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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.
Black cumin and TQ have shown their therapeutic promises against a range of neurological conditions, including neurodegenerative disorders (Alzheimer’s disease (AD), and Parkinson’s disease (PD)), ischemic stroke and acute brain injury, anxiety and depression, epilepsy, and schizophrenia (Table 1). Moreover, black cumin and TQ were shown to protect against various chemical-induced neuronal injury in experimental conditions (Table 1). The neuroprotective potentials of black cumin and TQ mostly stem from antioxidative and anti-inflammatory properties [21] (Figure 1).
Treatment with Doses | Experimental Model | Major Findings (Including Molecular Changes) |
References |
---|---|---|---|
Neuroinflammation | |||
TQ (12.5 μM for 24 h) |
LPS/IFNγ or H2O2-activated BV-2 microglial cell | ↓H2O2; ↑GSH; ↑SOD and CAT | [14] |
TQ (12.5 μM for 24 h) |
LPS/IFNγ or H2O2-activated BV-2 microglial cell | ↑Glutaredoxin-3, biliverdin reductase A, 3-mercaptopyruvate sulfurtransferase, and mitochondrial Lon protease; ↓IL-2, IL-4, IL-6, IL-10, and IL-17a, CFB, CXCL3 and CCL5 | [22] |
TQ (2.5–10 μM) |
LPS-activated neuroinflammation in BV-2 microglial cell | ↓ROS; ↑LKB1 and AMPK; ↑nuclear accumulation of SIRT1 | [23] |
Alzheimer’s disease | |||
TQ (100 nM) |
Aβ1–42-induced neurotoxicity in hiPSC-derived cholinergic neurons | ↑GSH; ↓ROS; ↓synaptic toxicity, attenuate cell death and apoptosis | [24] |
TQ fraction rich nanoemulsion of seeds (TQRFNE) (250 and 500 mg/kg BW) |
High fat/cholesterol diet-induced neurotoxicity in rats | ↓Aβ40 and Aβ42; ↑APP; ↓PSEN1 and PSEN2; ↓BACE1 and RAGE; ↑IDE and LRP1 | [25] |
TQ fraction rich nanoemulsion of Nigella seeds (TQRFNE) (250 and 500 mg/kg BW) |
High fat/cholesterol diet-induced neurotoxicity in rats | ↓Memory impairment; ↓lipid peroxidation and soluble Aβ levels; ↑total antioxidant status and antioxidants genes expression | [26] |
TQ (10, 20, and 40 mg/kg/day p.o. for 14 days) |
Combined AlCl3andD-Gal-induced AD in rats | Improved cognitive deficits; ↓Aβ formation and accumulation; ↓TNF-α and IL-1β; ↓TLRs pathway components; ↓NF-κB and IRF-3 mRNAs | [27] |
TQ (intragastrically, 20 mg/kg/day once daily for 14 days) |
Combined AlCl3 and D-Gal induced neurotoxicity in rats | ↑ Memory performance; ↑ SOD; ↓TAC; ↓MDA; ↓NO; ↓TNF-α; ↓AChE activity; ↑BDNF and Bcl-2 | [28] |
TQ (intragastrically, 20 mg/kg/day for 15 days) |
Aβ (1–42) infused rat model of AD | ↓Memory performance (Morris water maze test); ↓IFN-γ; ↑ DCX and MAP2 | [29] |
Parkinson’s disease | |||
TQ (100 nM) |
α-Synuclein-induced rat hippocampal and hiPSC-derived neurons | ↑Synaptophysin; ↓synaptic vesicle recycling; ↑spontaneous firing activity | [30] |
TQ (10 mg/kg BW, 1 week prior to MPTP at 25 mg/kg BW) |
MPTP-induced mouse PD model | ↓MDA; ↑GSH; ↑SOD; ↑CAT; ↓IL-1β and IL-6; ↓TNF-α; ↓COX-2 and iNOS; ↓α-synuclein aggregation | [31] |
TQ (7.5 and 15 mg/kg/day, p.o.) |
Rotenone-induced rat PD model | ↓Oxidative stress; ↑Parkin; ↓ Drp1; ↑dopamine; ↑TH levels | [32] |
Ischemic stroke | |||
Hydroalcoholic seed extract (20 mg/kg BW) |
Global ischemia in rats | ↓Brain edema and infarct volume; ↑VEGF, HIF and MMP9 | [33] |
TQ | Stroke-prone spontaneously hypertensive rats | ↓Chemoattractant protein-1, Cox-2, IL-1β, and IL-6 | [34] |
Traumatic brain injury | |||
TQ (5 mg/kg/day for seven days) |
Feeney’s falling weight-induced moderate head trauma | ↑Neuron densities; ↓MDA | [35] |
Anxiety and Depression | |||
Ethanolic seed extract | Chronic stress-induced depression model | ↓NO | [36] |
TQ-loaded solid lipid nanoparticle (20 mg/kg, p.o.) and TQ (20 mg/kg, p.o.) |
Chronic stress-induced depression model | ↓IL-6, TNFα; ↑BDNF; ↑5-HT; ↑IDO | [37] |
NSO (0.2 mL/kg for 20 days) |
Stress-induced depression model | ↑Memory performance (FST) | [38] |
Hydroalcoholic seed extract (200 and 400 mg/kg) |
Stress-induced depression and anxiety model | ↑Anxiolytic (Open field and elevated plus-maze test); ↓depression (FST) | [39] |
Epilepsy | |||
Ethanolic seed extract (400 mg/kg/day, p.o.) | PTZ-induced kindling mode | ↓Kindling development; ↑memory performance (Morris water maze test); ↓LTP | [40] |
NSO (400 and 600 mg/kg BW) | Electroshock-induced seizures | ↑Anticonvulsant activity | [41] |
TQ (10 mg/kg, i.p) |
Lithium chloride and pilocarpine-induced seizure | ↑Memory performance; ↑SOD; ↑Nrf2, HO-1 | [42] |
TQ (10 mg/kg, i.p) |
Lithium chloride and pilocarpine-induced seizure | ↑Memory performance; ↓COX-2, TNF-α and NF-κB | [43] |
Hydroalcoholic seed extract (200 and 400 mg/kg for 5 days) |
PTZ-induced seizure model | ↑Memory performance (Morris water maze and passive avoidance test); ↑ total thiol; ↓MDA | [44] |
Schizophrenia | |||
TQ (20 mg/kg, daily for 28 days, i.p.) |
Mice model of schizophrenia (haloperidol-induced catalepsy and apomorphine-induced climbing behavior) |
Anti-amnesic effect; ↓AChE activity; ↓ TBARS; ↑GSH and catalase; ↑dopamine level | [45] |
Miscellaneous effects | |||
Chemical-induced toxicity | |||
TQ (5 mg/kg, i.p. for 11days) |
Acrylamide-induced neurotoxicity in rats | Improved gait abnormalities; ↑GSH; ↓MDA;↓caspases 3 and 9, and Bax/Bcl-2, pP38/P38 and pJNK/JNK; ↓pERK/ERK; restore BBB integrity | [46] |
TQ (5 and 10 mg/kg, i.p., for 11 days) |
Acrylamide-Induced Peripheral Nervous System Toxicity in rats | Improved gait abnormalities; ↑GSH and ↓MDA;↓caspases 3 and 9, and Bax/Bcl-2, pP38/P38 and pJNK/JNK; ↓pERK/ERK | [47] |
TQ (10 µM and 20 µM) |
Arsenic-induced cytotoxicity in SH-SY5Y cells | Promotes DNA repairing; ↓ROS, balanced transmembrane potential; ↓ Bax and PARP-1, and ↑Bcl-2 | [48] |
TQ (5 mg/kg/day, for 3 days, p.o.) |
Arsenic-induced hippocampal toxicity in rats | Improve anxiety behavior (Open field test and elevated plus maze); ↑GSH and SOD; ↓DNA damage; ↓TNF-α and INF-γ | [49] |
TQ (2.5 and 5 mg/kg BW, for 8 days, p.o.) |
Arsenic-induced hippocampal toxicity in Wistar rats | ↑Δψm | [50] |
NSO (1 mL/kg BW for 7 days) |
Dichlorvos-induced oxidative and neuronal damage in rats | ↓Vacuolation in the frontal and cerebellar cortices;↑TAC and GSH↓ROS | [51] |
Radiotoxicity | |||
TQ | Radiation-induced oxidative stress in brain tissue | ↑Antioxidant enzymes | [52] |
Black cumin and its compounds are widely known for their potent anticancer actions. Accumulating evidence suggests that chemical constituents of black cumin seeds are chemopreventive and potent in inhibiting cell proliferation and provoking apoptosis (Table 2). In a recent study, administration of black cumin seed ethanolic extract (250 mg/kg; p.o. for 5 days) was reported to attenuate diethylnitrosamine (DENA)-induced liver carcinogenesis and reduce serum AFP and VEGF levels and liver HGFβ protein in rats [54].
Treatment with Doses | Experimental Model | Major Findings (Including Molecular Changes) |
References |
---|---|---|---|
Seeds incorporated silver nanoparticles (NS-AgNP) (25–200 µg/mL) |
Human breast cancer cell line (HCC-712) | Dose-dependent cytotoxicity; ↓cell density | [55] |
Aqueous seed extract (11.5 µg/mL) |
Human breast cancer cell line (MCF-7) | Potent cytotoxic effect with IC50 11.5 µg/mL; ↑caspase-3,8 and 9, and Bax | [56] |
NSO nanoemulsion (10–100 µL/mL) |
Human breast cancer cell line (MCF-7) | ↓Cell proliferation; ↑apoptosis and necrosis | [57] |
TQ (25 µmol/L) |
Human breast cancer cell line (MCF-7) | Inhibit tumor cell growth; ↑p53; induce apoptosis | [58] |
Seeds incorporated platinum nanoparticles (NS-PtNP) (25, 50, 100 and 150 µg/mL) |
HeLa cervical cancer and MDA-MB-231 breast cancer cell lines | Dose-dependent cytotoxic effect with IC50 value 36.86 µg/mL (MDA-MB-231) and 19.83 µg/mL (HeLa), respectively | [59] |
TQ (0.78 µM) |
HeLa cervical cancer cell line | Dose-dependent antiproliferative effect | [60] |
TQ (2, 4, 6 and 8 µM) |
Human colon cancer cell line (LoVo) | Inhibit metastasis; ↑JNK, p38; ↓P13K, ERK1/2, IKKα/β and NF-κB | [61] |
TQ (20 µmol/L) |
Human colon cancer cell line (LoVo) | Reduce cell proliferation; ↓p-P13K, p-Akt, p-GSK3β, β-catenin and COX-2; ↓PGE2, LEF-1 and TCF-4 | [62] |
TQ (10–120 µmol/L) |
Human bladder cancer cell lines (253J and T24) | Inhibit proliferation and metastasis; ↓MYC, Axin-2, MMP-7, MET and cyclin-D1; ↓Wnt/β-catenin signaling cascade | [63] |
TQ (40, 60 and 80 µM) |
Human bladder cancer cell lines (253J and T24) | Significant cytotoxicity and reduction in cell proliferation; ↑caspase-3, cleaved PARP, Bax, cyt c and AIF; ↑ER-stress marker GRP78, IRE1, ATF6, ATF4 and CHOP; ↓Bcl-2 and Bcl-xl; induce apoptosis | [64] |
TQ (10–50 µM) |
Pancreatic ductal adenocarcinoma cell lines (AsPC1 and MiaPaCa-2) | Inhibit cell viability; reduce tumor size; ↑p53, p21; ↓Bcl-2 and HDAC; induce apoptosis and G2 cell cycle arrest | [65] |
TQ (0.5–20 µM) |
Human renal tubular epithelial cell line (HK2) and human renal cancer cell lines (769-P and 786-O) | Inhibit metastatic phenotype and epithelial-mesenchymal transition; ↑E-cadherin; ↓Snail, ZEB1 and vimentin; ↑LKB1/AMPK signaling | [66] |
TQ (0–100 µmol/L) |
Human renal cancer cell lines (ACHN and 786-O) | Inhibition of metastasis; ↑LC3; ↑AMPK/mTOR signaling; induce autophagy | [67] |
TQ (40 and 50 µM) |
Human kidney cancer cell lines (A498 and Caki-1) | Anti-proliferative effects with GI50 value 40.07 µM (A498) and 51.04 µM (Caki-1), respectively; ↑Bax; ↓Bcl-2 and p-Akt; induce apoptosis | [68] |
Hexanic seed extract (0–150 µg/mL) |
Human ovary cancer cell line (A2780) | Strong cytotoxic activity of SF2 with IC50 10.89 µg/mL; ↑caspase-3 and 9; ↓MMP; induce apoptosis | [69] |
Seed extract and NSO with OM-90(0.5 and 2.4 mg/mL) | AGS human gastric adenocarcinoma cell line | Activates mitochondrial pathways; induce apoptosis | [70] |
TQ (0.1–30 µM) |
Human prostate cancer cell lines (PC3 and DU145) | Inhibit metastatic phenotype and epithelial-mesenchymal transition; ↓TGF-β, Smad2 and Smad3 | [71] |
TQ (0–80 µM) |
Head and neck squamous cells carcinoma cell lines (SCC25 and CAL27) | Dose-dependent cytotoxicity with IC50 value 12.12 µM (CAL27) and 24.62 µM (SCC25), respectively; induce apoptosis | [72] |
TQ + Resveratrol (46 µM) |
Hepatocellular carcinoma cell line (HepG2) | Significant cell inhibition; ↑caspase-3; ↓GSH and MDA; induce apoptosis | [73] |
NSO (50–250 µg/mL) |
Human liver cancer (HepG2), human breast cancer (MCF-7), human lung cancer (A-549) and normal human embryonic kidney (HEK293) cell lines | High cytotoxic effect in HepG2 cells with IC50 48µg/mL; ↑ROS and LPO; ↓GSH and MMP; ↑p53, caspase-3 and 9, Bax; ↓Bcl-2; induce apoptosis | [74] |
TQ (In vitro: 1–50 µMIn vivo: 20 and 100 mg/kg for 3 days; i.v.) |
TNBC cells and orthotopic TNBC xenograft mice model | Inhibit cell proliferation, migration and invasion; ↓tumor growth; ↓eEF-2K, Src/FAK and Akt | [75] |
TQ + Paclitaxel (In vitro: 0–100 µM In vivo: 2.4 mg/kg/day for 12 days; i.p) |
Mouse breast cancer cell line (4T1) and EAC cells-induced female Balb/c mice model | Dose-dependent cytotoxicity; ↑caspase-3,7 and 12, PARP; ↓p65, p53 and Akt1; ↓JAK-STAT signaling | [76] |
Ethanolic seed extract (250 mg/kg/day for 5 days, p.o.) |
Diethyl nitrosamine-induced hepatocarcinogenesis in Wistar rat model | Antiangiogenic effect; ↓serum VEGF and AFP levels, and liver HGFβ level | [54] |
Ethanolic seed extract and TQ (150, 250 and 300 mg/kg (extract) 6 days/week and 20 mg/kg (TQ) for 3 days/week, p.o.) |
Diethyl nitrosamine-induced hepatocellular carcinoma in albino-Wistar rat model | Reduction in cell proliferation; ↑Antioxidant activity; ↓PCNA, c-fos, Bcl-2; ↓EGFR/ERK1/2 signaling | [77] |
TQ + 5-fluorouracil (35 mg/kg/day for 3 days/week for 9 weeks; p.o.) |
Azoxymethane-induced colon cancer in Wistar rat model | Subdues tumor growth; ↑TGF-β1, TGF-β/RII, Smad4, DKK-1, CDNK-1A and GPx; ↓Wnt, β-catenin, NF-κB, VEGF, COX2, iNOS and TBRAS | [78] |
TQ + Piperine (10 mg/kg/day for 14 days; i.p) |
EMT6/P cells- inoculated Balb/c mice | Inhibit angiogenesis; ↓Tumor size; ↑serum INF-ᵧ level; ↓VEGF; induce apoptosis | [79] |
TQ + Resveratrol (50 mg/kg/day for 14 days; i.p) |
EMT6/P cells- inoculated Balb/c mice | Inhibit angiogenesis; ↓Tumor size; ↑serum INF-ᵧ level; ↓VEGF; induce apoptosis | [80] |