Rottlerin inhibits La Crosse virus-induced encephalitis in mice and blocks release of replicating virus from the Golgi body in neurons

Ojha, Durbadal; Winkler, Clayton W.; Leung, Jacqueline M.; Woods, Tyson A.; Chen, Catherine Z.; Nair, Vinod; Taylor, Katherine; Yeh, Charles D.; Tawa, Gregory J.; Larson, Carl L.; Zheng, Wei; Haigh, Cathryn L.; Peterson, Karin E.

doi:10.1038/s41564-021-00968-y

Cited by 21 publications

(17 citation statements)

References 45 publications

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“…In A549 cells, the CC 50 is 47.78 μmol/L, while it effectively inhibits the ZIKV replication at 2.5 μmol/L. This finding is consistent with other reports ( Ojha et al., 2021a ), and is also supported by a fact that rottlerin has been used as an herb in India, treating a variety of diseases including kapha and bleeding disorders, infection of worms, and abdominal tumors, etc. The reduction of cell viability caused by high dose rottlerin might be due to reduced ATP level or PKC activity.…”

Section: Discussionsupporting

confidence: 91%

“…Interestingly, rottlerin confers inhibitory activity against many pathogens, including viruses, parasite ( Ietta et al., 2017 ), and bacteria ( Pandey et al., 2016 ; Shivshankar et al., 2008 ) in cultured cells and in animal models ( Kang et al., 2021 ; Ojha et al., 2021a ). The anti-pathogen effect of rottlerin is exerted either through inhibiting the activation of PKCδ, such as human immunodeficiency virus (HIV-1), human T-lymphotropic virus (HTLV-1), Rift valley fever virus (RVFV), and porcine reproductive and respiratory syndrome virus (PRRSV) ( Contreras et al., 2012 ; Filone et al., 2010 ; Kang et al., 2021 ; Mori et al., 2015 ), or through reducing the ATP levels (such as rabies virus) ( Lama et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Rottlerin plays an antiviral role at early and late steps of Zika virus infection

Zhou¹,

Lin²,

Huang³

et al. 2022

Virologica Sinica

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Rottlerin plays an antiviral role at early and late steps of Zika virus infection

Zhou¹,

Lin²,

Huang³

et al. 2022

Virologica Sinica

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“…A robust IFN response protected LACV-infected NPCs from cell death, while both infected and adjacent neurons underwent apoptosis [ 101 ]. Treatment of 3 and 11 week old cortical organoids with rottlerin inhibited LACV replication and limited virus induced reduction in organoid viability [ 102 ].…”

Section: Resultsmentioning

confidence: 99%

Human Brain Organoids as Models for Central Nervous System Viral Infection

Depla

Mulder

Sá

et al. 2022

Viruses

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Pathogenesis of viral infections of the central nervous system (CNS) is poorly understood, and this is partly due to the limitations of currently used preclinical models. Brain organoid models can overcome some of these limitations, as they are generated from human derived stem cells, differentiated in three dimensions (3D), and can mimic human neurodevelopmental characteristics. Therefore, brain organoids have been increasingly used as brain models in research on various viruses, such as Zika virus, severe acute respiratory syndrome coronavirus 2, human cytomegalovirus, and herpes simplex virus. Brain organoids allow for the study of viral tropism, the effect of infection on organoid function, size, and cytoarchitecture, as well as innate immune response; therefore, they provide valuable insight into the pathogenesis of neurotropic viral infections and testing of antivirals in a physiological model. In this review, we summarize the results of studies on viral CNS infection in brain organoids, and we demonstrate the broad application and benefits of using a human 3D model in virology research. At the same time, we describe the limitations of the studies in brain organoids, such as the heterogeneity in organoid generation protocols and age at infection, which result in differences in results between studies, as well as the lack of microglia and a blood brain barrier.

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“… 27 Rottlerin, a PKC inhibitor, has antiviral role for La Crosse virus. 28 Clofibrate, peroxisome proliferator-activated receptor-alpha (PPARα) agonist, was reported to reduce oxidative stress, improved antioxidant status. 29 Ikarugamycin was showed anti antibacterial activity against Intracellular Staphylococcus aureus.…”

Section: Resultsmentioning

confidence: 99%

Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea

Wang¹,

Wang²,

Huang³

et al. 2022

JIR

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Objective Rosacea is a chronic inflammatory skin disease with high morbidity. Previous studies have described the contribution of skin barrier dysfunction (SBD) in the progression of rosacea, but the specific mechanism remains unclear. In this study, we aim to investigate the key genes that may involve SBD-mediated rosacea aggravation. Methods In this study, we evaluated the SBD patterns of rosacea based on the expression of 23 skin barrier-related genes (SBRGs) using a consensus clustering analysis, and revealed the SBD-mediated immune cells infiltration in rosacea using GSE65914 dataset. The key genes associated with SBD and rosacea progression were identified using WGCNA analysis and then verified in rosacea mice model. Results Two distinct SBD patterns (moderate- and high-SBD patterns) were determined in rosacea. GO, KEGG and GSEA analysis revealed the differently immune-related signal pathways between two SBD patterns in rosacea. The XCell immune cell assays showed that the increased immune infiltration with SBD. Subsequently, the WGCNA analysis identified STAT3 as the hub gene related to rosacea and SBD, and correlation analysis revealed that STAT3 could contribute to the progression of rosacea partly by dysregulating immune infiltration via activating the cytokine/chemokines signal. Finally, the up-regulated STAT3 was verified in the epidermis of rosacea tissues and correlated with SBRGs expression using IHC and epidermal transcriptome data of rosacea. The vivo experiment showed that tape stripping-induced SBD evidently induced the expression of STAT3 and increased CD4 + T cell infiltration in LL37-induced rosacea-like skin lesion in mice. Conclusion In conclusion, our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes.

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Rottlerin inhibits La Crosse virus-induced encephalitis in mice and blocks release of replicating virus from the Golgi body in neurons

Cited by 21 publications

References 45 publications

Rottlerin plays an antiviral role at early and late steps of Zika virus infection

Rottlerin plays an antiviral role at early and late steps of Zika virus infection

Human Brain Organoids as Models for Central Nervous System Viral Infection

Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea

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