Black Cumin (Nigella sativa L.): A Comprehensive Review on Phytochemistry, Health Benefits, Molecular Pharmacology, and Safety

Abstract

Mounting evidence support the potential benefits of functional foods or nutraceuticals for human health and diseases. Black cumin (Nigella sativa L.), a highly valued nutraceutical herb with a wide array of health benefits, has attracted growing interest from health-conscious individuals, the scientific community, and pharmaceutical industries. The pleiotropic pharmacological effects of black cumin, and its main bioactive component thymoquinone (TQ), have been manifested by their ability to attenuate oxidative stress and inflammation, and to promote immunity, cell survival, and energy metabolism, which underlie diverse health benefits, including protection against metabolic, cardiovascular, digestive, hepatic, renal, respiratory, reproductive, and neurological disorders, cancer, and so on. Furthermore, black cumin acts as an antidote, mitigating various toxicities and drug-induced side effects. Despite significant advances in pharmacological benefits, this miracle herb and its active components are still far from their clinical application. This review begins with highlighting the research trends in black cumin and revisiting phytochemical profiles. Subsequently, pharmacological attributes and health benefits of black cumin and TQ are critically reviewed. We overview molecular pharmacology to gain insight into the underlying mechanism of health benefits. Issues related to pharmacokinetic herb-drug interactions, drug delivery, and safety are also addressed. Identifying knowledge gaps, our current effort will direct future research to advance potential applications of black cumin and TQ in health and diseases.

Keywords: black seed; essential oil; molecular mechanism; nutraceutical; thymoquinone.

Figure 3

A schematic diagram illustrating the pathobiology of degenerative brain disorders and post-ischemic/traumatic consequences showing point of action of black cumin and TQ. The neuroprotective mechanisms of black cumin and TQ involve (1) attenuation of inflammatory response via inhibition of NF-κB signaling; (2) inhibition of COX-2 activity; (3) induction of antioxidant defense system via activation of Nrf2/ARE pathway; (4) cross-talk between Nrf2 and NF-κB; and (5) attenuation of oxidative stress in activated microglia; (6) protection against neuroinflammation by inhibiting NF-κB signaling; (7) priming of antioxidant defense system by activating Nrf2/ARE pathway; (8) prevention of apoptosis via downregulating pro-apoptotic JNK/Erk pathway; (9) activation of BDNF-dependent pro-survival pathway via inducing PI3K/Akt signaling; and (10) induction of mitophagy in neuron; (11) attenuation of I/R-injury via preventing excitotoxic depolarization in presynaptic terminal of neuron; (12) anticholinesterase activity; (13) anti-amyloidogenesis via blocking β-secretase activity; and (14) Aβ-clearance by upregulating IDE, LRP1, and RAGE. TLR, toll-like receptor; LPS, lipopolysaccharide; NF-κB (p50-p65), nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2-related factor 2; ARE, antioxidant response element; IkB, inhibitor of NF-κB; IKK, IκB kinase; Keap1, Kelch-like ECH-associated protein 1; COX2, cyclooxygenase 2; iNOS, inducible isoform of Nitric oxide synthase; ROS, reactive oxygen species; HO-1, heme oxygenase-1; NQO-1, NAD(P)H quinone oxidoreductase 1; PGE2, prostaglandin E2; NO, nitric oxide; IL-1β, interleukin-1β; IL1R, interleukin-1 receptor; APP, amyloid precursor protein; LRP1; Low-density lipoprotein receptor-related protein 1; IDE, insulin-degrading enzyme; RAGE, Receptor for advanced glycation end-products; JNK, c-Jun N-terminal kinases; GluN2B, N-methyl D-aspartate receptor subtype 2B; GFR, growth factor receptor; PI3K, phosphoinositide 3-kinases; Akt, protein kinase B; CREB, cAMP-response element binding protein; BDNF, Brain-derived neurotrophic factor; Drp1; dynamin-related protein-1; AChE, acetylcholinesterase; Ach, acetylcholine; ψ, mitochondrial membrane potential. This image is modified from [88].

Figure 7

Therapeutic window along with the toxic and lethal dose limit of intraperitoneally and orally administered TQ. (a) Toxic (n = 10) and non-toxic doses (n = 8) of TQ when intraperitoneally administered in animal models. (b) Toxic (n = 6) and non-toxic doses (n = 9) of TQ when orally administered in animal models. (c) LD50 values of TQ as determined after intraperitoneal (n = 3) and oral (n = 3) administration in animal models. n, number of test doses retrieved from ‘n’ number of studies [129,327,328,329,331,332,333,334,335,336]. Bold lines indicate medians. Boxes enclose 25th to 75th percentiles. Error bars enclose the data range, excluding outliers. Dots are data points of each tested dose; dots that are vertically outside the error bars are outliers, >1.5 times the interquartile range.

Figure 1

Research trends in black cumin. (A) Yearly appearance of publications. (B) Top 10 countries with the highest number of publications. (C) Document-wise proportional rate of publications. (D) Proportional rate of publications according to research areas. (E) Proportional rate of publications according to pharmacological effects. The data were retrieved from the Scopus database in June 2020.

Figure 2

Chemical structure of (A) terpenes and terpenoids, (B) phytosterols, (C) alkaloids, (D) tocols, and (E) polyphenols.

Figure 2

Chemical structure of (A) terpenes and terpenoids, (B) phytosterols, (C) alkaloids, (D) tocols, and (E) polyphenols.

Figure 2

Chemical structure of (A) terpenes and terpenoids, (B) phytosterols, (C) alkaloids, (D) tocols, and (E) polyphenols.

Figure 2

Chemical structure of (A) terpenes and terpenoids, (B) phytosterols, (C) alkaloids, (D) tocols, and (E) polyphenols.

Figure 2

Chemical structure of (A) terpenes and terpenoids, (B) phytosterols, (C) alkaloids, (D) tocols, and (E) polyphenols.

Figure 2

Chemical structure of (A) terpenes and terpenoids, (B) phytosterols, (C) alkaloids, (D) tocols, and (E) polyphenols.

Figure 4

Plausible anticancer mechanism of black cumin, TQ, and essential oil: triggering cellular apoptosis and cell cycle arrest by targeting multiple signaling pathways. Black cumin and its components provoked cancer-cell specific apoptosis via altering several signaling cascades, including PI3K/Akt/mTOR, Wnt/β-catenin, and NF-κB signaling. Black cumin and its components also caused DNA damage that involves several mechanisms such as ROS induction and subsequent increase in oxidative stress and mitochondrial dysfunction which eventually increase Bax/Bcl-2 ratio through c-Jun N-terminal kinase (p-JNK) pathway. Black cumin also suppressed Cyclin B1 and CDK1/2 expression through regulating STAT3 and MAPK pathways and caused cell cycle arrest. ROS, reactive oxygen species; MAPK, mitogen-activated protein kinase; STAT3, signal transducer and activator of transcription-3; JNK, c-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; CDK1/2, cyclin-dependent kinase 1/2; Cyclin B1, regulatory protein of maturation-promoting factor.

Figure 5

Hypothetical illustration showing black cumin action mechanism on reproduction. At the molecular level, black cumin exhibits its beneficial effects on reproduction via three major pathways: (1) adjust hormonal homeostasis, (2) enhance antioxidant capacity of reproductive tissue/cells, and (3) facilitate proper growth and maturation of germ cells and associated organs. A more detailed description of black cumin action can be found in the main text.

Figure 6

Comprehensive molecular mechanism of black cumin and TQ-mediated pharmacological actions. The general pharmacological effects are manifested by their capacity to attenuate oxidative stress by activating the antioxidant defense system (Nrf2 signaling), inhibit inflammation by activating anti-inflammatory signaling (NF-κB and TLR signaling), induce immunity by modulating innate and adaptive immune components, prevent apoptosis by upregulating pro-survival signals and downregulating pro-apoptotic signals (PI3K/Akt, JNK, and mTOR signaling). Other significant molecular mechanisms include induction of autophagy (SIRT1 signaling), priming of energy metabolism (AMPK-SIRT1-PGC-1α and PPARγ signaling), activation of growth factor signaling (PI3K/Akt signaling), and enhancement of protein clearance by upregulating LRP1. Through employing multiple of these pharmacological mechanisms, black cumin and TQ exerted their health benefits including protection against metabolic (obesity, dyslipidemia, and diabetes), cardiovascular, digestive, renal, hepatic, osteogenic, respiratory, reproductive, neurological and mental disorders, and various types of cancer.