Browsing by Subject "Melatonin"

Now showing 1 - 8 of 8
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    Circadian rhythms in diabetic retinopathy: an overview of pathogenesis and investigational drugs
    (Taylor & Francis, 2020) Bhatwadekar, Ashay D.; Rameswara, Varun; Ophthalmology, School of Medicine
    Introduction: Circadian rhythm is a natural endogenous process occurring roughly every 24 hours. Circadian rhythm dysfunction is involved in diabetic retinopathy (DR) pathogenesis. Interestingly, there are investigational drugs that exhibit potential in the treatment of DR by targeting circadian rhythm dysfunction. Areas covered: We performed a literature search in June 2020 using PubMed's Medical Subject Heading (MeSH) terms 'circadian clock,' 'circadian rhythms,' and 'diabetic retinopathy.' This article offers an overview of the physiology of the biological clock and clock regulatory genes and presents an examination of the retinal clock. It discusses the pathogenic mechanisms of DR and emphasizes how circadian rhythm dysfunction at structural, physiological, metabolic and cellular levels, plays a critical role in the development of DR. The latter part of the paper sheds light on those investigational drugs (such as melatonin, tasimelteon and metformin) which exhibit potential in the treatment of DR by the targeting of circadian rhythm dysfunction. Expert opinion: An enhanced understanding of circadian rhythm and its role in DR could offer therapeutic potential by targeting of circadian rhythm dysfunction.
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    Enhancement of the SESN2-SHP cascade by melatonin ameliorates hepatic gluconeogenesis by inhibiting the CRBN-BTG2-CREBH signaling pathway
    (Springer Nature, 2023) An, Seungwon; Nedumaran, Balachandar; Koh, Hong; Joo, Dong Jin; Lee, Hyungjo; Park, Chul-Seung; Harris, Robert A.; Shin, Keong Sub; Djalilian, Ali R.; Kim, Yong Deuk; Biochemistry and Molecular Biology, School of Medicine
    Melatonin is involved in the regulation of various biological functions. Here, we explored a novel molecular mechanism by which the melatonin-induced sestrin2 (SESN2)-small heterodimer partner (SHP) signaling pathway protects against fasting- and diabetes-mediated hepatic glucose metabolism. Various key gene expression analyses were performed and multiple metabolic changes were assessed in liver specimens and primary hepatocytes of mice and human participants. The expression of the hepatic cereblon (CRBN) and b-cell translocation gene 2 (BTG2) genes was significantly increased in fasting mice, diabetic mice, and patients with diabetes. Overexpression of Crbn and Btg2 increased hepatic gluconeogenesis by enhancing cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH), whereas this phenomenon was prominently ablated in Crbn null mice and Btg2-silenced mice. Interestingly, melatonin-induced SESN2 and SHP markedly reduced hepatic glucose metabolism in diabetic mice and primary hepatocytes, and this protective effect of melatonin was strikingly reversed by silencing Sesn2 and Shp. Finally, the melatonin-induced SESN2-SHP signaling pathway inhibited CRBN- and BTG2-mediated hepatic gluconeogenic gene transcription via the competition of BTG2 and the interaction of CREBH. Mitigation of the CRBN-BTG2-CREBH axis by the melatonin-SESN2-SHP signaling network may provide a novel therapeutic strategy to treat metabolic dysfunction due to diabetes.
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    Health advisory: melatonin use in children
    (American Academy of Sleep Medicine, 2023) Rishi, Muhammad Adeel; Khosla, Seema; Sullivan, Shannon S.; Medicine, School of Medicine
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    Lessons from a BACE1 inhibitor trial: off-site but not off base
    (Elsevier, 2014-10) Lahiri, Debomoy K.; Maloney, Bryan; Long, Justin M.; Greig, Nigel H.; Department of Medical & Molecular Genetics, IU School of Medicine
    Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-β peptide (Aβ). The rate-limiting step in the production of Aβ is the processing of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Aβ within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of β-galactoside α-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future.
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    Melatonin Alters Age-Related Changes in Transcription Factors and Kinase Activation
    (Springer Verlag, 2010-06-10) Bondy, Stephen C.; Li, Huihui; Zhou, Jun; Wu, Meixia; Bailey, Jason A.; Lahiri, Debomoy K.; Psychiatry, School of Medicine
    Male mice were fed 40 ppm melatonin for 2 months prior to sacrifice at age 26 months, and compared with both 26 and 4 month-old untreated controls. The nuclear translocation of NF-κB increased with age in both brain and spleen and this was reversed by melatonin only in brain. Another transcription factor, AP-1 was increased with age in the spleen and not in brain and this could be blocked by melatonin treatment. The fraction of the active relative to the inactive form of several enabling kinases was compared. The proportion of activated ERK was elevated with age in brain and spleen but this change was unresponsive to melatonin. A similar age-related increase in glial fibrillary acidic protein (GFAP) was also refractory to melatonin treatment. The cerebral melatonin M1 receptor decreased with age in brain but increased in spleen. The potentially beneficial nature of melatonin for the preservation of brain function with aging was suggested by the finding that an age-related decline in cortical synaptophysin levels was prevented by dietary melatonin.
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    Melatonin Treatment Enhances Aβ Lymphatic Clearance in a Transgenic Mouse Model of Amyloidosis
    (Bentham Science, 2018) Pappolla, M.A.; Matsubara, E.; Vidal, R.; Pacheco-Quinto, J.; Poeggeler, B.; Zagorski, M.; Sambamurti, K.; Pathology and Laboratory Medicine, School of Medicine
    Background: It has been postulated that inadequate clearance of the amyloid β protein (Aβ) plays an important role in the accumulation of Aβ in sporadic late onset Alzheimer's disease (AD). While the blood brain barrier (BBB) has taken the center stage in processes involving Aβ clearance, little information is available about the role of the lymphatic system. We previously reported that Aβ is cleared through the lymphatic system. We now assessed lymphatic Aβ clearance by treating a mouse model of AD amyloidosis with melatonin, an Aβ aggregation inhibitor and immuno-regulatory neurohormone. Objective: To confirm and expand our initial finding that Aβ is cleared through the lymphatic system. Lymphatic clearance of metabolic and cellular "waste" products from the brain into the peripheral lymphatic system has been known for a long time. However, except for our prior report, there is no additional experimental data published about Aβ being cleared into peripheral lymph nodes. Methods: For these experiments, we used a transgenic mouse model (Tg2576) that over-expresses a mutant form of the Aβ precursor protein (APP) in the brain. We examined levels of Aβ in plasma and in lymph nodes of transgenic mice as surrogate markers of vascular and lymphatic clearance, respectively. Aβ levels were also measured in the brain and in multiple tissues. Results: Clearance of Aβ peptides through the lymphatic system was confirmed in this study. Treatment with melatonin led to the following changes: 1-A statistically significant increase in soluble monomeric Aβ40 and an increasing trend in Aβ42 in cervical and axillary lymph nodes of treated mice. 2- Statistically significant decreases in oligomeric Aβ40 and a decreasing trend Aβ42 in the brain. Conclusion: The data expands on our prior report that the lymphatic system participates in Aβ clearance from the brain. We propose that abnormalities in Aβ clearance through the lymphatic system may contribute to the development of cerebral amyloidosis. Melatonin and related indole molecules (i.e., indole- 3-propionic acid) are known to inhibit Aβ aggregation although they do not reverse aggregated Aβ or amyloid fibrils. Therefore, these substances should be further explored in prevention trials for delaying the onset of cognitive impairment in high risk populations.
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    Melatonin: A Cutaneous Perspective on its Production, Metabolism, and Functions
    (Elsevier, 2018-03) Slominski, Andrzej T.; Hardeland, Ruediger; Zmijewski, Michal A.; Slominski, Radomir M.; Reiter, Russel J.; Paus, Ralf; Dermatology, School of Medicine
    Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. Although melatonin is best known to regulate circadian rhythmicity and lower vertebrate skin pigmentation, the full spectrum of functional activities of this free radical-scavenging molecule, which also induces/promotes complex antioxidative and DNA repair systems, includes immunomodulatory, thermoregulatory, and antitumor properties. Because this plethora of functional melatonin properties still awaits to be fully appreciated by dermatologists, the current review synthesizes the main features that render melatonin a promising candidate for the management of several dermatoses associated with substantial oxidative damage. We also review why melatonin promises to be useful in skin cancer prevention, skin photo- and radioprotection, and as an inducer of repair mechanisms that facilitate the recovery of human skin from environmental damage. The fact that human skin and hair follicles not only express functional melatonin receptors but also engage in substantial, extrapineal melatonin synthesis further encourages one to systematically explore how the skin's melatonin system can be therapeutically targeted in future clinical dermatology and enrolled for preventive medicine strategies.
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    Possible application of melatonin treatment in human diseases of the biliary tract
    (American Physiological Society, 2019-11) Baiocchi, Leonardo; Zhou, Tianhao; Liangpunsakul, Suthat; Ilaria, Lenci; Milana, Martina; Meng, Fanyin; Kennedy, Lindsey; Kusumanchi, Praveen; Yang, Zhihong; Ceci, Ludovica; Glaser, Shannon; Francis, Heather; Alpini, Gianfranco; Medicine, School of Medicine
    Melatonin was discovered in 1958 by Aaron Lerner. Its name comes from the ability of melatonin to change the shape of amphibian melanophores from stellate to roundish. Starting from the 1980s, the role of melatonin in the regulation of mammalian circadian and seasonal clocks has been elucidated. Presently, several other effects have been identified in different organs. For example, the beneficial effects of melatonin in models of liver damage have been described. This review gives first a general background on experimental and clinical data on the use of melatonin in liver damage. The second part of the review focuses on the findings related to the role of melatonin in biliary functions, suggesting a possible use of melatonin therapy in human diseases of the biliary tree.