Challenges and opportunities in the treatment of ulcerative colitis

Table 2 Medicinal plants used for the treatment of ulcerative colitis with their mechanism of action

Sr. No.	Plant	Mechanism	Ref.
1	Acacia ferruginea	Acacia ferruginea extract significantly resist UC via modulation of oxidant/anti-oxidant balance and inhibition of inflammatory mediators. Extract inhibited the activation and translocation of transcription factors (NF-κB subunits (p65/p50)	[37]
2	Passiflora edulis	Passiflora edulis peel can significantly resist 2,4,6-trinitrobenzenesulphonic acid-induced ulcerative colitis by modulating microbiota and could be used as a source of fiber and polyphenols in the prevention of oxidative stress through the improvement of serum and tissue antioxidant status	[38]
3	Arnebia euchroma	Effectiveness of a hydroxynaphthoquinone fraction from Arnebia euchroma was evaluated with TNBS-induced UC. The underlying mechanism may be associated with TNF-α inhibition in colonic tissue with the dose of 10 mg/kg	[39]
4	Cannabis	Cannabis had been used successfully to relieve the symptoms associated with IBD by inhalational route	[40]
5	Rhizophora apiculata	R. apiculata significantly resist acetic acid induced colitis in experimental mouse model by increasing anti-oxidant enzymes such as SOD and GSH and reducing LPO, NO and inflammatory mediators such as MPO, LDH, iNOS, COX-2 and TNF-α expressions. And also inhibits the translocation of NF-κB p65 and p50 subunits	[41]
6	Hymenaea stigonocarpa	Total flavonoid of stem bark extract and fruit pulp flour of Hymenaea stigonocarpa significantly resist TNBS-induced colonic damage in rats. Its mechanism may be related to inhibition of MPO and AP activities, reduction in colon MDA content, and counteraction of GSH depletion induced by inflammatory process	[42]
7	Helicteres angustifolia	Aqueous extract of Helicteres angustifolia significantly resist UC induced by TNBS by keeping balance of inflammatory factors in blood and also by improving increasing expression of IL-10 and decreasing the expressions of IL-6 and TNF-α	[43]
8	Ilex kudingcha	Methanol extracts of Ilex kudingcha increased glutathione and reduced colonic myeloperoxidase and malondialdehyde levels in the colon tissue and prevented edema, mucosal damage and loss of crypts. It also decreased anti-inflammatory effects by decreasing the levels of TNF-α, IL-1β and IL-6 in the colon tissues on 3% DSS-induced UC in mice	[44]
9	Peony	TGP showed positive effect in 2,4,6-trinitrobenzene sulfonic acid TNBS/ethanol-induced colitis by significant improvements of DAI, CMDI, HPS, and MPO activity. Moreover, administration of TGP (50 or 100 mg/kg per day) decreased the up-regulated levels of serum TNF-α and IL-1β, and expression of TNF-α and IL-1β mRNA and protein in colonic tissues, and increased the serum IL-10 and colonic IL-10 mRNA and protein level	[45]
10	Olea europaea	Total phenolic secoiridoid of oleuropein, the major phenolic secoiridoid in Olea europaea significantly resisted dextran sodium sulfate-induced chronic colitis in mice. It decreased inflammatory cell and released the inflammatory cytokines IL-1β and IL-6 with increased IL-10 levels in colon tissue. The anti-inflammatory mechanism of oleuropein was associated with the suppression of the phosphorylation of p38 mitogen-activated protein kinase and might be mediated by up-regulation of annexin A1	[46]
11	Plumbagin plants	Naphthoquinone constituent of Plumbagin plants significantly resist ulcerative colitis in mice by reducing the levels of proinflammatory cytokines (TNF-α, IFN-γ, and IL-17) but cytokine levels remained unaffected with restoration of goblet cells in colon of mice	[47]
12	Euphorbia granuleta	Alcohol extracts of Euphorbia granuleta (Euphorpiaceae) significantly resist UC by reducing the pro-inflammatory cytokine TNF-α and colonic MDA contents	[48]
13	Amaranthus roxburghianus	Combination of hydroalcoholic extract of roots of A. roxburghianus and piperine showed minimal ulceration, hemorrhage, necrosis and leucocyte infiltration and significantly reduced malondialdehyde and myeloperoxidase levels and increased glutathione levels in blood and tissue	[49]
14	Curcumin	Oral curcumin extract decreases colon injury with decreased inflammatory reactions, lipid peroxidation, apoptotic cell death, and modulating p38- and JNK-MAPK pathways in acetic acid-induced colitis	[50]
15	Bauhinia tomentosa	Extract of Bauhinia tomentosa significantly inhibit colitis by regulating the antioxidant and inflammatory mediators with decreasing myeloperoxidase, tumor necrosis factor and inducible nitric oxide synthase expression on acetic acid induced ulcerative colitis	[51]
16	Cistanche tubulosa	Echinacoside enriched extract of Cistanche tubulosa significantly resist DSS-induced colitis by protecting intestinal epithelium from inflammatory injury and by upregulating TGF-β1 which enhanced in vitro wound healing activity as well as with an increase in the number of Ki67(+) proliferating cells in diseased colons	[52]
17	Garcinia kola	A natural biflavonoid, kolaviron from the seeds of Garcinia kola significantly increase the inflammatory mediators, IL-1β and tumour necrosis factor alpha, in the colon of DSS-induced ulcerative colitis in rats The anti-colitis effect of kolaviron is related to its intrinsic anti-inflammatory and anti-oxidative properties	[53]
18	Marine mangrove Avicennia marina	Marine mangrove Avicennia marina extract significantly decreased the colonic lipid peroxides, glutathione peroxidase, serum nitric oxide and significantly increased the colonic and erythrocyte superoxide dismutase and glutathione levels against acetic acid-induced colitis due to the presence of higher levels of decanoic acid, DEHA, pentanoic acid, pyrrolidine, 4-chlorophenyl, thiazolidinones, and arabinopyranoside (flavonoid)	[54]
19	Soy extract	FSG with standardized isoflavone and stable BBI content exert cumulative or synergistic protection based on protease inhibition and ER-ligand activity in colitic rats. It improved the severity of colitis, by decreasing the TNBS-induced rise in gut permeability, visceral sensitivity, faecal proteolytic activity and PAR-2 expression at all post-TNBS points	[55]
20	Aegle marmelos	Effect of Aegle marmelos unripe fruit extract was studied on acetic acid induced ulcerative colitis and indomethacin-induced enterocolitis in Wistar albino rats. Its mechanism is related with protection in mast cell degranulation by significantly decreasing the MDA levels and increased SOD activity. Extract produced anti-inflammatory, antioxidant, and mast cell stabilizing effects demonstrating protective effect in inflammatory bowel disease	[56]
21	Andrographis paniculata	A. panculata extract at a dose of 1800 mg daily were found to be effective in the treatment of ulcerative colitis	[57]
22	Terminalia chebula	Fruit pulp of Terminalia chebula TCE (600 mg/kg) shows healing effect against acetic acid induced colitis in rats. TCE showed antibacterial activity and both TCE and SS enhanced the antioxidants, but decreased free radicals and myeloperoxidase activities affected in acetic acid-induced colitis	[58]
23	American ginseng	HAG cause apoptosis and suppress mouse colitis through a p53-mediated mechanism. HAG might be very effective in targeting the inflammatory cells and cancer cells since it induces apoptosis of inflammatory cells and cell cycle arrest in both p53-/- and WT p53 colon cancer cells	[59]
24	Vaccinium myrtillus	Anthocyanins from Vaccinium myrtillus were shown to have antioxidative and anti-inflammatory effects are useful in the treatment of UC	[60]
25	Moringa oleifera and Citrus sinensis	Results show that a combination of Moringa oleifera root extracts with Citrus sinensis fruit rind extract is effective in the treatment of UC and results are comparable with the standard drug prednisolone. The combination reduced the levels of MPO and MDA in blood and tissue	[61]
26	Lavandula intermedia	Lavandula intermedia protected acute colitis in a mouse model of caused by Citrobacter rodentium. It reduced intestinal tissue damage, and decreased infiltration of neutrophils and macrophages, with reduced levels of TNF-α, IFN-γ, IL-22, macrophage inflammatory protein-2α, and inducible nitric oxide synthase expression	[62]
27	Chelidonium majus	The CA, a constituent of Chelidonium majus L., has protective effects against DSS-induced UC. CA was found to regulate levels of IL-6 and tumor necrosis factor-α in serum. In colonic tissues, prostaglandin E(2) production levels and COX-2 and HIF-1α expression levels were increased by DSS, but CA attenuated increases in COX-2 and HIF-1α levels	[63]
28	Boswellia serrata	Extracts of the plant Boswellia serrata showed significant reduction in lipid peroxidation and SOD level and GPx glutathione level increased significantly. The activity might be due to presence of antioxidant substances	[64]
29	Apple polyphenol extract	Apple extract treatment reduced the severity of colitis. Apple polyphenols reduced the degradation of tissue transglutaminase protein occurring through calpain action. The efficacy of apple extract is mediated by its effects on COX-2 and TNF-α. The unbalance between calpain and tissue transglutaminase may play a role in colonic damage and future therapeutic interventions in ulcerative colitis can target this mechanisms	[65]
30	Cordia dichotoma	The bark of Cordia dichotoma f. (Boraginaceae) was used in the treatment of ulcerative colitis. Apigenin (5 mg/kg, p.o.) isolated from methanol extract of C. dichotoma bark showed significant healing and reduction in inflammatory enzymes when screened for UC	[66,67]
31	Vitex negundo	Ethanol extract of Vitex negundo Linn. (Verbenaceae) root is effective in the treatment of UC. Extract reduced MPO and MDA levels in blood and tissue	[68]

UC: Ulcerative colitis; TNBS: 2,4,6-trinitrobenzene sulfonic acid; IBD: Inflammatory bowel disorders; SOD: Superoxide dismutase; GSH: Glutathione; LPO: Lipid peroxides; NO: Nitric oxide; MPO: Myeloperoxidase; LDH: Lactate dehydrogenase; iNOS: Nitric oxide synthase; COX-2: Cyclooxygenase-2; TNF-α: Tumor necrosis factor-α; AP: Alkaline phosphatase; MDA: Malondialdehyde; DSS: Dextran sulfate sodium; TGP: Total glucosides of peony; CMDI: Colon macroscopic damage index; DAI: Disease activity index; HPS: Histopathological score; IL: Interleukin; TGF: Transforming growth factor; DEHA: Diethylhydroxylamine; FSG: Fermented soy germ extract; BBI: Bowman-birk bnhibitors; ER: Estrogen receptor; HAG: Hexane fraction of American ginseng; CA: Chelidonic acid; HIF-1α: Hypoxia induced factor-1α; GPx: Glutathione peroxidase.