A Septin Cytoskeleton-Targeting Small Molecule, Forchlorfenuron, Inhibits Epithelial Migration via Septin-Independent Perturbation of Cellular Signaling

Sun, Lei; Cao, Xuelei; Lechuga, Susana; Feygin, Alex; Naydenov, Nayden G.; Ivanov, Andrei I.

doi:10.3390/cells9010084

Cited by 18 publications

(17 citation statements)

References 59 publications

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“…The low toxicity level makes FCF a potential candidate for therapeutic applications of septin dependent disorders. However, off-target effects were reported before [ 40 , 41 ]. Modification of the chemical structure of FCF might lead to the development of new analogues with improved therapeutic potential and less side effects [ 42 , 43 ].…”

Section: Cell Biology Of Septinsmentioning

confidence: 98%

Septins in Infections: Focus on Viruses

2021

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Human septins comprise a family of 13 genes that encode conserved GTP-binding proteins. They form nonpolar complexes, which assemble into higher-order structures, such as bundles, scaffolding structures, or rings. Septins are counted among the cytoskeletal elements. They interact with the actin and microtubule networks and can bind to membranes. Many cellular functions with septin participation have been described in the literature, including cytokinesis, motility, forming of scaffolding platforms or lateral diffusion barriers, vesicle transport, exocytosis, and recognition of micron-scale curvature. Septin dysfunction has been implicated in diverse human pathologies, including neurodegeneration and tumorigenesis. Moreover, septins are thought to affect the outcome of host–microbe interactions. Implication of septins has been demonstrated in fungal, bacterial, and viral infections. Knowledge on the precise function of a particular septin in the different steps of the virus infection and replication cycle is still limited. Published data for vaccinia virus (VACV), hepatitis C virus (HCV), influenza A virus (H1N1 and H5N1), human herpesvirus 8 (HHV-8), and Zika virus (ZIKV), all of major concern for public health, will be discussed here.

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Section: Cell Biology Of Septinsmentioning

confidence: 98%

Septins in Infections: Focus on Viruses

2021

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“…The HT29 clone, HT29cl.f8, is derived from a single cell of HT29 and spontaneously polarizes under standard conditions in glucose and display important characteristics for permeability studies such as microvilli, tight junctions and a high TER [178]. This particular clone, can therefore be an alternative and have been used in several studies to model the intestinal barrier [179,180].…”

Section: Ht29 Cell Linementioning

confidence: 99%

The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability

Schoultz

Keita

2020

Cells

314

222

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The intestinal barrier is essential in human health and constitutes the interface between the outside and the internal milieu of the body. A functional intestinal barrier allows absorption of nutrients and fluids but simultaneously prevents harmful substances like toxins and bacteria from crossing the intestinal epithelium and reaching the body. An altered intestinal permeability, a sign of a perturbed barrier function, has during the last decade been associated with several chronic conditions, including diseases originating in the gastrointestinal tract but also diseases such as Alzheimer and Parkinson disease. This has led to an intensified interest from researchers with diverse backgrounds to perform functional studies of the intestinal barrier in different conditions. Intestinal permeability is defined as the passage of a solute through a simple membrane and can be measured by recording the passage of permeability markers over the epithelium via the paracellular or the transcellular route. The methodological tools to investigate the gut barrier function are rapidly expanding and new methodological approaches are being developed. Here we outline and discuss, in vivo, in vitro and ex vivo techniques and how these methods can be utilized for thorough investigation of the intestinal barrier.

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“…Indeed, several studies have demonstrated that loss of SEPT7 destabilizes other subunits of the septin oligomers and triggers their degradation. 27,28 The septin rod oligomers spontaneously collide to form short filaments that can further assemble by end-to-end joining or lateral interactions into bundles, rings, gauzes, and sheer-like structures (Figure 1). 8,29 It is noteworthy that the composition of septin oligomers is primarily based on the in vitro reconstitution studies that utilized purified recombinant septin proteins.…”

Section: Assembly and Interactions Of Septin Proteinsmentioning

confidence: 99%

“…85 Downregulation of SEPT2 and SEPT7 expression increases permeability of model bronchial and intestinal epithelial cell monolayers, respectively. 28,85 In vascular endothelium, loss of SEPT2 accelerates leakiness of a resting endothelial barrier, 86 as well as exaggerates barrier disruption and attenuates barrier recovery following endothelial stimulation with thrombin. 87 Interestingly, increased vascular permeability of SEPT2-depleted endothelium promotes transendothelial migration of natural killer cells.…”

Section: Regulation Of Tissue Barriersmentioning

confidence: 99%

“…Furthermore, possible off-target effects and animal tissue toxicity of FCF have been reported. 28,111,113 Nevertheless, studies utilizing FCF have laid the ground for the development of next-generation septin inhibitors. We expect that these inhibitors will be first developed as anticancer drugs, given the substantial body of evidence about mutations or altered expression of different septin paralogs being associated with tumorigenesis.…”

Section: Tissue Fibrosismentioning

confidence: 99%

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Novel Functions of the Septin Cytoskeleton

Ivanov

Naydenov

et al. 2021

The American Journal of Pathology

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Chronic inflammatory diseases cause profound alterations in tissue homeostasis, including unchecked activation of immune and nonimmune cells leading to disease complications such as aberrant tissue repair and fibrosis. Current anti-inflammatory therapies are often insufficient in preventing or reversing these complications. Remodeling of the intracellular cytoskeleton is critical for cell activation in inflamed and fibrotic tissues; however, the cytoskeleton has not been adequately explored as a therapeutic target in inflammation. Septins are GTP-binding proteins that self-assemble into higher order cytoskeletal structures. The septin cytoskeleton exhibits a number of critical cellular functions, including regulation of cell shape and polarity, cytokinesis, cell migration, vesicle trafficking, and receptor signaling. Surprisingly, little is known about the role of the septin cytoskeleton in inflammation. This article reviews emerging evidence implicating different septins in the regulation of hostpathogen interactions, immune cell functions, and tissue fibrosis. Targeting of the septin cytoskeleton as a potential future therapeutic intervention in human inflammatory and fibrotic diseases is also discussed.

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A Septin Cytoskeleton-Targeting Small Molecule, Forchlorfenuron, Inhibits Epithelial Migration via Septin-Independent Perturbation of Cellular Signaling

Cited by 18 publications

References 59 publications

Septins in Infections: Focus on Viruses

Septins in Infections: Focus on Viruses

The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability

Novel Functions of the Septin Cytoskeleton

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