Faculty Opinions recommendation of Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model.

This study aimed to assess the efficacy and explore the mechanisms of action of a potent phosphodiesterase (PDE)7A and a moderate PDE4B inhibitor GRMS-55 in a mouse model of autoimmune hepatitis (AIH). The concentrations of GRMS-55 and relevant biomarkers were measured in the serum of BALB/c mice with concanavalin A (ConA)-induced hepatitis administered with GRMS-55 at two dose levels. A semi-mechanistic PK/PD/disease progression model describing the time courses of measured biomarkers was developed. The emetogenicity as a potential side effect of the studied compound was evaluated in the α2-adrenoceptor agonist-induced anesthesia model. The results indicate that liver damage observed in mice challenged with ConA was mainly mediated by TNF-α and IFN-γ. GRMS-55 decreased the levels of pro-inflammatory mediators and the transaminase activities in the serum of mice with AIH. The anti-inflammatory properties of GRMS-55, resulting mainly from PDE7A inhibition, led to a high hepatoprotective activity in mice with AIH, which was mediated by an inhibition of pro-inflammatory signaling. GRMS-55 did not induce the emetic-like behavior. The developed PK/PD/disease progression model may be used in future studies to assess the potency and explore the mechanisms of action of new investigational compounds for the treatment of AIH.

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Berberine Prevents Disease Progression of Nonalcoholic Steatohepatitis through Modulating Multiple Pathways

Cells ◽

10.3390/cells10020210 ◽

2021 ◽

Vol 10 (2) ◽

pp. 210

Author(s):

Yanyan Wang ◽

Yun-Ling Tai ◽

Derrick Zhao ◽

Yuan Zhang ◽

Junkai Yan ◽

...

Keyword(s):

Bile Acid ◽

Mouse Model ◽

Disease Progression ◽

Nonalcoholic Steatohepatitis ◽

Noncoding Rna ◽

Metabolic Diseases ◽

Immune Cell ◽

Stellate Cell ◽

Clinical Investigation ◽

Beneficial Effects

Background and Aims: The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC–MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR’s beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.

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Hdac6 deletion delays disease progression in the SOD1G93A mouse model of ALS

Human Molecular Genetics ◽

10.1093/hmg/ddt028 ◽

2013 ◽

Vol 22 (9) ◽

pp. 1783-1790 ◽

Cited By ~ 76

Author(s):

Ines Taes ◽

Mieke Timmers ◽

Nicole Hersmus ◽

André Bento-Abreu ◽

Ludo Van Den Bosch ◽

...

Keyword(s):

Mouse Model ◽

Disease Progression ◽

Sod1g93a Mouse

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Slowing disease progression in the SOD1 mouse model of ALS by blocking neuregulin-induced microglial activation

Neurobiology of Disease ◽

10.1016/j.nbd.2017.12.012 ◽

2018 ◽

Vol 111 ◽

pp. 118-126 ◽

Cited By ~ 9

Author(s):

Jianguo Liu ◽

Elise Allender ◽

Jiajing Wang ◽

Eleanor H. Simpson ◽

Jeffrey A. Loeb ◽

...

Keyword(s):

Mouse Model ◽

Disease Progression ◽

Microglial Activation ◽

Sod1 Mouse

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T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0804610105 ◽

2008 ◽

Vol 105 (46) ◽

pp. 17913-17918 ◽

Cited By ~ 209

Author(s):

Isaac M. Chiu ◽

Adam Chen ◽

Yi Zheng ◽

Bela Kosaras ◽

Stefanos A. Tsiftsoglou ◽

...

Keyword(s):

T Cells ◽

Mouse Model ◽

Disease Progression ◽

Cholesterol Metabolism ◽

Cell Receptor ◽

Specific Flow ◽

Innate And Adaptive Immunity ◽

Expression Of Genes ◽

Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease, in which the role of inflammation is not well established. Innate and adaptive immunity were investigated in the CNS of the Superoxide Dismutase 1 (SOD1)G93A transgenic mouse model of ALS. CD4+ and CD8+ T cells infiltrated SOD1G93A spinal cords during disease progression. Cell-specific flow cytometry and gene expression profiling showed significant phenotypic changes in microglia, including dendritic cell receptor acquisition, and expression of genes linked to neuroprotection, cholesterol metabolism and tissue remodeling. Microglia dramatically up-regulated IGF-1 and down-regulated IL-6 expression. When mutant SOD1 mice were bred onto a TCRβ deficient background, disease progression was significantly accelerated at the symptomatic stage. In addition, microglia reactivity and IGF-1 levels were reduced in spinal cords of SOD1G93A (TCRβ−/−) mice. These results indicate that T cells play an endogenous neuroprotective role in ALS by modulating a beneficial inflammatory response to neuronal injury.

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N-Acylethanolamine Acid Amidase contributes to disease progression in a mouse model of multiple sclerosis

Pharmacological Research ◽

10.1016/j.phrs.2020.105064 ◽

2020 ◽

Vol 160 ◽

pp. 105064

Author(s):

Silvia Pontis ◽

Francesca Palese ◽

Maria Summa ◽

Natalia Realini ◽

Massimiliano Lanfranco ◽

...

Keyword(s):

Multiple Sclerosis ◽

Mouse Model ◽

Disease Progression

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The De-Ubiquitinating Enzyme Ataxin-3 does not Modulate Disease Progression in a Knock-in Mouse Model of Huntington Disease

Journal of Huntington s Disease ◽

10.3233/jhd-130058 ◽

2013 ◽

Vol 2 (2) ◽

pp. 201-215 ◽

Cited By ~ 14

Author(s):

Li Zeng ◽

Sara J. Tallaksen-Greene ◽

Bo Wang ◽

Roger L. Albin ◽

Henry L. Paulson

Keyword(s):

Mouse Model ◽

Disease Progression ◽

Huntington Disease

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Characterization of the Contribution of Genetic Background and Gender to Disease Progression in the SOD1 G93A Mouse Model of Amyotrophic Lateral Sclerosis: A Meta-Analysis

Journal of Neuromuscular Diseases ◽

10.3233/jnd-140068 ◽

2015 ◽

Vol 2 (2) ◽

pp. 137-150 ◽

Cited By ~ 40

Author(s):

Stephen R. Pfohl ◽

Martin T. Halicek ◽

Cassie S. Mitchell

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Disease Progression ◽

Genetic Background ◽

Meta Analysis ◽

And Gender ◽

Lateral Sclerosis ◽

Sod1 G93a Mouse

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Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease

Journal of Biological Rhythms ◽

10.1177/0748730418790401 ◽

2018 ◽

Vol 33 (5) ◽

pp. 535-554 ◽

Cited By ~ 11

Author(s):

Daniel S. Whittaker ◽

Dawn H. Loh ◽

Huei-Bin Wang ◽

Yu Tahara ◽

Dika Kuljis ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Progression ◽

Sleep Onset ◽

Lifestyle Changes ◽

Disease Stage ◽

Preclinical Model ◽

Delay Disease Progression ◽

Circadian Dysfunction

Huntington’s disease (HD) patients suffer from progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep-wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and excessive fatigue. The BACHD mouse model exhibits many HD core symptoms including circadian dysfunction. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early interventions that improve circadian rhythmicity could benefit HD symptoms and delay disease progression. We evaluated the effects of time-restricted feeding (TRF) on the BACHD mouse model. At 3 months of age, the animals were divided into 2 groups: ad lib and TRF. The TRF-treated BACHD mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle (ZT 15-21) of the period when mice are normally active (ZT 12-24). Following 3 months of treatment (when mice reached the early disease stage), the TRF-treated BACHD mice showed improvements in their locomotor activity and sleep behavioral rhythms. Furthermore, we found improved heart rate variability, suggesting that their autonomic nervous system dysfunction was improved. On a molecular level, TRF altered the phase but not the amplitude of the PER2::LUC rhythms measured in vivo and in vitro. Importantly, treated BACHD mice exhibited improved motor performance compared with untreated BACHD controls, and the motor improvements were correlated with improved circadian output. It is worth emphasizing that HD is a genetically caused disease with no known cure. Lifestyle changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of circadian-based treatment strategies in a preclinical model of HD.

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