Discovery of a natural small‑molecule AMP‑activated kinase activator that alleviates nonalcoholic steatohepatitis

Non-alcoholic steatohepatitis(NASH)is a primary cause of cirrhosis and hepatocellular carcinoma.Unfortunately,there is no approved drug treatment for NASH.AMP-activated kinase(AMPK)is an important metabolic sensor and whole-body regulator.It has been proposed that AMPK activators could be used for treating metabolic diseases such as obesity,type 2 diabetes and NASH.In this study,we screened a marine natural compound library by monitoring AMPK activity and found a potent AMPK activator,candidusin A(CHNQD-0803).Further studies showed that CHNQD-0803 directly binds recombinant AMPK with a K_(D) value of 4.728×10^(-8) M and activates AMPK at both molecular and intracellular levels.We then investigated the roles and mechanisms of CHNQD-0803 in PA-induced fat deposition,LPS-stimulated infammation,TGF-β-induced fbrosis cell models and the MCD-induced mouse model of NASH.The results showed that CHNQD-0803 inhibited the expression of adipogenesis genes and reduced fat deposition,negatively regulated the NF-κB-TNFαinfammatory axis to suppress infammation,and ameliorated liver injury and fbrosis.These data indicate that CHNQD-0803 as an AMPK activator is a novel potential therapeutic candidate for NASH treatment.

Geology and mineralization of the Hongqiling large magmatic nickel-copper-cobalt deposit(22×10^(4)t)in Jilin Province,China:A review

The Hongqiling large nickel-copper-cobalt deposit(hereafter referred to as the Hongqiling deposit),a typical mafic-ultramafic copper-nickel deposit in China,boasts proven Ni(Ni)resources of approximately 22×10^(4)t,associated copper resources of 2×10^(4)t,and associated cobalt(Co)resources of 0.5×10^(4)t,with Ni reserves ranking 10th among China's magmatic nickel deposits.Geotectonically,the Hongqiling deposit is situated in the superimposed zone between the Xing'an-Mongolian orogenic belt and the circum-Western Pacific's active continental margin belt.Its ore-bearing plutons occur within the metamorphic rocks of the Ordovician Hulan Group,with the emplacement of plutons and the locations of orebodies governed by the deep-seated Huifahe fault and its secondary NW-trending Fujia-Hejiagou-Beixinglong-Changsheng fault zone.In the deposit,the rock assemblages of ore-bearing plutons predominantly encompass gabbro-pyroxenite-olivine pyroxenite-pyroxene peridotite(pluton No.1)and norite-orthopyroxenite-harzburgite(pluton No.7),with ore-bearing lithofacies consisting primarily of olivine pyroxenite and pyroxenite facies.The Hongqiling deposit hosts stratoid,overhanging lentoid,veined,and pure-sulfide veined orebodies.Its ores principally contain metallic minerals including pyrrhotite,pentlandite,chalcopyrite,violarite,and pyrite.Despite unidentified magma sources of ore-bearing mafic-ultramafic rocks,it is roughly accepted that the magmatic evolution in the Hongqiling deposit primarily involved fractional crystallization and crustal contamination.The ore-forming materials were primarily derived from the upper mantle,mixed with minor crustal materials.The ore-bearing mafic-ultramafic rocks in the deposit,primarily emplaced during the Indosinian(208-239 Ma),were formed in an intense extension setting followed by the collisional orogeny between the North China Plate and the Songnen-Zhangguangcai Range Block during the Middle-Late Triassic.From the perspective of the metallogenic geological setting,surrounding rocks,ore-controlling structures,and rock assemblages,this study identified one favorable condition and seven significant indicators for prospecting for Hongqiling-type nickel deposits and developed a prospecting model of the Hongqiling deposit.These serve as valuable references for exploring similar nickel deposits in the region,as well as the deep parts and margins of the Hongqiling deposit.