Ameliorative potential of aliskiren in experimental colitis in mice

Patel, Rakesh B.; Prajapati, Kanaiyalal D.; Sonara, Bhavin M.; Sharma, Manoranjan; Patel, Hiren; Pawar, Vishwanath D.; Jain, Mukul

doi:10.1016/j.ejphar.2014.05.009

Cited by 16 publications

(8 citation statements)

References 44 publications

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“…Aliskiren administration significantly reduced the level of oxidative stress in the mice by enhancing the activities of SOD and GSH-Px while reducing the levels of MDA and •OH. Consistently, Patel et al (19) and Thomas et al (31) demonstrated that aliskiren can inhibit oxidative stress by reducing the generation of free radicals. Therefore, targeting oxidative stress provides a third mechanism underlying the anti-cachexia activity of aliskiren.…”

Section: Discussionmentioning

confidence: 69%

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Aliskiren targets multiple systems to alleviate cancer cachexia

et al. 2016

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To examine the effects of aliskiren, a small-molecule renin inhibitor, on cancer cachexia and to explore the underlying mechanisms. A cancer cachexia model was established by subcutaneously injecting C26 mouse colon carcinoma cells into isogenic BALB/c mice. Aliskiren was administered intragastrically [10 mg/kg body weight (BW)] on day 5 (as a preventive strategy, AP group) or on day 12 (as a therapeutic strategy, AT group) after C26 injection. Mice that received no C26 injection (healthy controls, HC group) or only C26 injection but not aliskiren (cancer, CA group) were used as controls. BW, tumor growth, whole body functions, and survival were monitored daily in half of the mice in each group, whereas serum, tumors, and gastrocnemius muscles were harvested from the other mice after sacrifice on day 20 for further analysis. Aliskiren significantly alleviated multiple cachexia‑associated symptoms, including BW loss, tumor burden, muscle wasting, muscular dysfunction, and shortened survival. On the molecular level, aliskiren antagonized cachexia‑induced activation of the renin‑angiotensin system (RAS), systematic and muscular inflammation, oxidative stress, and autophagy‑lysosome as well as ubiquitin‑proteasome stimulation. In addition, early administration of aliskiren before cachexia development (AP group) resulted in more robust effects in alleviating cachexia or targeting underlying mechanisms than administration after cachexia development (AT group). Aliskiren exhibited potent anti‑cachexia activities. These activities were achieved through the targeting of at least four mechanisms underlying cachexia development: RAS activation, increase in systematic inflammation, upregulation of oxidative stress, and stimulation of autophagy-lysosome pathway (ALP) and ubiquitin-proteasome pathway (UPP).

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Section: Discussionmentioning

confidence: 69%

“…In this study, we examined the efficacy of a novel direct renin inhibitor, aliskiren, on cancer cachexia. Previous studies showed that aliskiren can potently inhibit inflammation, reduce oxidative stress, and protect against tissue damage (18)(19)(20). However, minimal information is available on its actions in cancer cachexia.…”

Section: Introductionmentioning

confidence: 99%

Aliskiren targets multiple systems to alleviate cancer cachexia

et al. 2016

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“…In the sham control group (n = 6), DAI remained at zero throughout the study, while the mean score for the DSS group (n = 12) began to rise on day 5 and peaked on day 8, before declining on day 9. Cyclosporin A (CsA), with efficacy demonstrated previously in the DSS-colitis model, was chosen as a positive control [34–36]. In our study, CsA treatment (10 mg/kg i.p., n = 6) showed protection, with mean DAI peaking at 1.8 on day 8.…”

Section: Resultsmentioning

confidence: 99%

Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease

et al. 2019

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Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn’s patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1β in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD.

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“…Sections were mounted using Permount and observed under the light microscope (DP73; Olympus, Tokyo, Japan). A score was given as per the severity of pathology as described previously . Briefly, normal colon mucosa received a score of 0, slight oedema and infiltration of inflammatory cells received a score of 1; loss of basal crypts with moderate inflammation in lamina propria received a score of 2; total loss of basal crypts with severe inflammation in lamina propria, but with surface epithelium still remaining received a score of 3; and loss of all crypts and surface epithelium with severe inflammation in the mucosa, muscularis propria and submucosa received a score of 4.…”

Section: Methodsmentioning

confidence: 99%

Transplantation of human umbilical mesenchymal stem cells attenuates dextran sulfate sodium‐induced colitis in mice

Lin

Wang

et al. 2014

Clin Exp Pharma Physio

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Ulcerative colitis is a major form of inflammatory bowel disease and increases the risk of the development of colorectal carcinoma. The anti-inflammatory and immunomodulatory properties of mesenchymal stem cells (MSC) make them promising tools for treating immune-mediated and inflammatory diseases. However, the lack of robust technique for harvesting and expanding of MSC has hampered the use of bone marrow and umbilical cord blood derived MSC in clinical applications. In the present study, we investigated the intestinal protective effects of Wharton's jelly-derived umbilical MSC (UMSC) on dextran sulfate sodium-induced colitis in mice. The severity of colitis in mice was assessed using bodyweight loss, stool consistency, rectal bleeding, colon shortening and haematological parameters. Colonic myeloperoxidase and pro-inflammatory cytokines levels were also measured. Furthermore, the expression of cyclooxygenase 2 and inducible nitric oxide synthase in the colon were detected. In addition, intestinal permeability and tight junction proteins expressions in the colon were examined as well. The results showed that Wharton's jelly-derived UMSC significantly diminished the severity of colitis, reduced histolopathological score, and decreased myeloperoxidase activity and cytokines levels. Furthermore, the UMSC markedly decreased the expression of cyclooxygenase 2and inducible nitric oxide synthase in the colon. In addition, transplantation of UMSC reduced intestinal permeability and upregulated the expression of tight junction proteins. These results show that the anti-inflammation and regulation of tight junction proteins by Wharton's jelly-derived UMSC ameliorates colitis.

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Ameliorative potential of aliskiren in experimental colitis in mice

Cited by 16 publications

References 44 publications

Aliskiren targets multiple systems to alleviate cancer cachexia

Aliskiren targets multiple systems to alleviate cancer cachexia

Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease

Transplantation of human umbilical mesenchymal stem cells attenuates dextran sulfate sodium‐induced colitis in mice

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