The activity of 5′-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.

Sonodynamic therapy has attracted wide attention as a noninvasive therapy due to deep tissue penetration. However, the majority of sonosensitizers often suffer from poor physiological stability, rapid blood clearance and...

Bacterial blight (BB), caused by Xanthomonas oryzae pv. oryzae ( Xoo ), is a devastating disease in most of the rice growing regions worldwide. Among the 42 BB resistance ( R ) genes, Xa23 is an executor R gene, conferring broad-spectrum disease resistance to all naturally occurring biotypes of Xoo . In this study, CBB23, a rice line carrying Xa23 gene, was inoculated with wild PXO99 A and its mutant, P99M2, to retrieve the differentially expressed genes (DEGs). RNA-Seq analysis retrieved 1,235 DEGs ( p -value ≤ 0.05) at 12, 24, 36, and 48 hours of post inoculation (hpi). Gene ontology (GO) analysis classified the DEGs functionally into biological process, cellular component and molecular function. KEGG pathway analysis categorized the DEGs into 11 different pathways, and the ribosome is a prominent pathway followed by biosynthesis of phenylpropanoids. Gene co-expression network analysis identified the clusters of transcription factors (TFs) which may be involved in PXO99 A resistance. Additionally, we retrieved 67 differentially expressed TFs and 26 peroxidase responsive genes which may be involved in disease resistance mechanism. DEGs involved in the host-pathogen interaction, e.g., signaling mechanism, cell wall and plant hormones were identified. This data would be a valuable resource for researchers to identify the candidate genes associated with Xoo resistance.

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