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Therapeutic potential of melatonin in targeting molecular pathways of organ fibrosis

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Abstract

Fibrosis, the excessive deposition of fibrous connective tissue in an organ in response to injury, is a pathological condition affecting many individuals worldwide. Fibrosis causes the failure of tissue function and is largely irreversible as the disease progresses. Pharmacologic treatment options for organ fibrosis are limited, but studies suggest that antioxidants, particularly melatonin, can aid in preventing and controlling fibrotic damage to the organs. Melatonin, an indole nocturnally released from the pineal gland, is commonly used to regulate circadian and seasonal biological rhythms and is indicated for treating sleep disorders. While it is often effective in treating sleep disorders, melatonin's anti-inflammatory and antioxidant properties also make it a promising molecule for treating other disorders such as organ fibrosis. Melatonin ameliorates the necrotic and apoptotic changes that lead to fibrosis in various organs including the heart, liver, lung, and kidney. Moreover, melatonin reduces the infiltration of inflammatory cells during fibrosis development. This article outlines the protective effects of melatonin against fibrosis, including its safety and potential therapeutic effects. The goal of this article is to provide a summary of data accumulated to date and to encourage further experimentation with melatonin and increase its use as an anti-fibrotic agent in clinical settings.

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Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

AMPK:

5′Adenosine monophosphate-activated protein kinase

α-SMA:

α-Smooth muscle actin

ATF:

Activating transcription factor

ARDS:

Acute respiratory distress syndrome

ALT:

Alanine aminotransferase

AFLD:

Alcoholic fatty liver disease

AECs:

Alveolar epithelial cells

Ang II:

Angiotensin II

AST:

Aspartate aminotransferase

ADHD:

Attention deficit hyperactivity disorder

ASD:

Autism spectrum disorder,

BMAL1:

Basic Helix-Loop-Helix ARNT Like 1

BDL:

Bile duct ligation

BMMSCs:

Bone marrow-derived mesenchymal stem cell

BAL:

Bronchoalveolar lavage

CCl4 :

Carbon tetrachloride

CAT:

Catalase

CKD:

Chronic kidney disease

CTGF:

Connective tissue growth factor

COX-2:

Cyclooxygenase 2

CXCR4:

C-X-C motif chemokine receptor 4

DCM:

Diabetic cardiomyopathy

ER:

Endoplasmic reticulum

ESRD:

End-stage renal disease

EMT:

Epithelial–mesenchymal transition

eIF2A:

Eukaryotic translation initiation factor 2A

ECM:

Extracellular matrix

ERK:

Extracellular signal-regulated kinase

FGF:

Fibroblast growth factor

Gal-3:

Galectin-3

GAG:

Glycosaminoglycan

GSH-Px:

Glutathione peroxidase

HF:

Heart failure

HSP70:

Heat shock protein 70

HO:

Heme oxygenase

HSCs:

Hepatic stellate cells

HMGB1:

High-mobility group box 1

HIF-1α:

Hypoxia-inducible factor 1 α

HDAC:

Histone deacetylases

HA:

Hyaluronic acid

JAK:

Janus kinase

IPF:

Idiopathic pulmonary fibrosis

IRE:

Inositol-requiring ER-to-nucleus signal kinase

ITGA9:

Integrin subunit alpha 9

IL:

Interleukin

LN:

Laminin

L-NAME:

L-N(G)-Nitro arginine methyl ester

Mst1:

Macrophage stimulating 1

mTOR:

Mammalian target of rapamycin

MMP-13:

Matrix metalloproteinase-13

MSCs:

Mesenchymal stem cells

Mfn2:

Mitofusin

MI:

Myocardial infarction

Notch1:

Neurogenic locus notch homolog protein 1

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

Nrf2:

Nuclear factor erythroid-2-related factor 2

NF-kB:

Nuclear factor-kappa B

PSCs:

Pancreatic stellate cells

PPARα:

Peroxisome proliferator-activated receptor alpha

PI3K:

Phosphatidylinositol 3-kinase

PERK:

PKR-like ER kinase

PDGF:

Platelet-derived growth factor

Akt:

Protein kinase B

PINK1:

PTEN-induced kinase 1

ROS:

Reactive oxygen species

RIP1:

Receptor-interacting protein 1

RAGE:

Receptor for advanced glycation end products

SERCA:

Sarcoendoplasmic reticulum calcium ATPase

SAD:

Seasonal affective disorder

SIAH3:

Siah E3 Ubiquitin Protein Ligase Family Member 3

STAT:

Signal transducer and activator of transcription

SIRT:

Sirtuin

SYK:

Spleen tyrosine kinase

SOD:

Superoxide dismutase

TIMP:

Tissue inhibitor of metalloproteinase

TLR4:

Toll-like receptor 4

TGF-β:

Transforming growth factor beta

TAC:

Transverse aortic constriction

TNF:

Tumor necrosis factor

UPR:

Unfolded protein response

VEGF-A:

Vascular endothelial growth factor-A

XBP1:

X-box binding protein 1

YAP:

Yes-associated protein

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran

    Azam Hosseinzadeh, Mohammad Sheibani & Saeed Mehrzadi

  2. Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran

    Mohammad Hossein Pourhanifeh

  3. Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

    Shiva Amiri

  4. Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Mohammad Sheibani

  5. Clinical Research Development Unit of Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Rana Irilouzadian

  6. Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA

    Russel J. Reiter

Authors
  1. Azam Hosseinzadeh
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  2. Mohammad Hossein Pourhanifeh
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  3. Shiva Amiri
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  4. Mohammad Sheibani
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  5. Rana Irilouzadian
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  6. Russel J. Reiter
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  7. Saeed Mehrzadi
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Contributions

AH was involved in writing––original draft preparation and revising; SM did supervision; MHP, SA, MS, and RI were involved in writing––original draft preparation; RJR performed reviewing and editing.

Corresponding author

Correspondence to Saeed Mehrzadi.

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Hosseinzadeh, A., Pourhanifeh, M.H., Amiri, S. et al. Therapeutic potential of melatonin in targeting molecular pathways of organ fibrosis. Pharmacol. Rep 76, 25–50 (2024). https://doi.org/10.1007/s43440-023-00554-5

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