Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity

The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance.We focused on the effect of metformin on MVD,vascular maturity,and endothelial apoptosis of CRCs with a non-angiogenic phenotype,and further investigated its effect in overcoming chemoresistance.In situ transplanted cancer models were established to compare MVD,endothelial apoptosis and vascular maturity,and function in tumors from metformin-and vehicle-treated mice.An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis.Transcriptome sequencing was performed for genetic screening.Non-angiogenic CRC developed independently of angiogenesis and was characterized by vascular leakage,immaturity,reduced MVD,and non-hypoxia.This phenomenon had also been observed in human CRC.Furthermore,non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro.By suppressing endothelial apoptosis,metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity.Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling,which was abrogated by metformin administration.These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC.By suppressing endothelial apoptosis,metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.

Unexpected Chemistry from the Homogeneous Thermal Decomposition of Acetylene:An ab initio Study

The formation of the aromatic ring during the formation of polycyclic aromatic hydrocarbons (PAHs) remains controversial and the experimental evidence is still lacking. Moreover, the formation mechanism of benzene from acetylene in the gas phase has also puzzled organic chemists for decades. Here, ab initio molecular dynamics simulations and electronic structure calculations provide compelling evidence for an unexpected competitive reaction pathway in which the aromatic ring is formed through successive additions of vinylidene. Moreover, no collisions cause bond dissociation of the acetylene molecule during the formation of benzene in this work. This study reveals the key role for the vinylidene carbene and determines the lifetime of vinylidene.

Laser-rewritable room temperature phosphorescence based on in-situ polymerized tartaric acid

Organic room temperature phosphorescence(RTP)materials have potential applications in information technology and bioimaging.However,the precise control of the afterglow in reversible manners remains challenging for organic matters.Here,we report a kind of organic RTP material fabricated by simple heating mixtures of tartaric acid(TA)and aromatic acids,which can switch their phosphorescence by laser.Those mixtures show tunable phosphorescence from indigo to orange with phosphorescence efficiency of up to 53.99% due to locking different organic luminogens by the TA-formed matrix through the noncovalent interactions.The afterglow of those materials lasts a few seconds and disappears by water fumigation,which can be repeated in response to wet/heat stimuli.With drop-casting those materials on glass slides,a laser-repatternable phosphorescence is achieved by facile laser direct writing and quenched by water cyclically.Those results open the opportunity for the design of smart stimuli-responsive phosphorescence materials from sustainable natural products.