&lt;p&gt;Proteasome, a Promising Therapeutic Target for Multiple Diseases Beyond Cancer&lt;/p&gt;

Cao, Ya; Zhu, Huajian; He, Ruoyu; Kong, Limin; Shao, Jiaan; Zhuang, Ran; Xi, Jianjun; Zhang, Jiankang

doi:10.2147/dddt.s265793

Cited by 18 publications

(20 citation statements)

References 105 publications

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“…Inhibition of the proteasome has been validated as an important strategy in anticancer therapy. [45][46][47][48][49] We suggest that proteasome inhibition may offer a novel option to prevent degradation of occludin and to restore intestinal barrier function.…”

Section: Mucosal Immunitymentioning

confidence: 99%

Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases

Haderer

Neubert

Rinner

et al. 2021

Gut

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ObjectiveSpontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis with a 1-year mortality of 66%. Bacterial translocation (BT) from the intestine to the mesenteric lymph nodes is crucial for the pathogenesis of SBP.DesignSince BT presupposes a leaky intestinal epithelium, the integrity of mucus and epithelial cell junctions (E-cadherin and occludin) was examined in colonic biopsies from patients with liver cirrhosis and controls. SBP-inducing Escherichia coli (E. coli) and Proteus mirabilis (P. mirabilis) were isolated from ascites of patients with liver cirrhosis and co-cultured with Caco-2 cells to characterise bacteria-to-cell effects.ResultsSBP-derived E. coli and P. mirabilis led to a marked reduction of cell-to-cell junctions in a dose-dependent and time-dependent manner. This effect was enhanced by a direct interaction of live bacteria with epithelial cells. Degradation of occludin is mediated via increased ubiquitination by the proteasome. Remarkably, a novel bacterial protease activity is of pivotal importance for the cleavage of E-cadherin.ConclusionPatients with liver cirrhosis show a reduced thickness of colonic mucus, which allows bacteria-to-epithelial cell contact. Intestinal bacteria induce degradation of occludin by exploiting the proteasome of epithelial cells. We identified a novel bacterial protease activity of patient-derived SBP-inducing bacteria, which is responsible for the cleavage of E-cadherin structures. Inhibition of this protease activity leads to stabilisation of cell junctions. Thus, targeting these mechanisms by blocking the ubiquitin-proteasome system and/or the bacterial protease activity might interfere with BT and constitute a novel innovative therapeutic strategy to prevent SBP in patients with liver cirrhosis.

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Section: Mucosal Immunitymentioning

confidence: 99%

Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases

Haderer

Neubert

Rinner

et al. 2021

Gut

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“…The proteasome is an important drug target in a variety of diseases [10][11][12]. Currently, three proteasome inhibitors, approved by the American Food and Drug Administration (FDA), are clinically used for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MVL) patients: bortezomib (Velcade) [41], carfilzomib (Kyprolis) [42] and ixazomib (Ninlaro) [43].…”

Section: Resultsmentioning

confidence: 99%

“…In humans, the dysfunction of this proteolytic machinery leads to changes in protein profile and, ultimately, to serious health problems. Therefore, proteasome regulators are explored as promising therapeutic agents for a range of diseases (e.g., cancer, autoimmune disorders, inflammation, malaria) [10][11][12]. The majority of the known 20S proteasome inhibitors belongs to peptide-based structures such as peptide aldehydes, boronates, epoxyketones, or peptide vinyl sulfones [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Nostocyclopeptides as New Inhibitors of 20S Proteasome

et al. 2021

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Nostocyclopeptides (Ncps) are a small class of bioactive nonribosomal peptides produced solely by cyanobacteria of the genus Nostoc. In the current work, six Ncps were isolated from Nostoc edaphicum strain CCNP1411. The bioactivity of these compounds was tested in vitro against 20S proteasome, a proteolytic complex that plays an important role in maintaining cellular proteostasis. Dysfunction of the complex leads to many pathological disorders. The assays indicated selective activity of specific Ncp variants. For two linear peptide aldehydes, Ncp-A2-L and Ncp-E2-L, the inhibitory effects on chymotrypsin-like activity were revealed, while the cyclic variant, Ncp-A2, inactivated the trypsin-like site of this enzymatic complex. The aldehyde group was confirmed to be an important element of the chymotrypsin-like activity inhibitors. The nostocyclopeptides, as novel inhibitors of 20S proteasome, increased the number of natural products that can be considered potential regulators of cellular processes.

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“…d. Omeprazole: Proton pump inhibitor. Proton pump inhibition reduces the expression of proteasome subunits, leading to proteasome inhibition (Cao et al, 2020). e. PYR-41: Ubiquitin Proteasome inhibitor.…”

Section: Inhibitors Of Protein Homeostasismentioning

confidence: 99%

A Screen of Autophagy Compounds Implicates the Proteasome in Mammalian Aminoglycoside-Induced Hair Cell Damage

Draf

Wyrick

Chávez

et al. 2021

Front. Cell Dev. Biol.

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Introduction: Autophagy is a degradative pathway to safely break down and recycle dysfunctional cellular components. There is prior evidence of autophagy participation during hair cell (HC) damage. Our goal was to screen compounds targeting different aspects of autophagy for their effects on HC loss due to an ototoxic aminoglycoside, gentamicin (GM).Methods: The SELLECKChem autophagy compound library, consisting of 154 compounds with defined autophagy inducing or inhibitory activity, was used for targeted screening in vitro model of ototoxicity. Organ of Corti from postnatal days 3–5 pou4f3/GFP transgenic mice (HCs express green fluorescent protein) were utilized. The organs were micro-dissected, and basal and middle turns divided into micro-explants individually placed into the single wells of a 96-well plate. Samples were treated with 200 μM of GM plus three dosages of tested compound and cultured for 72 h. Negative controls were treated with media only; positive ototoxicity controls were treated with GM only.Results: The majority of the library compounds had no effect on GM-induced HC loss. However, 18 compounds exhibited a significant, protective effect, two compounds were protective at low dosage but showed enhanced GM toxicity at higher doses and one compound was toxic to HCs in the absence of GM.Conclusions: This study evaluated many autophagy compounds that have not been tested previously on HCs. The disparate results obtained underscore the complexity of autophagy events that can influence HC responses to aminoglycosides, but also implicate the proteosome as an important damage mechanism. The screening results can serve as basis for further studies with protective compounds as potential drug targets.

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<p>Proteasome, a Promising Therapeutic Target for Multiple Diseases Beyond Cancer</p>

Cited by 18 publications

References 105 publications

Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases

Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases

Nostocyclopeptides as New Inhibitors of 20S Proteasome

A Screen of Autophagy Compounds Implicates the Proteasome in Mammalian Aminoglycoside-Induced Hair Cell Damage

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