Diterpenoid alkaloids of Aconitum laciniatum and mitigation of inflammation by 14-O-acetylneoline in a murine model of ulcerative colitis

Wangchuk, Phurpa; Navarro, Séverine; Shepherd, Catherine; Keller, P. A.; Pyne, Stephen G.; Loukas, Alex

doi:10.1038/srep12845

Cited by 61 publications

(37 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although there are several medications on the market for IBD, they generally only provide temporary relief, and 70% of IBD patients require surgical intervention (2). Because the current treatments are not satisfactory, new drug leads are being sought from a range of sources, including small molecules from plants and bioactive regions of larger proteins (3)(4)(5)(6).…”

mentioning

confidence: 99%

An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease

Caceres

Bansal

Navarro

et al. 2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Edited by Wolfgang PetiInflammatory bowel diseases (IBDs) are a set of complex and debilitating diseases for which there is no satisfactory treatment. Recent studies have shown that small peptides show promise for reducing inflammation in models of IBD. However, these small peptides are likely to be unstable and rapidly cleared from the circulation, and therefore, if not modified for better stability, represent non-viable drug leads. We hypothesized that improving the stability of these peptides by grafting them into a stable cyclic peptide scaffold may enhance their therapeutic potential. Using this approach, we have designed a novel cyclic peptide that comprises a small bioactive peptide from the annexin A1 protein grafted into a sunflower trypsin inhibitor cyclic scaffold. We used native chemical ligation to synthesize the grafted cyclic peptide. This engineered cyclic peptide maintained the overall fold of the naturally occurring cyclic peptide, was more effective at reducing inflammation in a mouse model of acute colitis than the bioactive peptide alone, and showed enhanced stability in human serum. Our findings suggest that the use of cyclic peptides as structural backbones offers a promising approach for the treatment of IBD and potentially other chronic inflammatory conditions. Inflammatory bowel diseases (IBDs)3 are a set of chronic inflammatory disorders of the gastrointestinal tract; the two major forms are ulcerative colitis and Crohn's disease (1). Although there are several medications on the market for IBD, they generally only provide temporary relief, and 70% of IBD patients require surgical intervention (2). Because the current treatments are not satisfactory, new drug leads are being sought from a range of sources, including small molecules from plants and bioactive regions of larger proteins (3-6).Intriguingly, several small peptides, some comprising only three residues, have been shown to be effective in the treatment of experimental colitis in mice (7-11). One example is a tripeptide (MC-12) derived from annexin A1, a calcium-dependent phospholipid-binding, anti-inflammatory protein (12). Annexin A1 mediates expression of cytokines such as TNF-␣, IL-6, and IL-10. It is required for the inhibition of NF-B activity by anti-inflammatory drugs (13) and has recently been shown to be a potential biomarker of therapeutic efficacy for IBD (14). The N-terminal region of annexin A1 comprising residues 2-26 (Ac2-26) has been well studied (15, 16) and appears to have the same biological effects as the full-length protein (17). Analysis of a series of peptides based on the N-terminal sequence of annexin A1 showed that MC-12 (Ac-Gln-Ala-Trp) was the most potent inhibitor of NF-B activity in SW480 cells (13).Small peptides such as MC-12 are likely to be unstable and not viable drug leads, supported by the finding that high doses (25 mg/kg) of MC-12 were required to elicit an in vivo response in mouse colitis models, and it was more effective when injected compared with oral administration (18). Improving t...

show abstract

mentioning

confidence: 99%

An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease

Caceres

Bansal

Navarro

et al. 2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Five hookworm somatic tissue extracts were tested for their anti-inflammatory activities using the modified experimental design and TNBS induction in BALB/c mice as previously described by us (26). Extracts (50 μg/mouse) were administered intraperitoneally (i.p.)…”

Section: Resultsmentioning

confidence: 99%

“…We followed the modified experimental design and TNBS induction protocols described by us earlier (26). Mice were divided into three different groups as “Naïve”, “TNBS only” and “TNBS + Sample treatment”.…”

Section: Methodsmentioning

confidence: 99%

Hookworm-derived small molecule extracts suppress pathology in a mouse model of colitis and inhibit secretion of key inflammatory cytokines in primary human leukocytes

Wangchuk

Constantinoiu

Kouremenos

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Iatrogenic hookworm therapy shows promise for treating disorders that result from 27 a dysregulated immune system, including inflammatory bowel disease (IBD). Here we use a 28 metabolomics approach to characterize the non-protein small molecule complement of 29 hookworms. Gas chromatography-mass spectrometry and liquid chromatography-mass 30 spectrometry analyses of somatic tissue extracts revealed the presence of 52 polar metabolites 31 and 22 non-polar components including short chain fatty acids (SCFA). Several of these small 32 metabolites, notably the SCFA, have been shown to have anti-inflammatory properties in various 33 diseases, including IBD. Using a murine model of colitis and human peripheral blood 34 mononuclear cells, we demonstrate that somatic tissue extracts of the hookworm Ancylostoma 35 caninum contain small molecules with anti-inflammatory activities. Of the five extracts tested, 36 two of them significantly protected mice against T cell-mediated immunopathology and weight 37 loss in a chemically-induced colitis model. Moreover, one of the anti-colitic extracts suppressed 38 ex vivo production of inflammatory cytokines from primary human leukocytes. While the origin 39 of the SCFA (parasite or host microbiota-derived) present in the hookworm somatic tissue 40 extracts cannot be ascertained from this study, it is possible that A. caninum may be actively 41 promoting an anti-inflammatory host microbiome by facilitating immune crosstalk through SCFA 42 production. 43 44 Short chain fatty acids; GC-MS; Metabolome 46 47 48 49 50 3 51 52Inflammatory Bowel Disease (IBD) is associated with chronic inflammation of the 53 digestive tract, and primarily includes ulcerative colitis (UC) and Crohn's disease (CD). The 54 etiology of IBD is not well established but it is usually characterized by inflammation, loss of 55 appetite and weight, chronic diarrhea, bloody stools, fever, rectal bleeding, abdominal pain, 56 fatigue, and anemia (1-3). IBD has been linked to many extra-intestinal manifestations (4) and 57 implicated with mental health problems (5). Current treatments for IBD include, 5-58 aminosalicylates, glucocorticosteroids, immunomodulators and biologics, and proctocolectomy 59 as a last resort when drug treatment fails. Many of these drugs are often associated with side-60 effects and various postoperative complications (6, 7). Frontline biologics such as treatment with 61 anti-TNF monoclonal antibodies are only efficacious in some patients and treatment does not 62 result in long term cure (8). Failure of these frontline treatments is associated with elevated risk 63 of colon cancer, and can result in the need for surgical removal of the colon (partial or full). 64There is therefore an urgent need for new and effective anti-inflammatory drugs to treat IBD. 65Guided by millennia of host-parasite co-evolution, we (9-13) and others (14-16) have 66 demonstrated the therapeutic properties of experimental hookworm infection to treat 67 gastrointestinal (GI) inflammatory diseases. Hookworms resident in ...

show abstract

“…GC-MS was used to identify the phytochemical constituents of MESSM according to a previously described method. 28 The model of the instrument used is Agilent technologies…”

Section: Chemical Composition Of Messm Using Gas Chromatography-mass mentioning

confidence: 99%

Phytochemical Constituents, Antioxidant Activity and Toxicity Assessment of the Seed of Spondias mombin L. (Anacardiaceae)

Abiodun¹,

Nnoruka²,

Tijani³

2019

tjps

View full text Add to dashboard Cite

Objectives: Increased generation of free radicals exceeding the antioxidant capacity of the host is deleterious. Thus the search for new, potent and safe antioxidants will be a valuable addition to the limited antioxidant arsenals available. Therefore, the antioxidant activity, cytotoxicity potential and phytochemical constituents of 70% methanol extract of the seed of Spondias mombin (MESSM) was investigated. Material and Methods: Antioxidant activity of MESSM was evaluated in 1-Diphenyl-2picrylhydrazyl (DPPH), hydrogen peroxide and nitric oxide assays. Cytotoxicity of the extract was evaluated against rhabdomyosarcoma (RD) cell line in a MTT based assay. Phytochemical composition of MESSM was determined using the Gas Chromatography-Mass Spectrometry (GC-MS). Results: MESSM produced better antioxidant activity in DPPH (IC 50 = 58.64 ± 1.49 µg/mL) and H2O2 (IC50 = 44.03 ± 5.57 µg/mL) than in the NO (IC50 = 494.55 ± 12.68 µg/mL, p<0.0001) assays. Also, MESSM was non-toxic (CC 50 = 139.6 ± 0.54 µg/mL) in comparison to cyclophosphamide (CC50 = 0.97 ± 0.03 µg/mL) against rhabdomyosarcoma (RD) cell line. The major compounds in MESSM were dodecanoic acid (22.48%), tetradecanoic acid (17.95%), n-hexadecanoic acid (15.35 %), Capsaicin (12.11%) and dihydrocapsaicin (5.23 %). Conclusion: The seed extract of Spondias mombin lacked cytotoxicity potential. It contains non-toxic antioxidant compounds that could be explored in pharmaceutical and cosmetics industries for development of antioxidant agents.

show abstract

Diterpenoid alkaloids of Aconitum laciniatum and mitigation of inflammation by 14-O-acetylneoline in a murine model of ulcerative colitis

Cited by 61 publications

References 40 publications

An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease

An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease

Hookworm-derived small molecule extracts suppress pathology in a mouse model of colitis and inhibit secretion of key inflammatory cytokines in primary human leukocytes

Phytochemical Constituents, Antioxidant Activity and Toxicity Assessment of the Seed of Spondias mombin L. (Anacardiaceae)

Contact Info

Product

Resources

About