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World J Gastroenterol
2016 Oct 07;2237:8322-8333. doi: 10.3748/wjg.v22.i37.8322.
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Rhubarb extract partially improves mucosal integrity in chemotherapy-induced intestinal mucositis.
Bajic JE
,
Eden GL
,
Lampton LS
,
Cheah KY
,
Lymn KA
,
Pei JV
,
Yool AJ
,
Howarth GS
.
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To investigate the effects of orally gavaged aqueous rhubarb extract (RE) on 5-fluorouracil (5-FU)-induced intestinal mucositis in rats. Female Dark Agouti rats (n = 8/group) were gavaged daily (1 mL) with water, high-dose RE (HDR; 200 mg/kg) or low-dose RE (LDR; 20mg/kg) for eight days. Intestinal mucositis was induced (day 5) with 5-FU (150 mg/kg) via intraperitoneal injection. Intestinal tissue samples were collected for myeloperoxidase (MPO) activity and histological examination. Xenopus oocytes expressing aquaporin 4 water channels were prepared to examine the effect of aqueous RE on cell volume, indicating a potential mechanism responsible for modulating net fluid absorption and secretion in the gastrointestinal tract. Statistical significance was assumed at P < 0.05 by one-way ANOVA. Bodyweight was significantly reduced in rats administered 5-FU compared to healthy controls (P < 0.01). Rats administered 5-FU significantly increased intestinal MPO levels (≥ 307%; P < 0.001), compared to healthy controls. However, LDR attenuated this effect in 5-FU treated rats, significantly decreasing ileal MPO activity (by 45%; P < 0.05), as compared to 5-FU controls. 5-FU significantly reduced intestinal mucosal thickness (by ≥ 29% P < 0.001) as compared to healthy controls. LDR significantly increased ileal mucosal thickness in 5-FU treated rats (19%; P < 0.05) relative to 5-FU controls. In xenopus oocytes expressing AQP4 water channels, RE selectively blocked water influx into the cell, induced by a decrease in external osmotic pressure. As water efflux was unaltered by the presence of extracellular RE, the directional flow of water across the epithelial barrier, in the presence of extracellular RE, indicated that RE may alleviate water loss across the epithelial barrier and promote intestinal health in chemotherapy-induced intestinal mucositis. In summary, low dose RE improves selected parameters of mucosal integrity and reduces ileal inflammation, manifesting from 5-FU-induced intestinal mucositis.
Figure 1. Directional blockade of water flux through an aquaporin-4 channel by reconstituted aqueous rhubarb extract. A: Diagram of a water channel illustrating the intra-subunit water pores in each subunit of the tetramer; B: Illustration of the volume changes induced by osmotic gradients in mammalian AQP4-expressing Xenopus oocytes; C: Dose-dependent blockade of swelling but not shrinking responses by rhubarb extract (RE) in AQP4-expressing oocytes; D: Diagram of the hypothesized effect of blockade by extracellular RE at AQP4 channels present in the basolateral side of intestinal barrier epithelial cells, predicted to result in enhanced net fluid absorption.
Figure 2. Daily change in starting bodyweight (%) from days 0 to 8 in rats gavaged with water, LDR or HDR and intraperitoneally injected with saline or 5-FU on Day 5. Data are expressed as mean ± SEM. Mean values of 5-FU controls and 5-FU + LDR and 5-FU + HDR were significantly different when vs water + saline controls; bP < 0.01. LDR: Low-dose RE; HDR: High-dose RE; RE: Rhubarb extract.
Figure 3. Effects of rhubarb extract and 5-fluorouracil on disease activity scores on days 6 to 8 of the experimental period. Rats received a daily water, HDR or LDR gavage for an 8-d trial period and an intraperitoneal injection of 5-FU or saline on day 5. Disease activity scores were assigned on Days 6 to 8 based on overall condition, weight loss, stool consistency and rectal bleeding. bP < 0.01, eP < 0.001 vs water + saline; cP < 0.05 vs water + 5-FU. LDR: Low-dose RE; HDR: High-dose RE; RE: Rhubarb extract.
Figure 4. Histological damage assessed by semi-quantitative disease severity score of the jejunum, jejuno-ileum and ileum of rats. Data are expressed as median score (range). Mean values were significantly different vs water + 5-FU (fP < 0.001). JI: Jejuno-ileum; LDR: Low-dose RE; HDR: High-dose RE; RE: Rhubarb extract.
Figure 5. Myeloperoxidase activity present in the jejunum, jejuno-ileum and ileum of rats gavaged with water, low-dose or high-dose rhubarb extract (1 mL) for an 8-d trial period. Rats received an intraperitoneal injection of saline or 5-FU on day 5. Data were expressed as mean [MPO Units (U)/g] ± SEM. Mean values were significantly different (fP < 0.001) vs water + 5-FU. cP < 0.05 vs water + 5-FU. JI: Jejuno-ileum; LDR: Low-dose RE; HDR: high-dose RE; RE: Rhubarb extract.
Figure 6. Combination of villus height and crypt depth as a representation of overall mucosal thickness in female Dark Agouti rats. Effects of RE and 5-FU on villus height and crypt depth in female Dark Agouti rats. Rats received a daily water, HDR or LDR gavage for an 8-d trial period and an intraperitoneal injection of 5-FU or saline on Day 5. Mean values were significantly different vs water + 5-FU (cP < 0.05, fP < 0.001). aP < 0.05, eP < 0.001 vs water + saline. JI: Jejuno-ileum; LDR: Low-dose RE; HDR: High-dose RE; RE: Rhubarb extract.
Figure 7. A comparison of the histological structure of ileal sections in a healthy rat (A), after administration of 5-FU (B) and rats treated with LDR + 5-FU (C). Ileum sections of rats from the LDR + 5-FU treatment group (C) exhibited improved mucosal integrity as demonstrated by more defined villi and crypts in comparison to water + 5-FU controls (B). The black line on each diagram represents villus height in each section which was significantly shorter in 5-FU controls. Sections were stained with haematoxylin and eosin and mucosal thickness was analysed by quantitative measurements of villus height and crypt depth. Original photographs were captured at 4 Ã magnification. LDR: Low-dose rhubarb extract.
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