Design, Synthesis, and Antitumor Activities of Isomers of Artemisinin Dimer Derivatives.

In recent years, numerous studies have reported on the anti-tumor properties of artemisinin and its derivatives. However, the relationship between their artemisinin chirality and activity remains unknown. In this study, we synthesized a series of artemisinin dimer derivatives with three different chiral structures and tested their antiproliferative activity in MCF-7 and HepG2 cells using the CCK-8 assay. Interestingly, we discovered that artemisinin dimer derivatives with ß, ß and α, ß conformations at C-10 exhibited stronger anti-tumor activity than those with an α, α configuration in MCF-7 and HepG2 cells. Notably, compound 4 showed an activity of 0.06 µM in MCF-7 cells. This study demonstrates the relationship between the conformation and activity of artemisinin dimer derivatives, and these derivatives have the potential to be developed into anti-cancer drugs.

NRSF deficiency leads to abnormal postnatal development of dentate gyrus and impairment of progenitors in subgranular zone of hippocampus.

Neuron-restrictive silencing factor (NRSF) is a zinc-finger transcription factor that regulates expression of a diverse set of genes. However, NRSF function in brain development still remains elusive. In the present study, we generated NRSF-conditional knockout (NRSF-cKO) mice by hGFAP-Cre/loxp system to study the effect of NRSF deficiency on brain development. Results showed that NRSF conditional knockout caused a smaller hippocampus and a thinner granule cell layer (GCL) in mice. Moreover, the reduction and disarrangement of GFAP+ cells in subgranular zone (SGZ) of NRSF-cKO mice was accompanied with the decreased number of premature neurons, neural stem cells (NSCs) and neural progenitor cells (NPCs), as well as compromising the majority of mitotically active cells. The analysis of postnatal development of hippocampus indicated the existence of an abnormality at postnatal day (P) 8, rather than at P1, in NRSF-cKO mice, although the densities of Ki67+ cells with mitotic ability in dentate gyrus were relatively unaffected at P1 and P8. Meanwhile, NRSF deficiency led to abnormal organization of SGZ at P8 during postnatal development. RNA-Seq analysis revealed 79 deregulated genes in hippocampus of NRSF-cKO mice at P8, which were involved in p53 signal transduction, neuron migration and negative regulation of cell proliferation, etc. The deregulation of p53 pathway in NRSF-cKO mice at P1 and P8 was evidenced, of which p21/Cdkn1a was accumulated in a portion of NSCs and NPCs in hippocampus during postnatal development. Together, these results, for the first time, revealed that NRSF could significantly influence the postnatal development of hippocampus, especially the formation of SGZ.

The identities of insulin signaling pathway are affected by overexpression of Tau and its phosphorylation form.

Introduction: Hyperphosphorylated Tau formed neurofibrillary tangles was one of the major neuropathological hallmarks of Alzheimer's disease (AD). Dysfunctional insulin signaling in brain is involved in AD. However, the effect of Tau pathology on brain insulin resistance remains unclear. This study explored the effects of overexpressing wild-type Tau (WTau) or Tau with pseudo-phosphorylation at AT8 residues (PTau) on the insulin signaling pathway (ISP). Methods: 293T cells or SY5Y cells overexpressing WTau or PTau were treated with or without insulin. The elements in ISP or the regulators of IPS were analyzed by immunoblotting, immunofluorescent staining and co-immunoprecipitation. Akt inhibitor MK2206 was used for evaluating the insulin signaling to downstream of mTOR in Tau overexpressing cells. The effects of anti-aging drug lonafarnib on ISP in WTau or PTau cells were also analyzed with immunoblotting. Considering lonafarnib is an inhibitor of FTase, the states of Rhes, one of FTase substrate in WTau or PTau cells were analyzed by drug affinity responsive target stability (DARTS) assay and the cellular thermal shift assay (CETSA). Results: WTau or PTau overexpression in cells upregulated basal activity of elements in ISP in general. However, overexpression of WTau or PTau suppressed the ISP signaling transmission responses induced by insulin simulation, appearing relative higher response of IRS-1 phosphorylation at tyrosine 612 (IRS-1 p612) in upstream IPS, but a lower phosphorylation response of downstream IPS including mTOR, and its targets 4EPB1 and S6. This dysregulation of insulin evoked signaling transmission was more obvious in PTau cells. Suppressing Akt with MK2206 could compromise the levels of p-S6 and p-mTOR in WTau or PTau cells. Moreover, the changes of phosphatases detected in WTau and PTau cells may be related to ISP dysfunction. In addition, the effects of lonafarnib on the ISP in SY5Y cells with WTau and PTau overexpression were tested, which showed that lonafarnib treatment resulted in reducing the active levels of ISP elements in PTau cells but not in WTau cells. The differential effects are probably due to Tau phosphorylation modulating lonafarnib-induced alterations in Rhes, as revealed by DARTS assay. Conclusion and discussion: Overexpression of Tau or Tau with pseudo-phosphorylation at AT8 residues could cause an upregulation of the basal/tonic ISP, but a suppression of insulin induced the phasic activation of ISP. This dysfunction of ISP was more obvious in cells overexpressing pseudo-phosphorylated Tau. These results implied that the dysfunction of ISP caused by Tau overexpression might impair the physiological fluctuation of neuronal functions in AD. The different effects of lonafarnib on ISP between WTau and PTau cells, indicating that Tau phosphorylation mediates an additional effect on ISP. This study provided a potential linkage of abnormal expression and phosphorylation of Tau to the ISP dysfunction in AD.

Interaction between extracellular ATP5A1 and LPS alleviates LPS-induced neuroinflammation in mice.

Neuroinflammation is one of the main causes of Alzheimer's disease (AD). The presence of Lipopolysaccharide (LPS) in senile plaques (SP) of AD suggests that it plays a role in AD pathogenesis. ATP5A1 (F1F0-ATP synthase F1 α subunit) is abundant in SP. Further, the protein has recently been found to have an anti-infection role in zebrafish embryos. In the present study, we observed that LPS levels were higher in the brains of APP/PS1 mice than in control mice, and LPS co-localised with ATP5A1 in amyloid plaques. The interaction of recombinant ATP5A1(rATP5A1) and LPS was evidenced by cellular thermal shift assay and enzyme-linked immunosorbent assay-based binding assay in vitro. Neuroinflammation in the brain of a mouse model was induced by intracerebroventricular injection of LPS. The addition of rATP5A1 relieved LPS-induced reduction of spontaneous locomotor ability, depressive-like behaviour, and working memory impairment. Furthermore, rATP5A1 suppressed the activation of astrocytes and microglia, IL-1ß accumulation, and tau phosphorylation induced by LPS. Taken together, findings suggest that ATP5A1 is involved in the regulation of LPS-mediated neuroinflammation in AD.

A series of anionic host coordination polymers based on azoxybenzene carboxylate: structures, luminescence and magnetic properties.

A series of coordination polymers {[Ln(aobtc)(H2O)4]·Hbipy·H2O}n (H4aobtc = azoxybenzene-2,2',3,3'-tetracarboxylic acid, bipy = 4,4'-bipyridine, and Ln = Sm(1), Eu(2), Gd(3), Tb(4), Dy(5), Er(6)) have been synthesized and characterized systematically. The cationic Hbipy+ guest incorporated polymers are isostructural sets, featuring a one-dimensional (1D) zigzag double chain edifice composed of binuclear clusters [Ln2(H4aobtc)2], with the Hbipy+ guest being located on two sides. These 1D chains are further interlinked into a 2D layer structure, and further extended into a 3D framework through hydrogen bonding interactions. The luminescence emission spectra of polymers 2 and 3 are based on the H4aobtc acid ligands, while 1 and 4 display the characteristic f-f transitions of Ln(iii) ions. Magnetic measurements revealed the presence of ferromagnetic behavior in polymer 3. The magnetic behaviors of 4 and 6 are ascribed to the depopulation of the Stark levels and/or weak antiferromagnetic interactions within MOFs at lower temperature. Slow relaxation is observed through the alternating-current susceptibility measurements for 5 at lower temperature, and the coexistence of weak ferromagnetism corresponding to the spin-canting-like behavior.