A Case Report on Left-sided Appendicitis with Intestinal Malrotation

Kharel, Himal; Pokhrel, Nishan Babu; Kharel, Zeni; Sah, Dhruba Narayan

doi:10.7759/cureus.6687

Cited by 12 publications

(22 citation statements)

References 18 publications

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“…12,13 S1P is found in higher levels in the blood and lymphatic system than in tissues such as muscle and the epithelium. 14 Within cells, SphK1 is localized in the cytoplasm, whereas SphK2 is localized in the nucleus, leading to different roles for SphK isoforms in S1P production. 11,14 In mice, the knockout of SphK1 alleles results in ~50% reduction of S1P levels in the blood compared to wild-type mice.…”

Section: Graphical Abstract: Introductionmentioning

confidence: 99%

“…14 Within cells, SphK1 is localized in the cytoplasm, whereas SphK2 is localized in the nucleus, leading to different roles for SphK isoforms in S1P production. 11,14 In mice, the knockout of SphK1 alleles results in ~50% reduction of S1P levels in the blood compared to wild-type mice. 14 In contrast, knockout of SphK2 alleles in mice results in no significant change in the level of blood S1P relative to wild-type mice, and SphK2 selective inhibitors result in substantially increased (~133%) levels of S1P in blood of wild-type mice and rats.…”

Section: Graphical Abstract: Introductionmentioning

confidence: 99%

“…11,14 In mice, the knockout of SphK1 alleles results in ~50% reduction of S1P levels in the blood compared to wild-type mice. 14 In contrast, knockout of SphK2 alleles in mice results in no significant change in the level of blood S1P relative to wild-type mice, and SphK2 selective inhibitors result in substantially increased (~133%) levels of S1P in blood of wild-type mice and rats. 14 The same SphK2 selective inhibitors have the opposite effect in a cultured human cell line (U937), where SphK2 inhibition decreases the amount of cell-associated S1P compared to cells cultured in the absence of inhibitor.…”

Section: Graphical Abstract: Introductionmentioning

confidence: 99%

“…14 The same SphK2 selective inhibitors have the opposite effect in a cultured human cell line (U937), where SphK2 inhibition decreases the amount of cell-associated S1P compared to cells cultured in the absence of inhibitor. 14 Isoform-selective and dual SphK inhibitors are reported to decrease S1P levels in vitro. 15 Currently, the most successful inhibitors contain a guanidine-based, oxadiazole-containing scaffold with a variety of moieties extending from the lipid tail region of the inhibitor.…”

Section: Graphical Abstract: Introductionmentioning

confidence: 99%

“…4 These compounds have good pharmacokinetic properties that track well with a pharmacodynamic marker, S1P concentration, in mice. 16 While these compounds are potent and selective, more development is needed to enhance potency and isoform selectivity. Inhibitor studies performed on human and rat sphingosine kinases demonstrate isoform selectivity with K i values exhibiting >20-fold selectivity toward SphK2 over SphK1 in mice.…”

Section: Graphical Abstract: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

In Silico Characterization of Structural Distinctions between Isoforms of Human and Mouse Sphingosine Kinases for Accelerating Drug Discovery

Worrell

Santos

Bevan

2019

J. Chem. Inf. Model.

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Alterations in cellular signaling pathways are associated with multiple disease states including cancers and fibrosis. Current research efforts to attenuate cancers, specifically lymphatic cancer, focus on inhibition of two sphingosine kinase isoforms, sphingosine kinase 1(SphK1) and sphingosine kinase 2 (SphK2). Determining differences in structural and physicochemical binding site properties of SphKs is attractive to refine inhibitor potency and isoform selectivity. This study utilizes a predictive in silico approach to determine key differences in binding sites in SphK isoforms in human and mouse species. Homology modeling, molecular docking of inhibitors, analysis of binding pocket residue positions, development of pharmacophore models, and analysis of binding cavity volume were performed to determine isoform-and species-selective characteristics of the binding site and generate a system to rank potential inhibitors. Interestingly, docking studies showed compounds bound to mouse SphK1 in a manner more similar to human SphK2 than to human SphK1, indicating that SphKs in mice have structural properties distinct from humans that confounds prediction of ligand selectivity in mice. Our studies aid in the development and production of new compound classes by highlighting structural distinctions and identifying the role of key residues that cause observable, functional differences in isoforms and between orthologues.

show abstract

Section: Graphical Abstract: Introductionmentioning

confidence: 99%

Section: Graphical Abstract: Introductionmentioning

confidence: 99%

Section: Graphical Abstract: Introductionmentioning

confidence: 99%

Section: Graphical Abstract: Introductionmentioning

confidence: 99%

Section: Graphical Abstract: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

In Silico Characterization of Structural Distinctions between Isoforms of Human and Mouse Sphingosine Kinases for Accelerating Drug Discovery

Worrell

Santos

Bevan

2019

J. Chem. Inf. Model.

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Probing the substitution pattern of indole-based scaffold reveals potent and selective sphingosine kinase 2 inhibitors

Congdon

Fritzemeier

Kharel

et al. 2021

European Journal of Medicinal Chemistry

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Elevated levels of sphingosine 1-phosphate (S1P) and increased expression of sphingosine kinase isoforms (SphK1 and SphK2) have been implicated in a variety of disease states including cancer, inflammation, autoimmunity, among others. Consequently, the S1P signaling axis has become an attractive target for drug discovery. Selective inhibition of either SphK1 or SphK2 has been demonstrated to be effective in modulating S1P levels in animal models. While SphK1 inhibitors have received much attention, the development of potent and selective SphK2 inhibitors are emerging. Previously, our group reported a SphK2 naphthalene-based selective inhibitor, SLC5081308, which displays approximately 7-fold selectivity for hSphK2 over hSphK1 and has a SphK2 K i value of 1.0 μM. To improve SphK2 potency and selectivity, we designed, synthesized, and evaluated a series of indole-based compounds derived from SLC5081308. After investigating substitution patterns around the indole ring, we discovered that 1,5-disubstitution promoted optimal binding in the SphK2 substrate binding site and subsequent inhibition of enzymatic activity. Our studies led to the identification of SLC5101465 (6r, SphK2 K i = 90 nM, >110 fold selective for SphK2 over SphK1). Molecular modeling studies revealed key nonpolar interactions with Val308, Phe548, His556, and Cys533 and hydrogen bonds with both Asp211 and Asp308 as responsible for the high SphK2 inhibition and selectivity.

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Left-sided acute appendicitis in a patient with situs inversus totalis: A case report and a comprehensive review

Mahat,

Bhusal,

Yadav

et al. 2024

Radiology Case Reports

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A Case Report on Left-sided Appendicitis with Intestinal Malrotation

Cited by 12 publications

References 18 publications

In Silico Characterization of Structural Distinctions between Isoforms of Human and Mouse Sphingosine Kinases for Accelerating Drug Discovery

In Silico Characterization of Structural Distinctions between Isoforms of Human and Mouse Sphingosine Kinases for Accelerating Drug Discovery

Probing the substitution pattern of indole-based scaffold reveals potent and selective sphingosine kinase 2 inhibitors

Left-sided acute appendicitis in a patient with situs inversus totalis: A case report and a comprehensive review

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