Gadolinium chloride attenuates acetic acid-evoked colitis in mice by reducing neutrophil infiltration and pro-oxidative enzyme activity.

This study investigated the potential of gadolinium chloride (GdCl3), an inhibitor of kupffer cells on the myeloperoxidase (MPO) function, both in vivo on colon inflammation model and in vitro on thioglycollate-elicited peritoneal neutrophils. Colon inflammation was induced in mice (n = 7) by 4% acetic acid (AA) enema. GdCl3 (10 mg/kg) treatment was given 24 h before AA challenge. Clinical changes during the protocol were scored. Colons were segmented into distal and proximal parts for histological and biochemical assessment. Furthermore, myeloperoxidase (MPO) enzymes were extracted and analyzed by western blot. Short-term GdCl3 treatment inhibited dose-dependently superoxide anion (O2·-), alkaline phosphatase (ALP), and MPO release and promoted neutrophil apoptosis. In vivo, low-dose GdCl3 improved colitis scores and inhibited acute phagocyte recruitment and colon damage within the mucosa as revealed by the decrease in MPO, nitric oxide (NO), and malondialdehyde (MDA) levels. At the same time, GdCl3 restored catalase (CAT), superoxide dismutase (SOD) activities, and reduced glutathione (GSH) levels, thus reversing the MDA/GSH ratio in both distal and proximal colons. Compared to proximal, distal colon was more altered and displayed higher pathological manifestations. Lastly, the induction of apoptosis and regulation of the major nitrosative and oxidative functions of neutrophils by GdCl3 suggests its consideration as a beneficial tool in attenuating colon inflammation.

Arsenic trioxide ameliorates murine colon inflammation through inflammatory cell enzymatic modulation.

Arsenic trioxide (As2O3) is a trending subject in recent therapy approaches despite its described toxicity. In this work, we have investigated the use of arsenic trioxide in a murine model of chemically induced inflammatory bowel disease "colitis." Male mice were randomly separated into four different groups. Controls received vehicle, arsenic group had a daily injection of As2O3 (2.5 mg/kg, i.p.) for 2 days. Colitis was induced through intra-rectal instillation of 4% (v/v) solution of acetic acid in the second day. The treatment group (As2O3 + acetic acid) received the same treatment as the two previous groups. Twenty-four hours after colitis challenge, animals were sacrificed and organs (colons, livers, and kidneys) were taken for analysis. Disease-related macroscopic and microscopic symptoms, as well as histologic observations, showed a high index in the colitis group, which was greatly reduced by the As2O3 pretreatment. Similarly, colon length was reduced during colon inflammation, which was prevented in the presence of As2O3. Inflammatory cells and oxidative stress markers significantly increased during inflammation accompanied by a considerable reduction of antioxidants. As2O3 treatment managed to reverse these observations to normal levels. Mitochondrial implication was observed through mPTP opening phenomena and semi-quantitative cell death estimation. Low-dose As2O3 use as a mean of preventing the acute phase of colitis can be seen as an interesting approach which counts as a great addition to IBD available treatments.

Correction: Arsenic trioxide exposure accelerates colon preneoplasic aberrant crypt foci induction regionally through mitochondrial dysfunction.

[This corrects the article DOI: 10.1039/c7tx00213k.].

Arsenic trioxide exposure accelerates colon preneoplasic aberrant crypt foci induction regionally through mitochondrial dysfunction.

Arsenic poisoning is a worldwide problem. Thus, we studied the effects of arsenic trioxide (ATO) administration on a 1,2-dimethylhydrazine (DMH)-induced preneoplasic colon carcinogenesis model. Mice were separated into four study groups; the control group received only vehicles. The ATO group received daily a 2.5 mg kg-1 dose for 4 weeks. The DMH group received DMH (20 mg kg-1) twice in two weeks. The third group (D-ATO) had the same as the DMH group with ATO administration starting at week 10. At the end of 14 weeks, colons from sacrificed mice were taken, segmented into distal and proximal and subjected to aberrant crypt foci (ACF), aberrant crypt (AC) counting, alcian blue, H&E and Hoechst histological study and lastly oxidative stress marker analysis as well as mitochondrial swelling assessment. Data showed a significant increase in ACF and AC after DMH treatment, which was further increased after ATO addition. A perturbed histological structure was observed and loss of mucin producing cells in the colon tissue was observed. An important impact on the distal colon compared to the proximal one was noticed. The oxidative stress balance showed a similar pattern with an increase in MPO, NO/l-ornithine balance and MDA, while a decrease was observed in the antioxidant enzymes (CAT, SOD and GSH). In all parameters analyzed, the distal colons showed higher values than proximal. Furthermore, histological cell death analysis in combination with mitochondrial permeability pore opening suggested ATO contribution in the pathological effect. Our study has shown that ATO administration accelerated colon cancer development suggesting the heaviness of such treatments and the need to explore combinations and cycle type formulas.

Aberrant crypt foci are regionally affected by zinc treatment in a 1,2-dimethylhydrazine induced colon carcinogenesis model.

Zinc is a trace element widely known for its marked antioxidant properties. To gain more insight into the site- and time- specific mechanisms by which it induces chemoprevention, this study was elaborated over a pre-cancerous model of colon carcinogenesis. Colon cancer was induced by 1,2-dimethylhydrazine (DMH) in mice (20 mg/kg for 2 weeks) and groups of animals were supplemented with or without zinc sulfate (ZnSO4, 200 mg/L) in drinking water for 4, 10 or 14 weeks. Colon tissues were collected for pathological observation, analyzing aberrant crypt (AC) and aberrant crypt foci (ACF) formations, multiplicity and distribution. Similarly, histological assessment and mucin production, as well as oxidative stress markers estimation was performed for the different groups. Results showed a significant increase in ACF and AC numbers, ACF multiplicity and demonstrated stronger distal occurrence than in the proximal after DHM administration. Histopathological analysis presented marked structural alterations and mucin loss in the distal than the proximal colons. A significant increase in myeloperoxidase (MPO), nitric oxide (NO), L-ornithine and malondialdehyde (MDA) levels was observed followed by a significant decrease in antioxidant markers (superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH)). Oral ZnSO4 supplementation (continuous or partial) induced significant decrease in ACF, AC numbers and multiplicity, restored histological architecture and mucin production, and a significant decrease in proinflammatory markers while it reduced antioxidants to normal levels. From this study, insight was obtained on the use of ZnSO4 as a chemopreventive agent and shed light on its potential, as a supplement in nutraceutical approaches.