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Molecular mechanisms and signaling pathways of black cumin (Nigella sativa) and its active constituent, thymoquinone: a review

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Abstract

Background

Nigella sativa and its main bioactive ingredient, thymoquinone, exhibit various pharmacological activities, including neuroprotective, nephroprotective, cardioprotective, gastroprotective, hepatoprotective, and anti-cancer effects. Many studies have been conducted trying to elucidate the molecular signaling pathways that mediate these diverse pharmacological properties of N. sativa and thymoquinone. Accordingly, the goal of this review is to show the effects of N. sativa and thymoquinone on different cell signaling pathways.

Methods

The online databases Scopus, PubMed and Web of Science were searched to identify relevant articles using a list of related keywords such as Nigella sativa, black cumin, thymoquinone, black seed, signal transduction, cell signaling, antioxidant, Nrf2, NF-κB, PI3K/AKT, apoptosis, JAK/STAT, AMPK, MAPK, etc. Only articles published in the English language until May 2022 were included in the present review article.

Results

Studies indicate that N. sativa and thymoquinone improve antioxidant enzyme activities, effectively scavenges free radicals, and thus protect cells from oxidative stress. They can also regulate responses to oxidative stress and inflammation via Nrf2 and NF-κB pathways. N. sativa and thymoquinone can inhibit cancer cell proliferation through disruption of the PI3K/AKT pathway by upregulating phosphatase and tensin homolog. Thymoquinone can modulate reactive oxygen species levels in tumor cells, arrest the cell cycle in the G2/M phase as well as affect molecular targets including p53, STAT3 and trigger the mitochondrial apoptosis pathway. Thymoquinone, by adjusting AMPK, can regulate cellular metabolism and energy hemostasis. Finally, N. sativa and thymoquinone can elevate brain GABA content, and thus it may ameliorate epilepsy.

Conclusions

Taken together, the improvement of antioxidant status and prevention of inflammatory process by modulating the Nrf2 and NF-κB signaling and inhibition of cancer cell proliferation through disruption of the PI3K/AKT pathway appear to be the main mechanisms involved in different pharmacological properties of N. sativa and thymoquinone.

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Data availability

None to declare.

Abbreviations

ACC:

Acetyl-CoA carboxylase

AMPK:

AMP-activated protein kinase

Ang II:

Angiotensin II

ARE:

Antioxidant response element

ATF6:

Activating transcription factor 6

CAT:

Catalase

COX-2:

Cyclooxygenase-2

CRC:

Colorectal cancer

EMT:

Epithelial‑mesenchymal transition

ERK:

Extracellular signal-regulated kinase

GLUT4:

Glucose transporter 4

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GSH:

Glutathione

GST:

Glutathione S-transferase

HFD:

High-fat diet

HSCs:

Hepatic stellate cells

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

iNOS:

Inducible nitric oxide synthase

JNK:

C-JUN N-terminal kinase

LDL-C:

Low-density lipoprotein cholesterol

LKB1:

Liver kinase B1

LPS:

Lipopolysaccharide

MBP:

Myelin basic protein

MDA:

Malondialdehyde

MI:

Myocardial infarction

MMP:

Matrix metalloproteinase

MPO:

Myeloperoxidase

mTOR:

Mammalian target of rapamycin

NO:

Nitric oxide

NOX4:

NADPH Oxidase 4

NRCMs:

Neonatal rat cardiomyocytes

NSSP:

Nigella sativa seed polysaccharides

PCOS:

Polycystic ovary syndrome

PE:

Phenylephrine

PGC-1α:

Peroxisome proliferator-activated receptor-γ coactivator-1α

PGE2:

Prostaglandin E2

PPAR-γ:

Peroxisome proliferator-activated receptor-γ

PTEN:

Phosphatase and tensin homolog

PTZ:

Pentylenetetrazole

RA:

Rheumatoid arthritis

RCC:

Renal cell carcinoma

ROS:

Reactive oxygen species

SE:

Status epilepticus

siRNA:

Small interfering RNA

SIRT1:

Sirtuin1

SOD:

Superoxide dismutase

TAC:

Transverse aortic constriction

TGF-β:

Transforming growth factor β

TIMP:

Tissue inhibitor of metalloproteinase

TLR2:

Toll-like receptor 2

TNBC:

Triple-negative breast cancer

TNF-α:

Tumor necrosis factor-alpha

TQ:

Thymoquinone

VEGF:

Vascular endothelial growth factor

VSMCs:

Vascular smooth muscle cells

α-SMA:

α-Smooth muscle actin

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Authors and Affiliations

  1. School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Ehsan Sadeghi

  2. Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, P.O.Box: 1365-91775, Mashhad, Iran

    Mohsen Imenshahidi & Hossein Hosseinzadeh

  3. Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Mohsen Imenshahidi & Hossein Hosseinzadeh

Authors
  1. Ehsan Sadeghi
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  2. Mohsen Imenshahidi
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  3. Hossein Hosseinzadeh
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ES performed the literature search and wrote the manuscript. MI supervised the writing and style correction of the manuscript. HH conceptualized, supervised the study. ALL authors have read and approved the final manuscript.

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Correspondence to Hossein Hosseinzadeh.

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Sadeghi, E., Imenshahidi, M. & Hosseinzadeh, H. Molecular mechanisms and signaling pathways of black cumin (Nigella sativa) and its active constituent, thymoquinone: a review. Mol Biol Rep 50, 5439–5454 (2023). https://doi.org/10.1007/s11033-023-08363-y

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