cancer cells ‐Blank (without exosomes) ‐Exo ‐0 (untreated) ‐Exo‐MLT 1 mM = TNF Wang et al. [144] Desmoplastic reaction in breast cancer MCF‐7 breast cancer cells ‐CTRL ‐MLT 1mM ↓TNF Alvarez‐Garcia et al. [138] Polarization of colostrum macrophages in the presence of breast tumor cell Colostrum macrophages in coculture with MCF‐7 breast cancer cells ‐CTRL ‐MLT 100 nM ↓TNF Silva et al. [139] Immune dysfunction in children with Down syndrome Whole blood ‐CTRL (LPS) ‐LPS + MLT 42 µM ↓TNF Huggard et al. [140] Abbreviations: CP, chlorpyrifos; CTRL, control; Exo‐CTRL, hepatocellular carcinoma‐derived exosomes; Exo‐MLT, exosomes derived from hepatocellular carcinoma cells treated with melatonin; H 2 O 2 , hydrogen peroxide; H/R, hypoxia/reoxygenation; LPS, lipopolysaccharide; METH, methamphetamine; MLT, melatonin; PMA, phorbol myristate acetate; RA, rheumatoid arthritis; ↓TNF, decrease on TNF levels compared to the control group; = TNF, no significative changes on TNF levels with respect to the control group. 7of20 1600079x, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jpi.70025 by Readcube (Labtiva Inc.), Wiley Online Library on [11/06/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License TABLE 3 | Representation of the results of the electronic search of in vivo studies in humans. Pathology Experimental groups Melatonin dose Way of administration Duration Effects on TNF References Obesity in women ‐CTRL (placebo) n=23 ‐MLT n=23 6 mg/day Oral 40 days ↓TNF Mesri Alamdari et al. [145] Women with polycystic ovary syndrome (PCOS) ‐CTRL n=21 ‐MLT n=21 2 × 3 mg/day Oral 8 weeks ↓TNF Mousavi et al. [146] Nonalcoholic fatty liver disease ‐CTRL (placebo) n=23 ‐TRYPTOPHAN n=28 ‐MLT n=23 2 × 5 mg/day Oral 14 months ↓TNF Celinski et al. [147] Strenuous exercise ‐CTRL (placebo) n=10 ‐MLT n=10 Five capsules of 3 mg Oral 3 days ↓TNF Ochoa et al. [148] Patients undergoing coronary artery bypass grafting ‐CTRL (placebo) n=30 ‐MLT n=30 ‐NAC n=28 20 mg tablets Oral 24 h ↓TNF Shafiei et al. [149] Charcot‐Marie‐Tooth neuropathy ‐CTRL (placebo) n=8n ‐MLT n=3 70 mg/day Oral 6 months ↓TNF Chahbouni et al. [150] Rheumatoid arthritis ‐CTRL (placebo) n=38 ‐MLT n=37 10 mg/day Oral 6 months = TNF Forrest et al. [161] Multiple sclerosis treated with interferon ‐CTRL (placebo) n=25 ‐MLT n=25 3 mg/day Oral 6 months = TNF Yosefifard et al. [162] Relapsing remitting multiple sclerosis ‐CTRL (placebo) n=18 ‐MLT n=18 25 mg/day Oral 6 months ↓TNF Sanchez‐Lopez et al. [151] Parkinson's disease ‐CTRL (placebo) n=30‐ MLT n=30 2 × 5 mg/day Oral 12 weeks ↓TNF Daneshvar Kakhaki et al. [152] Chronic lung disease in premature newborns ‐CTRL (placebo) n=60 ‐MLT n=60 Ten doses of 10 mg/kg Intravenous 7 days ↓TNF Gitto et al. [153] Bronchopulmonary dysplasia in premature newborns ‐CTRL (placebo) n=55 ‐MLT n=55 Ten doses of 10 mg/kg Intravenous 7 days ↓TNF Gitto et al. [154] Surgical neonates ‐PLACEBO (surgical neonates) n=10 ‐MLT (surgical neonates) n=10 ‐CTRL (healthy neonates) n=20 Ten doses of 10 mg/kg Intravenous 7 days ↓TNF Gitto et al. [155] Nighttime endotoxaemia ‐CTRL n=6 ‐MLT n=6 100 mg Intravenous 8 h = TNF Alamili et al. [167] (Continues) 8of20 Journal of Pineal Research, 2025 1600079x, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jpi.70025 by Readcube (Labtiva Inc.), Wiley Online Library on [11/06/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License TABLE 3 | (Continued) Pathology Experimental groups Melatonin dose Way of administration Duration Effects on TNF References Daytime endotoxaemia ‐CTRL n=6 ‐MLT n=6 100 mg Intravenous 8 h = TNF Alamili et al. [168] Neoplastic cachexia ‐CTRL (supportive care) n=41 ‐Supportive care + MLT n=45 20 mg/day Oral 3 months ↓TNF Lissoni et al. [156] Cancer ‐CTRL (basal levels of TNF) ‐MLT (levels of TNF after treatment with MLT) 10 mg/day Oral 3 months ↑TNF Neri et al. [169] Chronic periodontitis in type 2 diabetes mellitus patients ‐CTRL (placebo) n=25 ‐MLT n=25 6 mg/day Oral 8 weeks = TNF Bazyar et al. [170] Generalized chronic periodontitis after scaling and root planning in insomniac individuals ‐CTRL (placebo) n=36 ‐MLT n=38 10 mg/day Oral 2 months ↓TNF El‐Sharkawy et al. [157] COVID‐19 patients ‐CTRL (placebo) n=20 ‐MLT n=20 9 mg/day Oral 14 days ↓TNF Esmaeili Gouvarchin Ghaleh et al. [158] Chronic kidney disease with low hemoglobin levels ‐CTRL (regular treatments) n=20 ‐Regular treatments + MLT n=20 5 mg/day Oral 12 weeks ↓TNF Hameed et al. [159] Renal ischemia‐reperfusion injury in renal transplant patients ‐CTRL (placebo) n=20 ‐MLT n=20 3 mg/day Oral 25 days ↓TNF Panah et al. 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