Table 2.
Phytoceuticals effects in acute pancreatitis (animal studies) and their proposed mechanism of action.
| Animals/cell type used | Dose, route of administration, duration of the study |
AP model | Findings | Ref. |
|---|---|---|---|---|
| Artemisinin (sesquiterpene lactone) found in Artemisia annua, fam. Asteraceae and its derivatives | ||||
|
| ||||
| Male Wistar rats | 50 mg/kg artemisinin | i.p. 20 μg/kg cerulein, 4 inj. at 1 h interval | ↑ apoptosis, caspase-3, ↓ necrosis, amylase, pancreatic edema, inflammatory cell infiltration, NF-κB, MPO, MIP-1α protein, IL-1β mRNA |
[89] |
|
| ||||
| Male SD rats | 0.70, 1.75 and 3.50 mg/kg artesunate | r.i.BPD 3.5% sodium taurocholate | ↑ survival rate ↓ pancreatic necrosis, hemorrhage, amylase, lipase, pancreatic release of IL-1β and IL-6 |
[90] |
|
| ||||
| Baicalin (flavone glucuronide) found in Scutellaria spp., fam. Lamiaceae | ||||
|
| ||||
| SD rats | 5%, i.v.b. 10 mg/100 g f.c.i.v.i. 10 mg/h/100 g | r.i.BPD 3.5% sodium taurocholate | ↓ renal pathological changes, mortality, renal Bcl-2 protein, serum NO, plasma endotoxin, serum BUN, IL-6, ET-1, TNF-α, PLA2. ↑ renal apoptotic indexes, Bax protein |
[91] |
|
| ||||
| Male SD rats | 5%, i.v.b. 10 mg/100 g f.c.i.v.i. 10 mg/h/100 g | r.i.BPD 3.5% sodium taurocholate | ↓ TNF-α, P-selectin, ↑ caspase-3 (↑ apoptosis) | [92] |
|
| ||||
| SD rats | 5%, i.v.b. 10 mg/100 g f.c.i.v.i. 10 mg/h/100 g | r.i.BPD 3.5% sodium taurocholate | ↓ mortality, endotoxin, TNF-α ↑ Bax protein, apoptosis index |
[93] |
|
| ||||
| SD rats | 5%, i.v.b. 10 mg/100 g f.c.i.v.i. 10 mg/h/100 g | r.i.BPD 3.5% sodium taurocholate | ↓ mortality, pathological severity scores, plasma endotoxin, serum PLA2, ET-1, NO, P-selectin | [94] |
|
| ||||
| Crambene (nitrile) found in brussels sprouts and other plants from fam. Cruciferae | ||||
|
| ||||
| Female CD-1 mice | i.v.b. 70 mg/kg | i.p. 50 μg/kg cerulein, 12 inj. at 1 h interval (4, 12, 24, 48 hours after pre-trt.) | ↓ amylase, pancreatic edema, necrosis (12 h after pre-trt.) ↑ apoptosis, caspase-3, -8, -9 |
[51] |
|
| ||||
| Male Swiss mice | i.v.b. 70 mg/kg | i.p. 50 μg/kg cerulein, 3/6/10 inj. at 1 h interval (12 hours after pre-trt.) | ↑ apoptosis ↓ MCP-1, IL-1β,TNF-α ↑ IL-10, TGF-β1 |
[95] |
|
| ||||
| Curcumin (polyphenol/diarylheptanoid) found in Curcuma longa, fam. Zingiberaceae | ||||
|
| ||||
| Albino rats | i.p. 50 mg/kg/d × 6 d (pre-AP induction, post-AP induction or no-AP induction, resp.) | 250 mg/100 g L-arginine i.p., twice at an interval of 1 h | ↓ amylase, lipase, NAP78, protein carbonyls, TNF-α, MPO, pancreatic fgl-2 ↑ caspase-3 (apoptosis) |
[96] |
|
| ||||
| Male SD rats | i.p. 100 mg/kg | r.i.BPD 5% sodium taurocholate | ↓ ascites, amylase, TNF-α, TLR4, NF-κB, IL-10 | [97] |
|
| ||||
| WA rats | i.g. 100 mg/kg (curcumin in alcohol) 20 d before AP induction and all through the study | r.i.BPD 3% sodium taurocholate | ↓ total histopathologic scores, trypsin activity, NF-κB, AP-1, chemokine, TNF-α, IL-6, iNOS, NO ↑ caspase-3 activity |
[98] |
|
| ||||
| Kun Ming male mice | i.p. 50 mg/kg/d × 6 d | i.p. 50 μg/kg cerulein | ↓ pancreas injury, amylase, ALT, AST, TNF-α, NF-κB-p65 ↑ PPARγ |
[99] |
|
| ||||
| Male SD rats | i.v. 35 mg/kg/h × 6 h | i.v. cerulein (5 μg/kg/h) × 6 h and i.g.ethanol diet × 6 wk → i.v. CCK-8 (3 nmol/kg/h) × 6 h | ↓ pancreas injury (histologic changes, amylase, trypsin, neutrophil infiltration) ↓ NF-κB (↓ IκB degradation), AP-1, IL-6, TNF-α, chemokine KC, iNOS | [100] |
|
| ||||
| Male SD rats | i.p. 20 mg/kg | 2 h ischemia → 6 h reperfusion | ↓ amylase, HO∙, NO, TNF-α, WBC count; (lung) ↓ iNOS, TNF-α, hyperreactivity |
[101] |
|
| ||||
| Embelin (benzoquinone derivative) found in Ardisia japonica, fam. Primulaceae, Embelia ribes Burm, fam. Primulaceae | ||||
|
| ||||
| Male SD rats and male Swiss Webster CD-1 mice | s.c. 20 mg/kg × 5 d | i.p. 50 μg/kg cerulein | ↓ pancreatic necrosis and ↑ apoptosis in mouse model, ↑ caspase-9, -3, -8 in mouse model | [7] |
|
| ||||
| Emodin (anthraquinone) found in Rheum spp., fam. Polygonaceae, Rhamnus spp., fam. Rhamnaceae, Fallopia japonica, fam. Polygonaceae | ||||
|
| ||||
| Male SD rats | i.v. 2.5 mg/kg q6 h | r.i.BPD 5% sodium taurocholate | ↑ pancreatic blood flow | [102] |
|
| ||||
| Male SD rats | i.v. 2.5 mg/kg q6 h | r.i.BPD 5% sodium taurocholate | ↓ TXB2 ↑ 6-keto-PGF1α, PGE2 ↓ mortality, pancreatic pathologic scoring |
[102] |
|
| ||||
| Male SD rats | i.v. 2.5 mg/kg q6 h | r.i.BPD 5% sodium taurocholate | ↓ TXB2 ↑ 6-keto-PGF1α, PGE2 ↓ mortality, amylase, lipase, ascites, pancreatic edema, inflammation, necrosis, bleeding, microthrombosis |
[103] |
|
| ||||
| Male SD rats | i.v. 2.5 mg/kg | r.i.BPD 5% sodium taurocholate | ↓ TNF-α, IL-6, edema, extravasation, histological score ↑ claudin-5, occludin |
[104] |
|
| ||||
| Male SD rats | i.v. 2.5 mg/kg | r.i.BPD 5% sodium taurocholate | ↓ TNF-α, IL-6, MPO, pulmonary extravasation & edema; ↑ claudin-4, claudin-5, occludin | [105] |
|
| ||||
| Male SD rats | orally 20/40/80 mg/kg × 28 days | r.i.BPD trinitrobenzene sulfonic acid | ↓ TGF-β1, pancreatic fibrosis, glandular atrophy, collagen, fibronectin, laminin | [106] |
|
| ||||
| SD rats | i.v. 2.5 mg/kg | r.i.BPD 3.5% sodium taurocholate | ↑ intestinal transit ↓ TNF-α, IL-1β, NF-κB-p65 |
[107] |
|
| ||||
| SD rats | i.v. 2.5 mg/kg | r.i.BPD 3.5% sodium taurocholate | ↓ amylase, histological damage, edema, vacuolization, inflammation, necrosis, NF-κB activation, TNF-α, IL-6, IL-1β, MDA ↑ SOD |
[108] |
|
| ||||
| SD rats | i.v. 2.5 mg/kg | r.i.BPD 1.5% sodium deoxycholate | ↑ mCD14 & ICAM-3 expression in pMΦs | [109, 110] |
|
| ||||
| SD rats | i.v. 2.5 mg/kg | r.i.BPD 1.5% sodium ursodeoxycholate | ↓ amylase, lung edema, pathological changes, serum TNF-α, SAP-induced acute lung injury ↑ AQP1 and AQP5 improved blood gases indexes |
[111] |
|
| ||||
| SD rats | i.v. 2.5 mg/kg | r.i.BPD 3% sodium cholate | ↓ apoptosis of intestinal mucosa cells, translocation of bacteria and endotoxin ↑ serum leptin, intestinal barrier function |
[112] |
|
| ||||
| RPA AR42J cells | 10 and 20 μM | cerulein (10−7 M) + lipoplysaccharide (10 mg/l) | ↓ amylase ↑ apoptotic indices & ↓ necrosis (↓ necrosis/apoptosis ratio); ↓ calcium overload in the cytoplasm ↓ ER stress transducers |
[113] |
|
| ||||
| Emodin (EM) + baicalin (BA)/baicalein (BAe) | ||||
|
| ||||
| Male SD rats | i.v. 2.5 mg/kg for EM, 20 mg/kg for BA | r.i.BPD 5% sodium taurocholate | ↓ amylase, TNF-α, IL-6, TLR4 expression in pancreas and lung, pancreatic and pulmonary damage | [44] |
|
| ||||
| Male SD rats | i.v. 2.5 mg/kg/6 h for EM, 20 mg/kg/6 h for BA | r.i.BPD 5% sodium taurocholate | ↓ mortality, ascites, pancreatic pathological scores, amylase, TNF-α, IL-6 | [114] |
|
| ||||
| Emodin (EM) + EEN | ||||
|
| ||||
| Male Wistar rats | EM (3.0 mg/100 g) by enteral tube q10 h × 6 times | r.i.BPD 5% sodium taurocholate | ↓ amylase, ALT, AST, MDA, hepatic & pancreatic MPO, TNF-α, AngII, CRP, endotoxin, lactate, mortality, pathological changes, ascites | [115] |
|
| ||||
| Hesperidin (flavone) found in citrus fruits | ||||
|
| ||||
| WA rats | 0.3 g/kg s.c. | cerulein 50 μg/kg hourly 7 times | ↓ amylase, inflammatory infiltrate, edema, ROS burden, NO | [116] |
|
| ||||
| RPA AR42J cells | 53.7 μg/L hesperidin | cerulein | ↑ cell viability, apoptosis index; ↓ necrosis, LDH released from the cells, ROS generation | [117] |
|
| ||||
| Honokiol (lignan) found in Magnolia officinalis (Magnoliaceae) | ||||
|
| ||||
| RPA AR42J cells | 9.07 μg/L honokiol | cerulein | ↑ cell viability, apoptosis index; ↓ necrosis, LDH released from the cells | [118] |
|
| ||||
| Ligustrazine (tetramethylpyrazine) found in Ligusticum wallichii, fam. Umbeliferae | ||||
|
| ||||
| Adult SD rats | i.p. 150 mg/kg/day, 3 days 10 min after the first cerulein injection |
i.p. 100 µg/kg/h cerulein, every 1 h, 6 times | ↓ amylase, pancreatic MPO, TNF-α, IL-1β, IL-6, p38, Erk ↑ p53, cleaved caspase-3, apoptosis of acinar cells |
[119] |
|
| ||||
| SD rats | NP | r.i.BPD 5% sodium taurocholate. | ↑ survival rate, 6-keto-PGF1 alpha ↓ LPO, TXB2 |
[120] |
|
| ||||
| Magnolol (lignan) found in Magnolia officinalis (Magnoliaceae) | ||||
|
| ||||
| RPA AR42J cells | 1.49 μg/L magnolol | cerulein | ↑ cell viability, apoptosis index; ↓ necrosis, LDH released from the cells, ROS generation | [117] |
|
| ||||
| BALB/c mice | i.v. magnolol immediately after the AP model was reproduced, then at 9, 12, 24 hours after modelling | i.p. cerulein hourly 7 times | ↓ amylase, pancreatic histopathologic score ↑ ratio of myeloid/lymphoid dendritic cells, ratio of IL-10/IFN-γ |
[121] |
|
| ||||
| Naringin (flavone) found in citrus fruits and tomatoes | ||||
|
| ||||
| RPA AR42J cells | 53.7 μg/L naringin | cerulein | ↑ cell viability, apoptosis index ↓ necrosis, LDH released from the cells, ROS generation |
[117, 118] |
|
| ||||
| Nordihydroguaiaretic acid (lignan) found in creosote bush, Larrea tridentata (Zygophyllaceae) | ||||
|
| ||||
| Swiss albino rats | 30 mg/kg/h, orally, thrice at 1 h intervals | cerulein |
in plasma: ↓ amylase; ↓ IGF-1 in pancreas: ↓ TBARS; ↑ SOD; ↑ GSH ↓ edema, damage score ↑ heat shock proteins ↓ MPO, NF-κB, TNF-α, phosphorylated p38 ↑ apoptotic cells number modulates the posttranslational modifications of histone H3 |
[122] |
|
| ||||
| Resveratrol (trans-3,5,4′-trihydroxystilbene) found in grapes, peanuts, soy, giant knotweed (Polygonum cuspidatum) beans | ||||
|
| ||||
| SD male rats | 30 mg/kg b.m. intraperitoneally | r.i.BPD 4% sodium taurocholate | ↓ NF-κB, TNF-α, IL-8 | [123] |
|
| ||||
| Male Wistar rats | 10 mg/kg i.p. 30 min pre-trt. | s.c. 3 × 75 μg/kg CCK-8 | ↓ amylase, lipase, total pancreatic histological damage, edema, acinar vacuolization ↑ catalase |
[124] |
|
| ||||
| Male SD rats | 10 mg/kg, injected through penal vein 5 min post-trt. | r.i.BPD 4% sodium taurocholate | ↓ severity, NF-κB, iNOS in pMΦs | [125] |
|
| ||||
| Male SD rats | i.v. 20 mg/kg, 5 min post-trt. | r.i.BPD 4% sodium taurocholate | ↑ SOD ↓ MDA, serum TNF-α, ICAM-1 and VCAM-1 expression in the intestine |
[126] |
|
| ||||
| Male SD rats | i.p. 10 mg/kg | r.i.BPD 4% sodium taurocholate | ↑ Bcl-2 ↓ Bax, caspases-3 expressions in brain, serum Zonula occludens 1 and Myelin basic protein |
[127] |
|
| ||||
| Male SD rats | i.v. 20 mg/kg, 10 min after SAP induction | r.i.BPD 4% sodium taurocholate | ↓ amylase, MDA, neutrophil infiltration in pancreas ↑ SOD |
[128] |
|
| ||||
| Dihydroresveratrol (trans-3,5,4′-trihydroxystilbene) found in grapes, peanuts, soy, giant knotweed (Polygonum cuspidatum) beans | ||||
|
| ||||
| SD rats | p.o. 10, 20, or 50 mg/kg/h | i.p. 50 μg/kg/h cerulein, 6 times and lipopolysaccharide 7.5 mg/kg, 1 time |
↓ amylase, lung injury, pulmonary levels of TNF-α, IL-1β, IL-6, NF-κB | [129] |
|
| ||||
| SD rats | NP | i.p. repetitive administration, cerulein 50 µg/kg/h followed LPS 7.5 mg/kg 1 time | ↓ amylase, lung injury, NF-κB, MPO | [130] |
|
| ||||
| Rhein (anthraquinone) found in Rheum spp. and in Senna spp. | ||||
|
| ||||
| RPA AR42J cells | 479, 119.8, and 29.9 μg/L rhein | cerulein | ↑ apoptotic-to-necrotic cell ratio, p53, cytochrome C, caspase-3, Bax/Bcl-2 ratio (dose dependent) | [53] |
|
| ||||
| male SD rats | 10 mg/kg rhein (conjugated with HPDM) | r.i.BPD 3% or 5% sodium taurocholate | ↓ amylase, MPO, histological damage in pancreas (inflammatory infiltrate, acinar cell vacuolization & necrosis), ↓ IL-6, TNF-α (in serum, pancreas, lung) | [131] |
|
| ||||
| RPA AR42J cells | 479 μg/L rhein | cerulein | ↑ cell viability, apoptosis index; ↓ necrosis, LDH released from the cells, ROS generation | [117] |
|
| ||||
| Rutin (rhamnoglucoside of quercetin) found in citrics, grapes, black tea, apple skin peels, amalaki (Emblica officinalis) | ||||
|
| ||||
| Swiss mice | p.o. 37.5, 75, or 150 mg/kg, after 24, 36, 48, and 60 h of AP induction | i.p. 8% L-arginine hydrochloride 4 g/kg twice | ↓ pain, amylase, lipase, CRP, IL-6, pancreatic MPO, edema index, necrosis, MDA, 3-nitrotyrosine ↑ apoptosis, catalase, SOD |
[132] |
|
| ||||
| Male albino Wistar rats | p.o. 100 mg/kg/day from the third week | p.o. ethanol (36% of total calories) 5 weeks, i.p. cerulein 20 µg/kg, thrice weekly, last 3 weeks |
↓ amylase, IL-1β, IL-18, caspase-1, ASC-NLRP3 ↓ MPO, TBARS, lipid hydroperoxides, oxidative stress index ↑ GPx, SOD, CAT |
[133] |
|
| ||||
| Male albino Wistar rats | p.o. 100 mg rutin/kg from 31st day till the experimental period | p.o. EtOH (8–12 g/kg/day) and HFD (22% fat) for 90 days | ↑ mRNA expressionof CARD ↓ PYD, caspase-1, and TNF-α expressions, serum IL-18 and IL-6 |
[134] |
AngII: angiotensin II, AP: acute pancreatitis, AP-1: activator protein-1, AQP: aquaporin, CARD: caspase activation recruitment domain, d.f.: disease-free, DMSO: dimethyl sulfoxide, EAEEN: emodin-assisted early enteral nutrition, EEN: early enteral nutrition, ER: endoplasmic reticulum, f.c.i.v.i.: followed by continuous i.v. infusion of, fgl2: Fibrinogen-Like Protein 2, HPDM = N,N,N′-trimethyl-N′-(4-hydroxy-3-methylbenzyl)-1,3-propane diamine, gr.: groups, i.g.: intragastric, i.p.: intraperitoneal, i.v.: intravenous, i.v.b.: i.v. bolus, iNOS: inducible NO synthase, LPO: lipid peroxide, mCD14: membrane-bound cluster of differentiation 14 protein, MCP-1: monocyte chemoattractant protein-1, MDA: malondialdehyde, MIP-1α: Macrophage inflammatory protein-1α, MPO: myeloperoxidase, NAP78: neutrophil-activating peptide 78, NO: nitric oxide, NP: not provided, PDTC: pyrrolidine dithiocarbamate, pMΦs: peritoneal macrophages, PYD: pyrin domain of apoptosis-associated speck-like protein, r.i.BPD:retrograde injection into the bilio-pancreatic duct of, resp.: respectively, RPA: rat pancreatic acinar, s.c.: subcutaneous injection, SAP: severe AP, SD: Sprague-Dawley, SS: Sandostatin, TLR-4: Toll-like receptor 4, trt.: treatment, WA: Wistar-Albino.