scholarly journals Albendazole reduces hepatic inflammation and endoplasmic reticulum-stress in a mouse model of chronic Echinococcus multilocularis infection

2022 ◽  
Vol 16 (1) ◽  
pp. e0009192
Author(s):  
Michael Weingartner ◽  
Simon Stücheli ◽  
Fadi Jebbawi ◽  
Bruno Gottstein ◽  
Guido Beldi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Echinococcus Multilocularis ◽  
Molecular Mechanisms ◽  
Disease Recurrence ◽  
Unfolded Protein ◽  
Programmed Death ◽  
Protein Response ◽  
Host Parasite ◽  
Related Proteins

Background Echinococcus multilocularis causes alveolar echinococcosis (AE), a rising zoonotic disease in the northern hemisphere. Treatment of this fatal disease is limited to chemotherapy using benzimidazoles and surgical intervention, with frequent disease recurrence in cases without radical surgery. Elucidating the molecular mechanisms underlying E. multilocularis infections and host-parasite interactions ultimately aids developing novel therapeutic options. This study explored an involvement of unfolded protein response (UPR) and endoplasmic reticulum-stress (ERS) during E. multilocularis infection in mice. Methods E. multilocularis- and mock-infected C57BL/6 mice were subdivided into vehicle, albendazole (ABZ) and anti-programmed death ligand 1 (αPD-L1) treated groups. To mimic a chronic infection, treatments of mice started six weeks post i.p. infection and continued for another eight weeks. Liver tissue was then collected to examine inflammatory cytokines and the expression of UPR- and ERS-related genes. Results E. multilocularis infection led to an upregulation of UPR- and ERS-related proteins in the liver, including ATF6, CHOP, GRP78, ERp72, H6PD and calreticulin, whilst PERK and its target eIF2α were not affected, and IRE1α and ATF4 were downregulated. ABZ treatment in E. multilocularis infected mice reversed, or at least tended to reverse, these protein expression changes to levels seen in mock-infected mice. Furthermore, ABZ treatment reversed the elevated levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in the liver of infected mice. Similar to ABZ, αPD-L1 immune-treatment tended to reverse the increased CHOP and decreased ATF4 and IRE1α expression levels. Conclusions and significance AE caused chronic inflammation, UPR activation and ERS in mice. The E. multilocularis-induced inflammation and consecutive ERS was ameliorated by ABZ and αPD-L1 treatment, indicating their effectiveness to inhibit parasite proliferation and downregulate its activity status. Neither ABZ nor αPD-L1 themselves affected UPR in control mice. Further research is needed to elucidate the link between inflammation, UPR and ERS, and if these pathways offer potential for improved therapies of patients with AE.

scholarly journals Albendazole reduces endoplasmic reticulum stress induced by Echinococcus multilocularis in mice

2021 ◽  
Author(s):  
Michael Weingartner ◽  
Fadi Jebbawi ◽  
Junhua Wang ◽  
Simon Stücheli ◽  
Bruno Gottstein ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Protein Expression ◽  
Echinococcus Multilocularis ◽  
Liver Tissue ◽  
Alveolar Echinococcosis ◽  
Surgical Intervention ◽  
Fatal Disease ◽  
Unfolded Protein ◽  
Protein Response

AbstractBackgroundEchinococcus multilocularis causes alveolar echinococcosis (AE), a rising zoonotic disease in the northern hemisphere. Treatment of this fatal disease is limited to chemotherapy using benzimidazoles and surgical intervention, with relatively frequent disease recurrence in cases without radical surgery. Elucidating the molecular mechanisms underlying E. multilocularis infections and host-parasite interactions aids developing novel therapeutic options. This study explored an involvement of unfolded protein response (UPR) and endoplasmic reticulum-stress (ERS) during E. multilocularis infection in mice.MethodsE. multilocularis- and mock-infected C57BL/6 mice were subdivided six weeks after infection into vehicle and albendazole (ABZ) treated groups. Eight weeks later, liver tissue was collected to examine mRNA, microRNA (miR) and protein expression of UPR- and ERS-related genes.ResultsE. multilocularis infection upregulated UPR- and ERS-related proteins, including ATF6, CHOP, GRP78, ERP72, H6PD and calreticulin, whilst PERK and its target eIF2α were not affected, and IRE1α and ATF4 were downregulated. ABZ treatment in E. multilocularis infected mice reversed the increased ATF6 and calreticulin protein expression, tended to reverse increased CHOP, GRP78, ERP72 and H6PD expression, and decreased ATF4 and IRE1α expression to levels seen in mock-infected mice. The expression of miR-146a-5p (downregulated by IRE1α) and miR-1839-5p (exhibiting a unique target site in the IRE1α 3’UTR) were significantly increased in E. multilocularis infected mice, an effect reversed by ABZ treatment. Other miRs analyzed were not altered in E. multilocularis infected mice.Conclusions and SignificanceAE causes UPR activation and ERS in mice. The E. multilocularis-induced ERS was ameliorated by ABZ treatment, indicating its effectiveness to inhibit parasite proliferation and downregulate its activity status. ABZ itself did not affect UPR in control mice. Identified miR-146a-5p and miR-1839-5p might represent biomarkers of E. multilocularis infection. Modulation of UPR and ERS, in addition to ABZ administration, could be exploited to treat E. multilocularis infection.Author summaryAlveolar echinococcosis is a zoonotic disease caused by the fox tapeworm Echinococcus multilocularis. Treatment of this fatal disease is limited to surgical intervention, preferably radical curative surgery if possible, and the use of parasitostatic benzimidazoles. It is not yet fully understood how the parasite can remain in the host’s tissue for prolonged periods, complicating the development of therapeutic applications. This work investigated an involvement of the unfolded protein response (UPR) and endoplasmic reticulum-stress (ERS) during E. multilocularis infection and upon treatment with albendazole (ABZ) in mice. The results revealed increased expression levels of the ERS sensor ATF6 and of downstream target genes in liver tissue of E. multilocularis- compared to mock-infected mice. Additionally, H6PD, generating NADPH within the endoplasmic reticulum, and the lectin-chaperone calreticulin were increased in E. multilocularis infected liver tissue while the expression of the ERS associated genes ATF4 and IRE1α were decreased. The miR-1839-5p and miR-146-p, linked to IRE1α, were elevated upon E. multilocularis infection, offering potential as novel biomarkers of alveolar echinococcosis. The observed gene expression changes were at least partially reversed by ABZ treatment. Whether modulation of UPR and ERS targets can improve the therapy of alveolar echinococcosis remains to be investigated.

scholarly journals Endoplasmic reticulum stress and pulmonary hypertension

2020 ◽  
Vol 10 (1) ◽  
pp. 204589401990012
Author(s):  
Yanan Hu ◽  
Wenhao Yang ◽  
Liang Xie ◽  
Tao Liu ◽  
Hanmin Liu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Pulmonary Hypertension ◽  
Endoplasmic Reticulum Stress ◽  
Molecular Mechanisms ◽  
Pathological Feature ◽  
Unfolded Protein ◽  
Mean Pulmonary Arterial Pressure ◽  
Potential Link ◽  
The Unfolded Protein Response ◽  
Protein Response

Pulmonary hypertension is a fatal disease of which pulmonary vasculopathy is the main pathological feature resulting in the mean pulmonary arterial pressure higher than 25 mmHg. Moreover, pulmonary hypertension remains a tough problem with unclear molecular mechanisms. There have been dozens of studies about endoplasmic reticulum stress during the onset of pulmonary hypertension in patients, suggesting that endoplasmic reticulum stress may have a critical effect on the pathogenesis of pulmonary hypertension. The review aims to summarize the rationale to elucidate the role of endoplasmic reticulum stress in pulmonary hypertension. Started by reviewing the mechanisms responsible for the unfolded protein response following endoplasmic reticulum stress, the potential link between endoplasmic reticulum stress and pulmonary hypertension were introduced, and the contributions of endoplasmic reticulum stress to different vascular cells, mitochondria, and inflammation were described, and finally the potential therapies of attenuating endoplasmic reticulum stress for pulmonary hypertension were discussed.

scholarly journals An essential dimer-forming subregion of the endoplasmic reticulum stress sensor Ire1

2005 ◽  
Vol 391 (1) ◽  
pp. 135-142 ◽  
Author(s):  
Daisuke Oikawa ◽  
Yukio Kimata ◽  
Masato Takeuchi ◽  
Kenji Kohno
Keyword(s):  
Endoplasmic Reticulum ◽  
Recombinant Protein ◽  
Endoplasmic Reticulum Stress ◽  
Transmembrane Protein ◽  
Type I ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Recombinant Fragments ◽  
Made In

The luminal domain of the type I transmembrane protein Ire1 senses endoplasmic reticulum stress by an undefined mechanism to up-regulate the signalling pathway for the unfolded protein response. Previously, we proposed that the luminal domain of yeast Ire1 is divided into five subregions, termed subregions I–V sequentially from the N-terminus. Ire1 lost activity when internal deletions of subregion II or IV were made. In the present paper, we show that partial proteolysis of a recombinant protein consisting of the Ire1 luminal domain suggests that subregions II–IV are tightly folded. We also show that a recombinant protein of subregions II–IV formed homodimers, and that this homodimer formation was impaired by an internal deletion of subregion IV. Furthermore, recombinant fragments of subregion IV exhibited a self-binding ability. Therefore, although its sequence is little conserved evolutionarily, subregion IV plays an essential role to promote Ire1 dimer formation.

scholarly journals Nox4 Mediates RANKL-induced ER-Phagy and Osteoclastogenesis via Activating ROS/PERK/eIF-2α/ATF4 Pathway

2020 ◽  
Author(s):  
Jing Sun ◽  
wugui chen ◽  
Songtao Li ◽  
Sizhen Yang ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Bone Resorption ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Nuclear Factor Κb ◽  
Protein Levels ◽  
Unfolded Protein ◽  
Regulatory Effects ◽  
Protein Response

Abstract Background: Receptor activator of nuclear factor-κB ligand (RANKL) has been found to induce osteoclastogenesis and bone resorption. However, the underlying molecular mechanisms remain unclear. Methods: Osteoclastogenesis was evaluated by number of TRAP-positive multinuclear (≥3) osteoclasts, bone resorption pits and expression levels of related genes. Autophagy activity were evaluated by LC3-II/LC3-I ratio, number of autophagic vacuoles and adenovirus-mRFP-GFP-tagged LC3 reporting system; Inhibitor chloroquine (CQ) was used to verified the role of autophagy in RANKL-induced osteoclastogenesis; Via downregulating Nox4 with inhibitor (DPI) and retrovirus-conveyed shRNA, we further explored the importance of Nox4 in RANKL-induced autophagy and osteoclastogenesis, as well as the regulatory effects of Nox4 on nonmitochondrial reactive oxygen species (ROS) and PERK/eIF-2α/ATF4 pathway. Intracellular ROS scavenger (NAC), mitochondrial-targeted antioxidant (MitoTEMPO) and inhibitor of PERK (GSK2606414) were also employed to investigate the role of ROS and PERK/eIF-2α/ATF4 pathway in RANKL-induced autophagy and osteoclastogenesis. Results: RANKL markedly increased autophagy, while CQ treatment caused reduction of RANKL-induced autophagy and osteoclastogenesis. Consistent with the increased autophagy, the protein levels of Nox4 were significantly increased, and Nox4 was selectively localized within the endoplasmic reticulum (ER) after RANKL stimulation. DPI and shRNA efficiently decreased the protein level and (or) activity of Nox4 in the ER and inhibited RANKL-induced autophagy and osteoclastogenesis. Mechanistically, we found that Nox4 regulates RANKL-induced autophagy activation and osteoclastogenesis by stimulating the production of nonmitochondrial ROS. Additionally, Nox4-derived nonmitochondrial ROS dramatically activate PERK/eIF-2α/ATF4, which is a critical unfolded protein response (UPR)-related signaling pathway during ER stress. Blocking the activation of the PERK/eIF-2α/ATF4 signaling pathway either by Nox4 shRNA, ROS antioxidant or PERK inhibitor (GSK2606414) treatment significantly inhibited endoplasmic reticulum autophagy (ER-phagy) during RANKL-induced osteoclastogenesis. Conclusions: Our findings provide new insights into the processes of RANKL-induced osteoclastogenesis and will help the development of new therapeutic strategies for osteoclastogenesis-related diseases.

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