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AMPK activator O304 protects against kidney aging through promoting energy metabolism and autophagy

ABSTRACT: AMPK activator O304 protects against kidney aging through promoting energy metabolism and autophagy

PROVIDER: PRJNA791683 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17313554_1.fastq.gz	Fastqsanger.gz
	SRR17313554_2.fastq.gz	Fastqsanger.gz
	SRR17313555_1.fastq.gz	Fastqsanger.gz
	SRR17313555_2.fastq.gz	Fastqsanger.gz
	SRR17313556_1.fastq.gz	Fastqsanger.gz

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AMPK activator O304 protects against kidney aging through promoting energy metabolism and autophagy

Project description:Energy homeostasis plays a key role in retarding aging, and mitochondria are responsible for energy production.AMPK plays a central role in maintaining energy homeostasis and mitochondrial homeostasis, and commands autophagy, a clearing and recycling process to maintain cellular homeostasis. However, the effect of AMPK activators on kidney aging has not been fully elucidated. We testified the effects of O304, a novel direct AMPK activator, in naturally aging mice model and D-galactose (D-gal)-treated renal tubular cell culture. We identified that O304 perfectly protects against cellular senescence and aged-related fibrosis in kidneys. Also, O304 restored energy metabolism, promoted autophagy, and preserved mitochondrial homeostasis. Transcriptomic sequencing also proved that O304 induced fatty acid metabolism, mitochondrial biogenesis and ATP process, and downregulated cell aging, DNA damage response and collagen organization. All these results suggest that O304 has a strong potential to retard aged kidney injury through regulating AMPK-induced multiple pathways.

2022-01-27 | GSE192512 | GEO

Pan-AMPK activator O304 prevents gene expression changes and re-mobilization of histone marks in islets of diet-induced obese mice (RNA-Seq)

Project description:AMP-activated protein kinase (AMPK) have an important role in cellular energy homeostasis and has emerged as a promising target for treatment of Type 2 Diabetes (T2D) due to its beneficial effects on insulin sensitivity and glucose homeostasis. O304 is a pan-AMPK activator that has been shown to improve glucose homeostasis in both mouse models of diabetes and in human T2D subjects. Here, we describe the genome-wide transcriptional profile and chromatin landscape of pancreatic islets following O304 treatment of mice fed high-fat diet (HFD). O304 largely prevented genome-wide gene expression changes associated with HFD feeding in CBA mice and these changes were associated with remodelling of active and repressive chromatin marks. In particular, the increased expression of the β-cell stress marker Aldh1a3 in islets from HFD mice is completely abrogated following O304 treatment, which is accompanied by loss of active chromatin marks in the promoter as well as distant non-coding regions upstream of the Aldh1a3 gene. Moreover, O304 treatment restored dysfunctional glucose homeostasis as well as expression of key markers associated with β-cell function in mice with already established obesity. Our findings provide preclinical evidence that O304 is a promising therapeutic compound not only for T2D remission but also for restoration of β-cell function following remission of T2D diabetes.

2021-12-20 | GSE190812 | GEO

Pan-AMPK activator O304 prevents gene expression changes and re-mobilization of histone marks in islets of diet-induced obese mice (ChIP-Seq)

2021-12-20 | GSE190810 | GEO

AMPK Activator O304 Protects Against Kidney Aging Through Promoting Energy Metabolism and Autophagy.

Project description:Aging is an important risk factor for kidney injury. Energy homeostasis plays a key role in retarding aging, and mitochondria are responsible for energy production. In the kidney, renal tubular cells possess high abundance of mitochondria to meet the high energy consumption. AMPK is an evolutionarily conserved serine/threonine kinase which plays a central role in maintaining energy homeostasis and mitochondrial homeostasis. Besides that, AMPK also commands autophagy, a clearing and recycling process to maintain cellular homeostasis. However, the effect of AMPK activators on kidney aging has not been fully elucidated. To this end, we testified the effects of O304, a novel direct AMPK activator, in naturally aging mice model and D-Galactose (D-Gal)-treated renal tubular cell culture. We identified that O304 beneficially protects against cellular senescence and aged-related fibrosis in kidneys. Also, O304 restored energy metabolism, promoted autophagy and preserved mitochondrial homeostasis. Transcriptomic sequencing also proved that O304 induced fatty acid metabolism, mitochondrial biogenesis and ATP process, and downregulated cell aging, DNA damage response and collagen organization. All these results suggest that O304 has a strong potential to retard aged kidney injury through regulating AMPK-induced multiple pathways. Our results provide an important therapeutic approach to delay kidney aging.

| S-EPMC8924548 | biostudies-literature

O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function

Project description:In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In insulin deficient STZ treated diabetic mice the dual AMPK activator and mitochondrial uncoupler O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, thus improving glucose homeostasis. In obese In type 2 diabetic db/db mice, O304 additionally preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. It remains however unclear whether these effects of O304 is mediated by a direct protective effect on β-cells, or indirectly by improving glucose homeostasis thereby inducing β-cell rest. To investigate the ability of O304 to directly mitigate the detrimental effect of hyperglycemia on β-cell function, we exposed isolated islets ex vivo to normoglycemic and hyperglycemic comdition in the abscence or prescene of O304.

2023-08-17 | GSE240298 | GEO

Pan-AMPK activator O304 prevents gene expression changes and re-mobilization of histone marks in islets of diet-induced obese mice

Project description:Pan-AMPK activator O304 prevents gene expression changes and re-mobilization of histone marks in islets of diet-induced obese mice

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AMPK activator-treated human cardiac spheres have enhanced maturation and enable pathological modeling

Project description:To investigate the functions of AMPK activation on maturation of hiPSC derived cardiomyocytes, we treated 3D hiPSC derived cardiomyocytes with AMPK activator EX229 at 10 µM for 7 days. Transcriptomic analyse was performed to identify molecular actions of AMPK activation.

2022-05-27 | GSE203480 | GEO

Pan-AMPK activator O304 prevents gene expression changes and re-mobilization of histone marks in islets of diet-induced obese mice (ChIP-Seq)

Project description:Pan-AMPK activator O304 prevents gene expression changes and re-mobilization of histone marks in islets of diet-induced obese mice (ChIP-Seq)

| PRJNA788507 | ENA

Pan-AMPK activator O304 prevents gene expression changes and re-mobilization of histone marks in islets of diet-induced obese mice (RNA-Seq)

Project description:Pan-AMPK activator O304 prevents gene expression changes and re-mobilization of histone marks in islets of diet-induced obese mice (RNA-Seq)

| PRJNA788506 | ENA

A new LKB1 activator, Piericidin Analogue S14, attenuates tubular cell senescence and renal fibrosis through promoting AMPK-induced autophagy and mitochondrial homeostasis pathway [II]

Project description:AMP-activated protein kinase (AMPK) stabilizes tubular cell metabolism and protects against renal fibrosis through promoting autophagy and mitochondrial homeostasis. Liver kinase B1 (LKB1) is the key regulator for AMPK activation. However, the direct activators of LKB1 are scarce in commercial. In this study, we report a novel LKB1 activator, the piericidin analogue S14 (PA-S14), which was isolated from the culture broth of a marine-derived Streptomyces strain by our group. PA-S14 binds with residue D176 in LKB1 kinase domain, and then induces LKB1 phosphorylated activation and its complex formation with MO25 and STRADα. Furthermore, PA-S14 promotes AMPK activation to enhance LC3B-II/LC3B-I ratio, trigger autophagosome formation and increase autophagic flux. PA-S14 exhibits perfect protective effects on stabilizing mitochondrial homeostasis, inhibiting tubular cell senescence, and retarding fibrogenesis in various CKD models (UUO, UIRI and adriamycin nephropathy models) and TGF-β-stimulated tubular cell culture. Transcriptomics sequencing and site-specific mutation analysis further prove that PA-S14 is a novel lead compound of LKB1 activator, which perfectly protects against renal fibrosis through inducing AMPK-mediated autophagy and mitochondrial homeostasis.

2022-10-26 | GSE193072 | GEO

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