Table 4.

The beneficial effects of TQ against COVID-19 pathophysiological effects.

COVID-19 Complications	Thymoquinone	References
Cardiac damage	-Protects against hyperlipidemia, cyclophosphamide, doxorubicin and diesel exhaust particle-induced cardiac damage or changes -Counteracts sepsis-induced elevation in p62 and increases beclin-1 expression -Reduced infarct size, improved cardiac function, reduced myocardial enzyme LDH and CK-MB activities and inhibited oxidative stress	[21,48,209,210,211,212]
Lung injury, ARDS, COPD, pulmonary fibrosis	-Inhibited nuclear factor kappa-B (NF-ĸB) in lung tissue -Ameliorates the pathological changes of chronic asthma, inhibits inflammatory changes by antagonizing IL-4/5, and a single dose prevented asthma in the guinea pig model -Showed anti-neoangiogenic effects through inhibition of expression of VEGFR2/PI3K/Akt-signaling pathway -Decreased the inflammatory and apoptotic index levels in rats exposed to cigarette smoke and showed anti-inflammatory and cytoprotective effects against cigarette smoke-induced COPD and LPS induced acute lung injury by COX inhibition -Downregulated pro-fibrosis genes and decreased oxidative stress in lung fibrosis -Counteracted emphysema in air alveoli, lymphoid hyperplastic cells activation surrounding the bronchioles, inflammatory cell infiltration -Ameliorated pulmonary arterial hypertension, Induced relaxation of the precontracted pulmonary artery and caused a decrease in the tension of pulmonary arterial rings precontracted with phenylephrine -Reduced alterations in lungs and inflammatory markers induced by cyclophosphamide and toluene, decreased lipid peroxidation and restored antioxidants -Showed inhibitory effects on the aggregation of inflammatory cells in bronchoalveolar lavage (BAL) fluid and in lung tissues -Significantly decreased serum IgE and showed superior inhibitory effects on iNOS and TGF-β1	[22,213,214,215,216,217,218,219,220,221,222,223]
Liver injury, elevated liver enzymes	-Effectively improved the plasma and liver antioxidant capacity and enhanced the expression of liver antioxidant genes of hypercholesterolemic rats -Protects against oxidative liver damage and ductular proliferation -Reduced liver injury and tumor markers expressions;thus its beneficial in the treatment of hepatocellular carcinoma -Protected against cyclophosphamide, tamoxifen, cypermethrin, cadmium, anti-TB drugs, aflatoxinB1, acetaminophen and paracetamol-induced hepatotoxicity/necrosis/cirrhosis and fibrosis by decreasing the elevated ALT, AST and ALP, enhanced regeneration after tissue damage, decreased oxidative protein damage and increased SOD expression and GSH -Ameliorated liver fibrosis via blocking TLR4 expression and PI3K phosphorylation on the activated hepatic stellate cells -Reduced thioacetamide-induced liver fibrosis and inflammation by decreasing proinflammatory cytokines, inhibiting PI3K phosphorylation and enhanced p-AMPK and liver kinase B (LKB-1)	[20,23,24,53,153,224,225,226,227,228,229,230,231,232]
Kidney damage	-Attenuated oxidative stress and inflammation-reducing renal ischemia-induced damage and several drugs-induced nephrotoxicities -Reversed the vancomycin and doxorubicin-induced nephrotoxicity, reversed elevated serum blood urea nitrogen, creatinine, MDA and urinary albumin excretion -Protected kidney against urinary tract infections (Escherichia coli) induced pyelonephritis -Showed protective action against cypermethrin induced shrinkage of glomeruli and necrosis of renal tubules in kidneys (in mice)	[24,25,226,233,234]
Neurological disease, cognitive decline	-Induced a significant increase in expression of neuroprotective proteins such as biliverdin reductase-A, 3-mercaptopyruvate sulfurtransferase, glutaredoxin-3, and mitochondrial Lon protease, a significant decrease in expression of inflammatory cytokines, and NF-κB pathway -Decreased malondialdehyde and nitric oxide metabolites in the brain -Enhanced the thiol content and superoxide dismutase and catalase activities and serum T4 level -Protected against PTU-induced memory impairments in rats -Reversed learning and memory impairments, brain tissue-oxidative damage in hypothyroid juvenile rats and alleviated changes in the hippocampal lipid peroxide level and SOD and AChE activities -Have a protective effect on learning and memory function. It significantly increased the expression of Nrf2, HO-1 proteins and SOD in the hippocampus	[51,235,236,237]
GIT	-Showed significant antimicrobial activity against anaerobic bacteria, thus can be used against diarrhea -Prevented and significantly reduced the appearance of diarrhea and body weight loss in mice and ameliorates dextran sulfate sodium-induced colitis -Inhibited proton pump, acid secretion and neutrophil infiltration, while enhancing mucin secretion, reduces ulcer index, markers of oxidative stress and nitric oxide production -TQ+ ranitidine showed synergistic effects and a more significant decrease in ulcer index -Suppressed spontaneously contracting rabbit jejunum and also relaxed high K induced contractions in the jejunum and guinea-pig ileum, thus can be used in colic and diarrhea	[18,26,44,45,238]
Allergy, allergic conjunctivitis	-Inhibited histamine production -Decreases the symptoms of allergic conjunctivitis almost the same as dexamethasone -Suppressed the Total IgE, OVA-specific IgE and Recruitment of Inflammatory cells -Alleviated allergic inflammation and may be valuable for treating allergic rhinitis	[239,240]
Acute pancreatitis and elevated lipase	-Decreased lipase\amylase ratio -Decreased oxidative stress markers, pancreatic 4-hydroxynonenal (4-HNE), protein carbonyl content and protected pancreatic acinar cells from oxidative stress -Attenuated GSH depletion and increased the activity of GST	[16,241]

Abbreviations: LDH: lactate dehydrogenase; CK-MB: creatininekinase-MB; ARDS: acute respiratory distress syndrome; COPD: chronic obstructive pulmonary disease.