Small-molecule Molephantin induces apoptosis and mitophagy flux blockage through ROS production in glioblastoma.

Glioblastoma (GBM), one of the most malignant brain tumors in the world, has limited treatment options and a dismal survival rate. Effective and safe disease-modifying drugs for glioblastoma are urgently needed. Here, we identified a small molecule, Molephantin (EM-5), effectively penetrated the blood-brain barrier (BBB) and demonstrated notable antitumor effects against GBM with good safety profiles both in vitro and in vivo. Mechanistically, EM-5 not only inhibits the proliferation and invasion of GBM cells but also induces cell apoptosis through the reactive oxygen species (ROS)-mediated PI3K/Akt/mTOR pathway. Furthermore, EM-5 causes mitochondrial dysfunction and blocks mitophagy flux by impeding the fusion of mitophagosomes with lysosomes. It is noteworthy that EM-5 does not interfere with the initiation of autophagosome formation or lysosomal function. Additionally, the mitophagy flux blockage caused by EM-5 was driven by the accumulation of intracellular ROS. In vivo, EM-5 exhibited significant efficacy in suppressing tumor growth in a xenograft model. Collectively, our findings not only identified EM-5 as a promising, effective, and safe lead compound for treating GBM but also uncovered its underlying mechanisms from the perspective of apoptosis and mitophagy.

Lycopodium Alkaloids from Huperzia serrata and Their Anti-acetylcholinesterase Activities.

One new fawcettimine-type alkaloid (1), one new miscellaneous-type alkaloid (2), four new lycodine-type alkaloids (3-6), and eight known ones (7-14) were isolated from the whole plants of Huperzia serrata. Their structures and absolute configurations were elucidated based on spectroscopic data, X-ray diffraction, ECD calculation and Mosher's method. Compound 1 was a rare C18 N2 -type Lycopodium alkaloid, possessing serratinine skeleton with an amide side chain in C-5. The absolute configuration of the 18-OH of compounds 4-6 were first determined by Mosher's method. Moreover, compounds 1-14 were assayed anti-acetylcholinesterase effect in vitro, and compound 7 showed significant anti-acetylcholinesterase activity with an IC50 value of 16.18±1.64 µM.

Two new clerodane diterpenoids and a new pyran-2-one derivative with anti-neuroinflammatory activities from Croton crassifolius.

Two new clerodane diterpenoids (1 and 2), a new pyran-2-one derivative (3), along with five known compounds (4‒8), were isolated from Croton crassifolius. Notably, crassifolin X (1) is a novel clerodane diterpenoid, characterized with a peculiar δ-lactone core being formed between C-1 and C-4. Their structures, including absolute configurations, were established on the basis of spectroscopic methods (UV, IR, HRESIMS and NMR), and circular dichroism experiments. In addition, all compounds were evaluated for their anti-neuroinflammatory activities based on the expression of TNF-α and IL-6 levels on LPS-induced BV2 cells, and compounds 1‒3 and 5 showed potential anti-neuroinflammatory activity.

A screened PirB antagonist peptide antagonizes Aß42-mediated inhibition of neurite outgrowth in vitro.

Alzheimer's disease (AD) is a type of progressive neurodegenerative disease, and amyloid ß-protein 42 (Aß42) serves an important role in the pathological process of development of AD. Paired immunoglobulin-like receptor B (PirB) is a functional receptor for myelin inhibitors of neuron regeneration in the CNS, and it has also been identified to function as a high-affinity receptor for Aß. Here, we used a phage display to identify a specific PirB antagonist peptide 11(PAP11, PFRLQLS), which could reverse Aß42-induced neurotoxicity and promote neurite outgrowth in vitro. Immunofluorescence analysis showed that PAP11 colocalized with PirB on the membrane of cortical neurons. Horseradish peroxidase-streptavidin-biotin assay further proved that PAP11 directly binds to PirB and the dissociation constant (Kd) was 0.128µM. PAP11 functionally antagonized the neurite outgrowth inhibitory effect induced by Aß42 in cortical neurons, and the underlying mechanism was associated with a PirB-ROCK2/CRMP2 signaling pathway. The novel PirB antagonist peptide PAP11 may be a promising candidate therapeutic agent for the treatment of AD and other neurodegenerative diseases. KEY POINTS: • PAP11 was the first PirB antagonist peptide screened by phage display technology. • PAP11 could protect neurons by blocking the binding of Aß42 and PirB. • PAP11 reverse inhibitory effect of neurite outgrowth through ROCK2/CRMP2 pathway.

Interface Engineering for the Enhancement of Carrier Transport in Black Phosphorus Transistor with Ultra-Thin High-k Gate Dielectric.

Black phosphorus (BP) is the most stable allotrope of phosphorus which exhibits strong in-plane anisotropic charge transport. Discovering its interface properties between BP and high-k gate dielectric is fundamentally important for enhancing the carrier mobility and electrostatics control. Here, we investigate the impact of interface engineering on the transport properties of BP transistors with an ultra-thin hafnium-dioxide (HfO2) gate dielectric of ~3.4 nm. A high hole mobility of ~536 cm(2)V(-1)s(-1) coupled with a near ideal subthreshold swing (SS) of ~66 mV/dec were simultaneously achieved at room temperature by improving the BP/HfO2 interface quality through thermal treatment. This is attributed to the passivation of phosphorus dangling bonds by hafnium (Hf) adatoms which produces a more chemically stable interface, as evidenced by the significant reduction in interface states density. Additionally, we found that an excessively high thermal treatment temperature (beyond 200 °C) could detrimentally modify the BP crystal structure, which results in channel resistance and mobility degradation due to charge-impurities scattering and lattice displacement. This study contributes to an insight for the development of high performance BP-based transistors through interface engineering.

Black Phosphorus Transistors with Near Band Edge Contact Schottky Barrier.

Black phosphorus (BP) is a new class of 2D material which holds promise for next generation transistor applications owing to its intrinsically superior carrier mobility properties. Among other issues, achieving good ohmic contacts with low source-drain parasitic resistance in BP field-effect transistors (FET) remains a challenge. For the first time, we report a new contact technology that employs the use of high work function nickel (Ni) and thermal anneal to produce a metal alloy that effectively reduces the contact Schottky barrier height (ΦB) in a BP FET. When annealed at 300 °C, the Ni electrode was found to react with the underlying BP crystal and resulted in the formation of nickel-phosphide (Ni2P) alloy. This serves to de-pin the metal Fermi level close to the valence band edge and realizes a record low hole ΦB of merely ~12 meV. The ΦB at the valence band has also been shown to be thickness-dependent, wherein increasing BP multi-layers results in a smaller ΦB due to bandgap energy shrinkage. The integration of hafnium-dioxide high-k gate dielectric additionally enables a significantly improved subthreshold swing (SS ~ 200 mV/dec), surpassing previously reported BP FETs with conventional SiO2 gate dielectric (SS > 1 V/dec).