Mild electrical stimulation with heat shock attenuates renal pathology in adriamycin-induced nephrotic syndrome mouse model

Abstract Nephrotic syndrome (NS) is a renal disorder that is characterized by massive proteinuria, hypoalbuminemia and edema. One of the main causes of NS is focal segmental glomerulosclerosis (FSGS), which has extremely poor prognosis. Although steroids and immunosuppressants are the first line of treatment, some FSGS cases are refractory, prompting the need to find new therapeutic strategies. We have previously demonstrated that an optimized combination treatment of mild electrical stimulation (MES) and heat shock (HS) has several biological benefits including the amelioration of the pathologies of the genetic renal disorder Alport syndrome. Here, we investigated the effect of MES + HS on adriamycin (ADR)-induced NS mouse model. MES + HS suppressed proteinuria and glomerulosclerosis induced by ADR. The expressions of pro-inflammatory cytokines and pro-fibrotic genes were also significantly downregulated by MES + HS. MES + HS decreased the expression level of cleaved caspase-3 and the number of TUNEL-positive cells, indicating that MES + HS exerted anti-apoptotic effect. Moreover, MES + HS activated the Akt signaling and induced the phosphorylation and inhibition of the apoptotic molecule BAD. In in vitro experiment, the Akt inhibitor abolished the MES + HS-induced Akt-BAD signaling and anti-apoptotic effect in ADR-treated cells. Collectively, our study suggested that MES + HS modulates ADR-induced pathologies and has renoprotective effect against ADR-induced NS via regulation of Akt-BAD axis.

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Mild Electrical Stimulation and Heat Shock Ameliorates Progressive Proteinuria and Renal Inflammation in Mouse Model of Alport Syndrome

PLoS ONE ◽

10.1371/journal.pone.0043852 ◽

2012 ◽

Vol 7 (8) ◽

pp. e43852 ◽

Cited By ~ 16

Author(s):

Tomoaki Koga ◽

Yukari Kai ◽

Ryosuke Fukuda ◽

Saori Morino-Koga ◽

Mary Ann Suico ◽

...

Keyword(s):

Electrical Stimulation ◽

Heat Shock ◽

Mouse Model ◽

Alport Syndrome ◽

Renal Inflammation

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IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases

Scientific Reports ◽

10.1038/s41598-019-53240-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 9

Author(s):

Arun K. Kannan ◽

Zhi Su ◽

Donna M. Gauvin ◽

Stephanie E. Paulsboe ◽

Ryan Duggan ◽

...

Keyword(s):

T Cells ◽

Mouse Model ◽

Skin Diseases ◽

Treg Cells ◽

Model Systems ◽

Cell Plasticity ◽

Inflammatory Skin Diseases ◽

Pro Inflammatory Cytokines

AbstractFoxp3+ regulatory T cells (Tregs) represent a major fraction of skin resident T cells. Although normally protective, Tregs have been shown to produce pro-inflammatory cytokines in human diseases, including psoriasis. A significant hurdle in the Treg field has been the identification, or development, of model systems to study this Treg plasticity. To overcome this gap, we analyzed skin resident Tregs in a mouse model of IL-23 mediated psoriasiform dermatitis. Our results demonstrate that IL-23 drove the accumulation of Tregs; including a subpopulation that co-expressed RORγt and produced IL-17A. Genesis of this population was attenuated by a RORγt inverse agonist compound and clinically relevant therapeutics. In vitro, IL-23 drove the generation of CD4+Foxp3+RORγt+IL-17A+ cells from Treg cells. Collectively, our data shows that IL-23 drives Treg plasticity by inducing a population of CD4+Foxp3+RORγt+IL-17A+ cells that could play a role in the disease pathogenesis. Through this work, we define an in vitro system and a pre-clinical in vivo mouse model that can be used to further study Treg homeostasis and plasticity in the context of psoriasis.

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Wolbachia heat shock protein 60 induces pro-inflammatory cytokines and apoptosis in monocytes in vitro

Microbes and Infection ◽

10.1016/j.micinf.2012.01.008 ◽

2012 ◽

Vol 14 (7-8) ◽

pp. 610-618 ◽

Cited By ~ 8

Author(s):

Vijayan Kamalakannan ◽

Sreenivas Kirthika ◽

Kalyanaraman Haripriya ◽

Subash Babu ◽

Rangarajan Badri Narayanan

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Inflammatory Cytokines ◽

Heat Shock Protein 60 ◽

Pro Inflammatory Cytokines

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Hepatitis B virus induces sorafenib resistance in liver cancer via upregulation of cIAP2 expression

Infectious Agents and Cancer ◽

10.1186/s13027-021-00359-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Shouhua Zhang ◽

Nuoya Li ◽

Yanling Sheng ◽

Wen Chen ◽

Qiangliang Ma ◽

...

Keyword(s):

Liver Cancer ◽

Mouse Model ◽

Cell Viability ◽

Caspase 3 ◽

Cancer Cell Line ◽

Akt Inhibitor ◽

Sorafenib Treatment ◽

Apoptosis Protein ◽

The Impact

Abstract Background HBV promotes cell survival by upregulating the expression of the cellular inhibitor of apoptosis protein 2 (cIAP2), however whether it is involved in HBV-induced sorafenib resistance in liver cancer remains unclear. Methods cIAP2 overexpression and knockdown was adopted to assess the involvement of cIAP2 in HBV-induced sorafenib resistance. Anti-HBV drug lamivudine and Akt inhibitor were used to investigate the impact of HBV replication on cIAP2 expression and sorafenib resistance. Xenotransplantation mouse model was used to confirm the data on cell lines in vitro. Results Liver cancer cell line HepG2.215 showed increased cIAP2 expression and enhanced resistance to sorafenib. Upon sorafenib treatment, overexpression of cIAP2 in HepG2 lead to decreased cleaved caspase 3 level and increased cell viability, while knockdown of cIAP2 in HepG2.215 resulted in increased level of cleaved caspase 3 and decreased cell viability, suggesting the involvement of cIAP2 in HBV-induced sorafenib resistance. Furthermore, anti-HBV treatment reduced cIAP2 expression and partially restored sorafenib sensitivity in HepG2.215 cells. Xenotransplantation mouse model further confirmed that co-treatment with lamivudine and sorafenib could reduce sorafenib-resistant HepG2.215 tumor cell growth. Conclusion cIAP2 is involved in HBV-induced sorafenib resistance in liver cancer and anti-HBV treatments reduce cIAP2 expression and partially restore sorafenib sensibility.

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Fingolimod phosphate inhibits astrocyte inflammatory activity in mucolipidosis IV

Human Molecular Genetics ◽

10.1093/hmg/ddy182 ◽

2018 ◽

Vol 27 (15) ◽

pp. 2725-2738 ◽

Cited By ~ 9

Author(s):

Laura D Weinstock ◽

Amanda M Furness ◽

Shawn S Herron ◽

Sierra S Smith ◽

Sitara B Sankar ◽

...

Keyword(s):

Mouse Model ◽

Protein Signaling ◽

Loss Of Function ◽

Neurodevelopmental Disease ◽

Mapk Pathways ◽

Inflammatory Activation ◽

Mucolipidosis Iv ◽

Pro Inflammatory Cytokines

Abstract Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dysfunction and loss of vision. Currently there is no therapy for MLIV. It is caused by loss of function of the lysosomal channel mucolipin-1, also known as TRPML1. Knockout of the Mcoln1 gene in a mouse model mirrors clinical and neuropathologic signs in humans. Using this model, we previously observed robust activation of microglia and astrocytes in early symptomatic stages of disease. Here we investigate the consequence of mucolipin-1 loss on astrocyte inflammatory activation in vivo and in vitro and apply a pharmacologic approach to restore Mcoln1−/− astrocyte homeostasis using a clinically approved immunomodulator, fingolimod. We found that Mcoln1−/− mice over-express numerous pro-inflammatory cytokines, some of which were also over-expressed in astrocyte cultures. Changes in the cytokine profile in Mcoln1−/− astrocytes are concomitant with changes in phospho-protein signaling, including activation of PI3K/Akt and MAPK pathways. Fingolimod promotes cytokine homeostasis, down-regulates signaling within the PI3K/Akt and MAPK pathways and restores the lysosomal compartment in Mcoln1−/− astrocytes. These data suggest that fingolimod is a promising candidate for preclinical evaluation in our MLIV mouse model, which, in case of success, can be rapidly translated into clinical trial.

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Mild electrical stimulation with heat shock reduces inflammatory symptoms in the imiquimod-induced psoriasis mouse model

Experimental Dermatology ◽

10.1111/exd.13720 ◽

2018 ◽

Vol 27 (10) ◽

pp. 1092-1097 ◽

Cited By ~ 2

Author(s):

Yu Tsurekawa ◽

Misaki Morita ◽

Mary Ann Suico ◽

Masataka Moriuchi ◽

Yoshio Nakano ◽

...

Keyword(s):

Electrical Stimulation ◽

Heat Shock ◽

Mouse Model

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Mild electrical stimulation and heat shock suppress renal pathology in adriamycin-induced nephrotic syndrome model

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.wcp2018.0_po1-3-17 ◽

2018 ◽

Vol WCP2018 (0) ◽

pp. PO1-3-17

Author(s):

Keisuke Teramoto ◽

Kohei Omachi ◽

Tsubasa Yokota ◽

Misato Kamura ◽

Yu Tsurekawa ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Electrical Stimulation ◽

Heat Shock ◽

Renal Pathology

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AKT inhibitor SC66 inhibits proliferation and induces apoptosis in human glioblastoma through down-regulating AKT/β-catenin pathway

10.21203/rs.3.rs-17363/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lun Gao ◽

Junhui Liu ◽

Pengfei Xu ◽

Gang Deng ◽

Baohui Liu ◽

...

Keyword(s):

Cell Cycle ◽

Mouse Model ◽

Migration And Invasion ◽

Control Group ◽

Dependent Manner ◽

Akt Inhibitor ◽

Antitumor Effects ◽

Xenograft Mouse Model ◽

Limited Effectiveness

Abstract Background ： Glioblastoma multiforme (GBM) is the most common and deadliest type of primary malignant tumor in the adult central nervous system. Temozolomide (TMZ) has limited effectiveness on glioblastoma, so it is urgent to develop new drugs to improve the prognosis of patients. SC66, a novel AKT inhibitor, was reported to exert antiproliferative activity in many types of cancer cells. However, it remains unclear whether SC66 has antitumor effects in GBM. Methods : Cell count kits-8(CCK8) assay, EdU-DNA incorporation assay and colony formation assay were used to evaluate cell proliferation of U87 and U251 cells.Wound -healing assay and transwell assay were used to detect migration and invasion. The cell cycle and apoptosis were detected by flow cytometry. Finally, xenograft mouse model was established to demonstrate the antitumor effect of SC66 in vitro. Results :SC66 obviously suppressed U87 and U251 cells proliferation in a dose-dependent manner. Additionally, SC66 treatment was found to significantly inhibit the invasion and migration of GBM cells as detected by Transwell invasion and wound healing assays. Moreover, treatment of SC66 induced GBM cells apoptosis through up-regulating BAX, Cleaved -caspase3 and down-regulating Bcl-2. SC66 also could arrested cell cycle in G0/G1 phase by decreasing cyclin D1.Furthermore, the results of western blot showed that SC66 significantly reduced level of phosphorylation of AKT, p-GSK-3β and β-catenin, while no change was observed in level of AKT and GSK3β.Then a GSK3-inhibitor,IM-12 was used and IM-12 could significantly restored proliferation, migration and invasion of glioma cells treated with SC66.Meanwhile, SC66 showed significantly suppressed the tumorigenicity compared to the control group in the xenograft mouse model. Conclusion : AKT inhibitor SC66 exerted powerful antitumor activity via down-regulating AKT/β-catenin pathways in vitro and in vivo. It might be as a potential chemotherapy drug to improve the therapeutic efficacy of GBM treatments.

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LY53857, a 5HT2 Receptor Antagonist, Delays Occlusion and Inhibits Platelet Aggregation in a Rabbit Model of Carotid Artery Occlusion

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646420 ◽

1991 ◽

Vol 66 (03) ◽

pp. 355-360 ◽

Cited By ~ 4

Author(s):

Harve C Wilson ◽

William Coffman ◽

Anne L Killam ◽

Marlene L Cohen

Keyword(s):

Electrical Stimulation ◽

Platelet Aggregation ◽

Carotid Artery ◽

Receptor Antagonist ◽

Artery Occlusion ◽

Carotid Artery Occlusion ◽

Rabbit Platelet ◽

Rabbit Platelets ◽

5Ht2 Receptor

SummaryThe present study was designed to evaluate the effectiveness of the ergoline 5HT2 receptor antagonist, LY53857 in a rabbit model of vascular arterial occlusion. LY53857 (1 and 10 εM) inhibited serotonin amplified platelet aggregation responses to threshold concentrations of ADP in rabbit platelets in vitro. LY53857 (1 εM) not only inhibited the serotonin component of rabbit platelet aggregation, but also inhibited in vitro aggregation induced by ADP (48.7 ± 16.7% inhibition), collagen (76.1 ± 15.9% inhibition) and U46619 (65.2 ± 12.3% inhibition). The effectiveness of this ergoline 5HT2 receptor antagonist in blocking aggregation to ADP, collagen and U46619 may be related to its ability to inhibit a serotonin component of platelet aggregation since rabbit platelets possess high concentrations of serotonin that may be released during aggregation produced by other agents. Based on the effectiveness of LY53857 to inhibit rabbit platelet aggregation, we explored the ability of LY53857 to extend the time to carotid artery occlusion in rabbits following electrical stimulation of the artery. Reproducible carotid artery occlusion was induced in rabbits by moderate stenosis coupled to arterial cross clamping, followed by electrical stimulation. With this procedure, occlusion occurred at 47.0 ± 7 min (n = 30) after initiation of the electrical stimulation. Animals pretreated with LY53857 (50 to 500 εg/kg i.v.) showed a delay in the time to carotid artery occlusion (at 100 εg/kg i.v. occlusion time extended to 164 ± 16 min). Furthermore, ex vivo platelet aggregation from animals treated with LY53857 (300 εg/kg i.v.) resulted in 40.5% inhibition of platelet aggregation in response to the combination of ADP (1 εM) and serotonin (1 εM). These studies document the ability to obtain reproducible arterial occlusion in the rabbit and showed that intravenously administered LY53857 prolonged the time to carotid artery occlusion. Prolongation of carotid artery occlusion time was accompanied by inhibition of serotonin-amplified ADP-induced aggregation in rabbit platelets, an effect observed both in vitro and ex vivo. Thus, the rabbit is a useful model for studying the effectiveness of 5HT2 receptor antagonists in prolonging vascular occlusion induced by insult of the carotid artery.

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