Corneal neuropathic pain in irritable bowel syndrome: clinical findings and in vivo corneal confocal microscopy

2021 ◽  
Author(s):  
Ipek Çigdem Uçar ◽  
Fehim Esen ◽  
Semra Akkaya Turhan ◽  
Halit Oguz ◽  
Hak Celal Ulasoglu ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Neuropathic Pain ◽  
Confocal Microscopy ◽  
Clinical Findings ◽  
Corneal Confocal Microscopy ◽  
Irritable Bowel

scholarly journals Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 606 ◽  
Author(s):  
Steven M. Muskal ◽  
Joe Sliman ◽  
John Kokai-Kun ◽  
Mark Pimentel ◽  
Vince Wacher ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Structural Information ◽  
Methanogenic Archaea ◽  
Clinical Findings ◽  
Ligand Docking ◽  
Cholesterol Lowering ◽  
Lactone Form ◽  
Natural Ligand ◽  
Irritable Bowel

Methane produced by the methanoarchaeonMethanobrevibacter smithii(M. smithii) has been linked to constipation, irritable bowel syndrome with constipation (IBS-C), and obesity. Lovastatin, which demonstrates a cholesterol-lowering effect by the inhibition of HMG-CoA reductase, may also have an anti-methanogenesis effect through direct inhibition of enzymes in the archaeal methanogenesis pathway. We conducted protein-ligand docking experiments to evaluate this possibility. Results are consistent with recent clinical findings.METHODS: F420-dependent methylenetetrahydromethanopterin dehydrogenase (mtd), a key methanogenesis enzyme with a known sequence but no tertiary protein structural information, was modeled for two different methanogenic archaea:M. smithiiandMethanopyrus kandleri. Once protein models were developed, ligand-binding sites were identified. Multiple ligands and their respective protonation, isomeric and tautomeric representations were docked into each site, including F420-coenzyme (natural ligand), lactone and β-hydroxyacid forms of lovastatin and simvastatin, and other co-complexed ligands found in related crystal structures.RESULTS: 1) Generally, for each modeled site the lactone form of the statins had more favorable site interactions compared to F420; 2) The statin lactone forms generally had the most favorable docking scores, even relative to the native template PDB ligands; and 3) The statin β-hydroxyacid forms had less favorable docking scores, typically scoring in the middle with some of the F420 tautomeric forms. Consistent with these computational results were those from a recent phase II clinical trial (NCT02495623) with a proprietary, modified-release lovastatin-lactone (SYN-010) in patients with IBS-C, which showed a reduction in symptoms and breath methane levels, compared to placebo.CONCLUSION: The lactone form of lovastatin exhibits preferential binding over the native-F420 coenzyme ligandin silicoand thus could inhibit the activity of the keyM. smithiimethanogenesis enzymemtdin vivo. Statin lactones may thus exert a methane-reducing effect that is distinct from cholesterol lowering activity, which requires HMGR inhibition by statin β-hydroxyacid forms.

scholarly journals Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 606 ◽  
Author(s):  
Steven M. Muskal ◽  
Joe Sliman ◽  
John Kokai-Kun ◽  
Mark Pimentel ◽  
Vince Wacher ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Methanogenic Archaea ◽  
Clinical Findings ◽  
Ligand Docking ◽  
Cholesterol Lowering ◽  
Lactone Form ◽  
Natural Ligand ◽  
Tautomeric Forms ◽  
Irritable Bowel

Methane produced by the methanoarchaeonMethanobrevibacter smithii(M. smithii) has been linked to constipation, irritable bowel syndrome with constipation (IBS-C), and obesity. Lovastatin, which demonstrates a cholesterol-lowering effect by the inhibition of HMG-CoA reductase, may also have an anti-methanogenesis effect through direct inhibition of enzymes in the archaeal methanogenesis pathway. We conducted protein-ligand docking experiments to evaluate this possibility. Results are consistent with recent clinical findings.METHODS: F420-dependent methylenetetrahydromethanopterin dehydrogenase (mtd), a key methanogenesis enzyme was modeled for two different methanogenic archaea:M. smithiiandMethanopyrus kandleri. Once protein models were developed, ligand-binding sites were identified. Multiple ligands and their respective protonation, isomeric and tautomeric representations were docked into each site, including F420-coenzyme (natural ligand), lactone and β-hydroxyacid forms of lovastatin and simvastatin, and other co-complexed ligands found in related crystal structures.RESULTS: 1) Generally, for each modeled site the lactone form of the statins had more favorable site interactions compared to F420; 2) The statin lactone forms generally had the most favorable docking scores, even relative to the native template PDB ligands; and 3) The statin β-hydroxyacid forms had less favorable docking scores, typically scoring in the middle with some of the F420 tautomeric forms. Consistent with these computational results were those from a recent phase II clinical trial (NCT02495623) with a proprietary, modified-release lovastatin-lactone (SYN-010) in patients with IBS-C, which showed a reduction in symptoms and breath methane levels, compared to placebo.CONCLUSION: The lactone form of lovastatin exhibits preferential binding over the native-F420 coenzyme ligandin silicoand thus could inhibit the activity of the keyM. smithiimethanogenesis enzymemtdin vivo. Statin lactones may thus exert a methane-reducing effect that is distinct from cholesterol lowering activity, which requires HMGR inhibition by statin β-hydroxyacid forms.

scholarly journals Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 606 ◽  
Author(s):  
Steven M. Muskal ◽  
Joe Sliman ◽  
John Kokai-Kun ◽  
Mark Pimentel ◽  
Vince Wacher ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Methanogenic Archaea ◽  
Clinical Findings ◽  
Ligand Docking ◽  
Cholesterol Lowering ◽  
Lactone Form ◽  
Natural Ligand ◽  
Tautomeric Forms ◽  
Irritable Bowel

Methane produced by the methanoarchaeonMethanobrevibacter smithii(M. smithii) has been linked to constipation, irritable bowel syndrome with constipation (IBS-C), and obesity. Lovastatin, which demonstrates a cholesterol-lowering effect by the inhibition of HMG-CoA reductase, may also have an anti-methanogenesis effect through direct inhibition of enzymes in the archaeal methanogenesis pathway. We conducted protein-ligand docking experiments to evaluate this possibility. Results are consistent with recent clinical findings.METHODS: F420-dependent methylenetetrahydromethanopterin dehydrogenase (mtd), a key methanogenesis enzyme was modeled for two different methanogenic archaea:M. smithiiandMethanopyrus kandleri. Once protein models were developed, ligand-binding sites were identified. Multiple ligands and their respective protonation, isomeric and tautomeric representations were docked into each site, including F420-coenzyme (natural ligand), lactone and β-hydroxyacid forms of lovastatin and simvastatin, and other co-complexed ligands found in related crystal structures.RESULTS: 1) Generally, for each modeled site the lactone form of the statins had more favorable site interactions compared to F420; 2) The statin lactone forms generally had the most favorable docking scores, even relative to the native template PDB ligands; and 3) The statin β-hydroxyacid forms had less favorable docking scores, typically scoring in the middle with some of the F420 tautomeric forms. Consistent with these computational results were those from a recent phase II clinical trial (NCT02495623) with a proprietary, modified-release lovastatin-lactone (SYN-010) in patients with IBS-C, which showed a reduction in symptoms and breath methane levels, compared to placebo.CONCLUSION: The lactone form of lovastatin exhibits preferential binding over the native-F420 coenzyme ligandin silicoand thus could inhibit the activity of the keyM. smithiimethanogenesis enzymemtdin vivo. Statin lactones may thus exert a methane-reducing effect that is distinct from cholesterol lowering activity, which requires HMGR inhibition by statin β-hydroxyacid forms.

In vivo corneal confocal microscopy in keratoconus

2005 ◽  
Vol 25 (3) ◽  
pp. 254-260 ◽  
Author(s):  
Joanna G. Hollingsworth ◽  
Nathan Efron ◽  
Andrew B. Tullo
Keyword(s):  
Confocal Microscopy ◽  
Corneal Confocal Microscopy

IFN-γ and TNF-α decrease serotonin transporter function and expression in Caco2 cells

2007 ◽  
Vol 292 (3) ◽  
pp. G779-G784 ◽  
Author(s):  
Kevin F. Foley ◽  
Cristen Pantano ◽  
Allison Ciolino ◽  
Gary M. Mawe
Keyword(s):  
Ulcerative Colitis ◽  
Irritable Bowel Syndrome ◽  
Conditioned Medium ◽  
Human Lymphocytes ◽  
Protein Levels ◽  
Tnf Α ◽  
Ifn Γ ◽  
5 Ht Uptake ◽  
Irritable Bowel

Recent studies have shown that mucosal serotonin (5-HT) transporter (SERT) expression is decreased in animal models of colitis, as well as in the colonic mucosa of humans with ulcerative colitis and irritable bowel syndrome. Altered SERT function or expression may underlie the altered motility, secretion, and sensation seen in these inflammatory gut disorders. In an effort to elucidate possible mediators of SERT downregulation, we treated cultured colonic epithelial cells (Caco2) with conditioned medium from activated human lymphocytes. Application of the conditioned medium caused a decrease in fluoxetine-sensitive [3H]5-HT uptake. Individual proinflammatory agents were then tested for their ability to affect uptake. Cells were treated for 48 or 72 h with PGE2 (10 μM), IFN-γ (500 ng/ml), TNF-α (50 ng/ml), IL-12 (50 ng/ml), or the nitric oxide-releasing agent S-nitrosoglutathione (GSNO; 100 μM). [3H]5-HT uptake was then measured. Neither PGE nor IL-12 had any effect on [3H]5-HT uptake, and GSNO increased uptake. However, after 3-day incubation, both TNF-α and IFN-γ elicited significant decreases in SERT function. Neither TNF-α nor IFN-γ were cytotoxic when used for this period of time and at these concentrations. These two cytokines also induced decreases in SERT mRNA and protein levels. By altering SERT expression, TNF-α and IFN-γ could contribute to the altered motility and expression seen in vivo in ulcerative colitis or irritable bowel syndrome.

scholarly journals The use of confocal microscopy in experimental studies and clinical practice of an endocrinologist: modern opportunities

2019 ◽  
Vol 65 (3) ◽  
pp. 174-183
Author(s):  
Natalya G. Mokrysheva ◽  
Sergey L. Kiselev ◽  
Natalia V. Klementieva ◽  
Anna M. Gorbacheva ◽  
Ivan I. Dedov
Keyword(s):  
Confocal Microscopy ◽  
Experimental Studies ◽  
Three Dimensional ◽  
Imaging Method ◽  
New Methods ◽  
Corneal Confocal Microscopy ◽  
Endocrine Ophthalmopathy ◽  
Fundamental Research

Confocal microscopy is a modern imaging method that provides ample opportunities for in vitro and in vivo research. The clinical part of the review focuses on well-established techniques, such as corneal confocal microscopy for the diagnosis of diabetic neuropathy or endocrine ophthalmopathy; new methods are briefly described (intraoperative evaluation of tissues obtained by removing pituitary adenomas, thyroid and parathyroid glands). In the part devoted to fundamental research, the use of confocal microscopy to characterize the colocalization of proteins, as well as three-dimensional intracellular structures and signaling pathways in vivo, is considered. Indicators of intracellular calcium are analyzed.

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