Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling

The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyclopamine (Cyc), an alkaloid from the Veratrum plant, is a specific natural product inhibitor of the Hh pathway that acts by targeting smoothened (SMO) protein. However, its poor solubility, acid sensitivity, and weak potency relative to other Hh antagonists prevent the clinical development of Cyc as a therapeutic agent. Here, we report properties of cyclopamine tartrate salt (CycT) and its activities in Hh signaling-mediated cancer in vitro and in vivo. Unlike Cyc, CycT is water soluble (5-10 mg/mL). The median lethal dose (LD50) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T1/2) of CycT was not significantly different from that of Cyc. We showed that CycT had a higher inhibitory activity for Hh signaling-dependent motor neuron differentiation than did Cyc (IC50 = 50 nmol/L for CycT vs. 300 nmol/L for Cyc). We also tested the antitumor effectiveness of these Hh inhibitors using two mouse models of basal cell carcinomas (K14cre:Ptch1neo/neo and K14cre:SmoM2YFP). After topical application of CycT or Cyc daily for 21 days, we found that all CycT-treated mice had tumor shrinkage and decreased expression of Hh target genes. Taken together, we found that CycT is an effective inhibitor of Hh signaling-mediated carcinogenesis.

A novel genomic prediction method combining randomized Haseman-Elston regression with a modified algorithm for Proven and Young for large genomic data

Computational efficiency has become a key issue in genomic prediction(GP) owing to the massive historical datasets accumulated. We developed hereby a new super-fast GP approach(SHEAPY) combining randomized Haseman-Elston regression(RHE-reg) with a modified Algorithm for Proven and Young(APY) in an additive-effect model, using the former to estimate heritability and then the latter to invert a large genomic relationship matrix for best linear prediction. In simulation results with varied sizes of training population, GBLUP, HEAPY|A and SHEAPY showed similar predictive performance when the size of a core population was half that of a large training population and the heritability was a fixed value, and the computational speed of SHEAPY was faster than that of GBLUP and HEAPY|A. In simulation results with varied heritability, SHEAPY showed better predictive ability than GBLUP in all cases and than HEAPY|A in most cases when the size of a core population was 4/5 that of a small training population and the training population size was a fixed value. As a proof of concept, SHEAPY was applied to the analysis of two real datasets. In an Arabidopsis thaliana F2 population, the predictive performance of SHEAPY was similar to or better than that of GBLUP and HEAPY|A in most cases when the size of a core population(2 0 0) was 2/3 of that of a small training population(3 0 0). In a sorghum multiparental population,SHEAPY showed higher predictive accuracy than HEAPY|A for all of three traits, and than GBLUP for two traits. SHEAPY may become the GP method of choice for large-scale genomic data.

Hyperactivity of a midbrain dopamine to 5-HT circuit causes anorexia

Anorexia nervosa(AN)is a severe eating disorder that can eventually lead to death,buteffective the rapiesare missing dueto a lack of knowledge about its pathophysiology.Dopamine(DA)neurons in theventral tegmental area(VTA)and serotonin(5-HT)neurons in the dorsal Raphe nucleus(DRN)play essential roles in the control of eating and have been reported to be as sociated with human AN(Zhou and Palmiter,1995;Xu et al.,2017;Watson et al.,2019;He et al.,2021).

Hunger extends lifespan by modulating histone proteins

In a recent study published in Science,Weaver et al.provided insights into the effects of hunger on longevity.Inducing a state of hunger,either through restricting isoleucine intake or by stimulating R50H05 hunger neurons,resulted in an extension of lifespan in fruit flies.This effect is mediated by the modula-tion of histone proteins in the brain.