2-APQC,a small-molecule activator of Sirtuin-3(SIRT3),alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis

Sirtuin 3(SIRT3)is well known as a conserved nicotinamide adenine dinucleotide^(+)(NAD^(+))-dependent deacetylase located in the mitochondria that may regulate oxidative stress,catabolism and ATP production.Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis,myocardial fibrosis and even heart failure(HF),through its deacetylation modifications.Accordingly,discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed.Herein,we identified a new small-molecule activator of SIRT3(named 2-APQC)by the structure-based drug designing strategy.2-APQC was shown to alleviate isoproterenol(ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models.Importantly,in SIRT3 knockout mice,2-APQC could not relieve HF,suggesting that 2-APQC is dependent on SIRT3 for its protective role.Mechanically,2-APQC was found to inhibit the mammalian target of rapamycin(mTOR)-p70 ribosomal protein S6 kinase(p70S6K),c-jun N-terminal kinase(JNK)and transforming growth factor-β(TGF-β)/small mother against decapentaplegic 3(Smad3)pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis.Based upon RNA-seq analyses,we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1(PYCR1)axis was closely assoiated with HF.By activating PYCR1,2-APQC was shown to enhance mitochondrial proline metabolism,inhibited reactive oxygen species(ROS)-p38 mitogen activated protein kinase(p38MAPK)pathway and thereby protecting against ISO-induced mitochondrialoxidative damage.Moreover,activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase(AMPK)-Parkin axis to inhibit ISO-induced necrosis.Together,our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis,which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.

Effects of dietary management combined with exercise interventions on type 2 diabetes:A pilot before-after study in the same patient

This work was supported by the National Key Research and Development Program of China(2022YFC3500401),the National Natural Science Foundation of China(No.82205250)and the Natural Science Foundation of Shandong Province,China(No.ZR2021QH056).

Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions

Drug repurposing or repositioning has been well-known to refer to the therapeutic applications of a drug for another indication other than it was originally approved for.Repurposing non-oncology small-molecule drugs has been increasingly becoming an attractive approach to improve cancer therapy,with potentially lower overall costs and shorter timelines.Several non-oncology drugs approved by FDA have been recently reported to treat different types of human cancers,with the aid of some new emerging technologies,such as omics sequencing and artificial intelligence to overcome the bottleneck of drug repurposing.Therefore,in this review,we focus on summarizing the therapeutic potential of non-oncology drugs,including cardiovascular drugs,microbiological drugs,small-molecule antibiotics,anti-viral drugs,anti-inflammatory drugs,antineurodegenerative drugs,antipsychotic drugs,antidepressants,and other drugs in human cancers.We also discuss their novel potential targets and relevant signaling pathways of these old non-oncology drugs in cancer therapies.Taken together,these inspiring findings will shed new light on repurposing more non-oncology small-molecule drugs with their intricate molecular mechanisms for future cancer drug discovery.

Regulated cell death(RCD)in cancer:key pathways and targeted therapies

Regulated cell death(RCD),also well-known as programmed cell death(PCD),refers to the form of cell death that can be regulated by a variety of biomacromolecules,which is distinctive from accidental cell death(ACD).Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis,which may ultimately lead to the establishment of different potential therapeutic strategies.Hitherto,targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue,which has rapidly progressed in many types of human cancers.Thus,in this review,we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways,but the crucial pathways of other RCD subroutines,including necroptosis,pyroptosis,ferroptosis,parthanatos,entosis,NETosis and lysosomedependent cell death(LCD)in cancer.Moreover,we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment,such as single-target,dual or multiple-target small-molecule compounds,drug combinations,and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.