Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver disease DOI Creative Commons
Lijuan Wang, Chenglei Zhang, Jie Ma

et al.

European journal of medical research, Journal Year: 2025, Volume and Issue: 30(1)

Published: April 17, 2025

Abstract Background Non-alcoholic steatohepatitis (NASH) progression is strongly associated with deteriorating hepatic function, primarily driven by free cholesterol (FC) accumulation-induced lipotoxicity. Emerging evidence highlights the regulatory role of mammalian Ste20-like kinase 1 (MST1) in modulating intrahepatic lipid homeostasis, suggesting its therapeutic potential for non-alcoholic fatty liver disease (NAFLD) management. This investigation seeks to elucidate pathophysiological mechanisms through which MST1 modulates NASH progression. Methods The experimental design employed two murine genetic models—wild-type (WT) controls and MST1-knockout (MST1-KO) specimens—subjected a nutritionally modified Western diet (WD) enriched saturated fats, simple carbohydrates, dietary induce pathogenesis. Lentiviral transduction techniques facilitated targeted overexpression WT animals maintained on this regimen. Parallel vitro investigations utilized HepG2 hepatocyte cultures exposed acid (FFA) cocktails comprising palmitic oleic acids, coupled CRISPR-mediated suppression complementary gain-of-function manipulations delineate molecular mechanisms. Results triggers sterol biosynthesis activation, resulting pathological FC overload concurrent transcriptional suppression. Genetic ablation amplifies retention potentiates histopathological inflammation, while reconstitution mitigates steatotic deposition attenuates inflammatory cascades. Mechanistic profiling revealed MST1-mediated AMPKα phosphorylation at Thr172, suppresses cholesterogenic enzyme expression via element-binding transcription factor 2 (SREBP2) axis modulation. cascade demonstrates dose-dependent inhibition HMGCR activity, resolving FC-induced hepatotoxicity. Crucially, orchestrates AMPK/SREBP2 crosstalk maintain knockout models exhibiting 67% elevated SREBP2 nuclear translocation compared controls. Conclusions involving AMPK emerges as promising modality metabolism. It significant arresting cascades extracellular matrix remodeling characteristic studies confirm that effectively de novo lipogenesis enhancing efflux capacity, thereby establishing dual-target strategy against both metabolic dysfunction fibrotic transformation preclinical models.

Language: Английский

Spatial biology – unravelling complexity within the glioblastoma microenvironment DOI Creative Commons
Stephen Robinson,

Chrysa Filippopoulou,

Simoni Besta

et al.

Trends in Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

HighlightsThe ability to understand molecular differences at a single cell level, and with increasing granularity, through spatial profiling is starting unravel the complexity of glioblastoma tumour microenvironment (TME).Identifying variations in distribution different types providing novel insights into biology leading identification TME-based subtypes.Greater understanding relationships between types, rare, but biologically important, states identifying new biomarkers for predicting an individual's response treatment suggesting resistance mechanisms.AbstractThe advent refinement state-of-the-art technologies have facilitated analysis that combines advantages high-throughput techniques preserve tissue architecture. This combination cellular phenotyping retained context provides much greater interactions within (TME). For glioblastoma, its significant intra-tumoural heterogeneity, plasticity, complex TME, appreciating these patterns may prove key improving patient outcomes. review examines advances techniques, discusses how methodologies are being applied study explores information improves TME. Ultimately, it this will accelerate more effective treatments glioblastoma.

Language: Английский

Citations

0
Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver disease DOI Creative Commons
Lijuan Wang, Chenglei Zhang, Jie Ma

et al.

European journal of medical research, Journal Year: 2025, Volume and Issue: 30(1)

Published: April 17, 2025

Abstract Background Non-alcoholic steatohepatitis (NASH) progression is strongly associated with deteriorating hepatic function, primarily driven by free cholesterol (FC) accumulation-induced lipotoxicity. Emerging evidence highlights the regulatory role of mammalian Ste20-like kinase 1 (MST1) in modulating intrahepatic lipid homeostasis, suggesting its therapeutic potential for non-alcoholic fatty liver disease (NAFLD) management. This investigation seeks to elucidate pathophysiological mechanisms through which MST1 modulates NASH progression. Methods The experimental design employed two murine genetic models—wild-type (WT) controls and MST1-knockout (MST1-KO) specimens—subjected a nutritionally modified Western diet (WD) enriched saturated fats, simple carbohydrates, dietary induce pathogenesis. Lentiviral transduction techniques facilitated targeted overexpression WT animals maintained on this regimen. Parallel vitro investigations utilized HepG2 hepatocyte cultures exposed acid (FFA) cocktails comprising palmitic oleic acids, coupled CRISPR-mediated suppression complementary gain-of-function manipulations delineate molecular mechanisms. Results triggers sterol biosynthesis activation, resulting pathological FC overload concurrent transcriptional suppression. Genetic ablation amplifies retention potentiates histopathological inflammation, while reconstitution mitigates steatotic deposition attenuates inflammatory cascades. Mechanistic profiling revealed MST1-mediated AMPKα phosphorylation at Thr172, suppresses cholesterogenic enzyme expression via element-binding transcription factor 2 (SREBP2) axis modulation. cascade demonstrates dose-dependent inhibition HMGCR activity, resolving FC-induced hepatotoxicity. Crucially, orchestrates AMPK/SREBP2 crosstalk maintain knockout models exhibiting 67% elevated SREBP2 nuclear translocation compared controls. Conclusions involving AMPK emerges as promising modality metabolism. It significant arresting cascades extracellular matrix remodeling characteristic studies confirm that effectively de novo lipogenesis enhancing efflux capacity, thereby establishing dual-target strategy against both metabolic dysfunction fibrotic transformation preclinical models.

Language: Английский

Citations

0