Table 1.

In vivo and in vitro studies on the effect of different types of honey

Effect of honey in in vivo study
A combination of insulin and honey	This combination inhibited neuronal cell death in different hippocampal areas of streptozotocin-induced diabetic rats [56].
Alimento Supervis and Alimento Mieleucalipto, which are derived from chestnut honey	Oral pretreatment (2 g/kg), once daily for 7 consecutive days, prevented indomethacin-induced gastric lesions in rats by reducing the ulcer index, microvascular permeability, and myeloperoxidase activity of the stomach [70].
Tualang honey (TH)	TH has almost the equal effects when compared with the conventional treatment in treating alkali injury on rabbit’s eye based on no significant difference in the level of total antioxidant status as well as lipid peroxidation products in aqueous humour, vitreous humour and serum between honey treated and the conventional treated group [71].
Manuka honey (MH)	MH significantly increase enzymatic (GPx and SOD), nonenzymatic (GSH) antioxidants levels and anti-inflammatory cytokine IL-10 levels. It normalized cell cycle distribution and significantly lowered apoptosis in gastric mucosa [72].
Honey	Intrarectal honey administration is as effective as prednisolone treatment in an inflammatory model of colitis [73].
Honey	Honey prevented gastric mucosal lesions induced by ethanol, indomethacin, and acidified ASA. The protection was almost total when using ethanol or acidified ASA as a damaging agent; whereas protection against indomethacin was moderate [74].
Honey	Honey significantly increased CAT, GR, TAS, TGSH, GSH and GSH:GSSG ratio and significantly reduced activities of SOD and GPx, MDA levels and FPG in diabetic rats [75].
Melipona marginata honey (MMH)	MMH reduced ear edema and reactive oxygen species production. It also decreased the myeloperoxidase activity [34].
Honey	Honey suppressed the phosphorylation of NFkB in cisplatin-induced kidney dysfunction [76].
Honey	There was almost 100% protection against gastric damage with the highest dose (5 g/kg) of honey used. However, there was only partial protection (58%) against ethanol-induced gastric lesions [77].
Honey	Honey significantly increased high density lipoprotein (HDL) cholesterol while it significantly reduced hyperglycemia, triglycerides (TGs), very low-density lipoprotein (VLDL) cholesterol, non-HDL cholesterol, coronary risk index (CRI) and cardiovascular risk index (CVRI). It also significantly reduced TGs and VLDL cholesterol [78].
Tualang honey (TH)	TH significantly reduced blood glucose levels compared to the diabetic control rats’ group. It significantly reduced elevated MDA levels and restored SOD and CAT activities [79].
Gelam honey (GH)	GH gave its anti-inflammatory effects by reducing the rat paw edema size and inhibiting the production of proinflammatory mediators NO, PGE2, TNF-α, and IL-6 in plasma, and suppress the expression of iNOS, COX-2, TNF-α, and IL-6 in paw tissue [80].
Gelam honey (GH)	GH exhibited its inhibitory effects by attenuating NF-kB translocation to the nucleus and inhibiting IkBa degradation, with subsequent decrease of inflammatory mediators COX-2 and TNF-a [55]
Mad honey or rhododendron honey	It significantly lowered MDA levels and TNF-α and MMP-9 expression, and increased antioxidant enzyme activities and IL-10 expression in male Wistar albino rats with streptozotocin-induced diabetes mellitus [81]
Honeybee venom (HBV)	Low doses of HBV have been shown to treat RA with anti-inflammatory and antioxidant effects, by preventing DNA damage. After low-doses of HBV treatment IL-1β, IL-6, TNF-α, TGF-β1, TOS, OSI, MPO and MNL-DNA damage levels significantly decreased according to the PC, while IFN-γ and TAS levels increased [82].
Trihoney (a combination of three types of natural honey namely: Trigona, mellifera, and Dorsata)	It significantly lowered serum IL-1β and IL-6 compared to the high cholesterol diet group of male New Zealand white rabbits and resulted in significant reduction of serum TNF-α compared to high cholesterol diet group [83].
Honey	It inhibited edema and pain in inflammatory tissues as well as showing potent inhibitory activities against NO and PGE2 in both non-immune inflammatory and nociceptive model, and lipopolysaccharide (LPS) in the immune inflammatory model [84].
Manuka Honey (MH)	In inflammatory model of colitis, oral administration of MH (5 g/kg) and combination with sulfasalazine (360 mg/kg) with MH (5 g/kg) significantly reduced the colonic inflammation [85].
Honey	Honey-treated in dextran sodium sulphate-induced colitis group significantly exhibited the down-regulation of oxidative, inflammatory, and apoptotic markers (interleukin-1β and − 6, superoxide dismutase, reduced glutathione, tumour necrosis factor-α, NO synthase, caspase-3, CD34, Ki67, S100, c-kit, and neuron-specific enolase) [86].
Effect of honey in in vitro study
A combination of Gelam honey and ginger extract	modulate Ras/ERK and PI3K/AKT pathway genes, upregulate caspase 9 and IκB genes accompanied by downregulation of the KRAS, ERK, AKT, Bcl-xL, NFkB (p65) genes in a synergistic manner in colon cancer HT29 cells [87].
A combination of Bee honey (BH) and Nigella sativa (NS)	significantly decrease in both the number of viable HepG2 cells and the levels of nitric oxide on one hand, but improvement of the total antioxidant status and caspase-3 activity [88].
Manuka honey (MH)	MH protected mitochondrial functionality, promoted cell proliferation, and activated the AMPK/Nrf2/ARE signaling pathway, expression of the antioxidant enzymes SOD and CAT in Primary Human Dermal Fibroblasts (HDFa) [89].
Stingless bee honey	Two out of eight stingless bee honey types (Meliponinae) from southern Brazil increase the secretion of anti-inflammatory cytokine (interleukin-10) in RAW 264.7 macrophages [90].
Kelulut honey	at a concentration of 1%; v/v significantly inhibited nitric oxide (NO) production in LPS-induced RAW 264.7 cells compared to control cells [91].
Tualang honey	inhibited UVB-induced DNA damage, and enhanced repair of UVB-mediated formation of cyclobutane pyrimidine dimers and 8-oxo-7,8-dihydro-2′-deoxyguanosine, inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in murine keratinocyte cell line, inhibited UVB-induced inflammatory cytokines and inducible nitric oxide synthase protein expression, inhibited UVB-induced COX-2 expression and PGE2 production [92].
Manuka honey (MH)	MH protected mouse RAW-264.7 macrophages against LPS-induced inflammation, by improving viability, promoting proliferation, reducing apoptosis, and enhancing energetic metabolism. These effects were linked to the capacity of MH in modulating the expression of several proteins involved in apoptosis, inflammation, metabolism, and mitochondrial biogenesis, such as caspase 3, p38, pErk1/2, AMPK, SIRT1 and PGC1α [93].
Manuka honey (MH)	MH inhibited LPS induced ROS and nitrite accumulation. It suppressed TNF-α, IL-1β and IL-6, and iNOS [94].
Honey	IL-6 secretion was remarkably reduced by all honey varieties in a comparable level indicating the potential anti-inflammatory property of arid region honey [95].
Greek thyme honey-derived monoterpene	significant apoptotic activity in PC-3 cells (prostate cancer cells), mediated, at least in part, through reduction of NF-κB activity and IL-6 secretion [96].
Honey ethyl acetate extract and honey methanol extract	The highest inhibition percentages of NO production in RAW264.7 cells treated with honey extracts after LPS and IFN-γ stimulation were 80% (4.3 μmol/L of NO) and 40% (16 μmol/L) for honey ethyl acetate extract and honey methanol extract (100 μg/mL), respectively [97].
Honey bee larva powder	exhibits anti-inflammatory activity by decreasing the production of nitric oxide (NO) and the cytokine level of interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage [98].
Honey bee (Apis mellifera) venom	inhibited lipid accumulation and C/EBPα and PPARγ gene expression during intermediate and late 3 T3-L1 cell differentiation. It also suppressed gene expression of pro-inflammatory cytokines (COX-2, iNOS, MCP-1, TNF-α, IL-1β and IL-6) in LPS-stimulated macrophages, and in co-culture of 3 T3-L1 adipocytes and RAW264.7 macrophages [99].
Honeys produced from Echium plantagineum L	decrease NO levels in lipopolysaccharide-stimulated murine macrophage-like cells (RAW 264.7) up to 40% at concentrations of 0.25 mg/mL [100].
Kelulut honey (KH)	KH exerted anti-inflammatory activity in LPS-induced RAW 264.7 cells, where a significant reduction in NO levels was observed at 1% compared to the untreated cells (LPS-induced RAW 264.7 cells) [91].
Honey from different floral sources, including Bidens pilosa, Dimocarpus longan, Litchi chinensis, Citrus maxima, and Aglaia formosana.	Honey from Bidens pilosa had significantly greater scavenging activities for 1,1-diphenyl-2-picrylhydrazyl (DPPH·), more reducing power, higher antibacterial activity against gram-positive and gram-negative bacteria compared to others. However, B. pilosa honey showed little inhibitory activity against IL-8 secretion, compared to other honeys [101].
Honey proteins	Honey proteins/peptides fractionated by size exclusion chromatography into five peaks with molecular masses in the range of 2–450 kDa inhibit reactive oxygen species production in zymosan-activated human neutrophils and murine macrophages, significantly suppressed the nitric oxide production by LPS-activated murine macrophages, inhibited the phagocytosis latex bead macrophages, did not affect the production of IL-1β; however, TNF-α production was significantly suppressed [102].
Manuka honey (MH)	MH (0.5%) significantly increases the release of CXCL8/IL-8, CCL2/MCP-1, CCL4/MIP-1β, CCL20/MIP-3α, IL-4, IL-1ra, and FGF-13 while reducing proteinase 3 release in the anti-inflammatory-stimulated models. However, higher dose of MH (3%) significantly increased the release of TNF-α and CXCL8/IL-8 while reducing the release of all other analytes [103].
Tesco and Manuka honeys	Both honeys gave significant protective effect against H2O2-induced DNA damage in Caco-2 cells, following digestion [43].
Bracatinga (Mimosa scabrella Bentham) honeydew honeys	It reduced the nitric oxide secretion as well as the inflammatory mediators: tumor necrosis factor-alpha, interleukin-6, monocyte chemoattractant protein 1, interleukin-12p70, interferon-gamma and interleukin-10 [104].
Honeys (Manuka, pasture, and jelly bush)	All honeys significantly increased the TNF-α, IL-1β and IL-6 release from MM6 cells (and human monocytes) when compared with untreated and artificial-honey-treated cells. Jelly bush honey significantly induced the maximal release of each cytokine compared with manuka, pasture or artificial honeys. The effect of honey on wound healing may in part be related to the stimulation of inflammatory cytokines from monocytic cells [105].
Manuka honey (MH)	A 5.8-kDa component in MH stimulated the production of TNF-α via TLR4 which could improve wound healing [106].