Reductive lipid nanoparticles loaded with vinorelbine inhibit chemotherapy-induced invasion of cancer cells by modulating ENPP2

Cancer is a predominant culprit behind worldwide death and accounts for up to 10 million deaths every year.Chemotherapy is the primary therapeutic method employed for cancer in clinical settings and is essential in controlling tumor progression.Despite the advances in this field,tumor invasion and metastasis during treatment remain a significant cause of treatment failure.Nevertheless,the underlying mechanisms involving such a disappointing phenomenon are still not fully elucidated.Vinorelbine(VNB)extends the lifespan of many cancer patients in the clinic as an emerging chemotherapy drug approved by Food and Drug Administration(FDA).However,VNB-induced tumor metastasis is still an intractable problem,which may be closely related to the abnormal oxidative stress generated during VNB-mediated treatment.Hence,the study aims to construct a reductive nanosystem loaded with VNB,called VNB-VNP,to improve cancer cure rates and reduce tumor metastasis.With the reductive component vitamin E,VNB-VNP can effectively reduce oxidative stress and significantly outperform free VNB in preventing tumor progression.The transcriptome analysis shows that VNB-VNP can alleviate the over-expression of ectonucleotide pyrophosphatase/phosphodiesterase 2(ENPP2),which may be the main reason why VNB-VNP can inhibit tumor invasion and metastasis.Overall,the research designs a new platform for VNB treatment,which demonstrates promising efficacy in inhibiting neoplastic progression and identifies a new mechanism associated with VNB-induced tumor metastasis,which may offer several valuable references for enhancing chemotherapy efficacy in clinical anti-tumor therapy.

环核苷酸磷酸二酯酶:神经精神疾病的药物作用靶标(英文)

OBJECTIVE To investigate the relationship between the neurochemical and behavioral effects of inhibitors of cyclic nucleotide phosphodiesterases 2(PDE2) and PDE4 in the hope of identifying promising therapeutic targets and indications. METHODS Depression-and anxiety-like behaviors were evaluated by forced swimming,tail suspending and elevated plus maze tests. The memory enhancing effects were evaluated by Morris water maze test. RESULTS Inhibition of PDE4 results in antidepressant-like and memory-enhancing effects,in part due to increased cyclicAMP signaling.While targeting PDE4 subtypes(PDE4A-D) pharmacologically has proven challenging due to a highly conserved inhibitor-binding site in the catalytic region of the enzyme,some promise is offered by recently identified negative allosteric modulators of PDE4,which can act in a subtype-specific manner.While PDE2 has not been studied as extensively,it has been shown to be coded for by a single mammalian gene and to be highly expressed in the brain. Its inhibition results in anxiolytic-and antidepressant-like effects as wells as reducing oxidative stress and affording some degree of neuroprotection;these actions appear to be due to increased cyclicGMP signaling,even though PDE2 catalyzes the hydrolysis of both cyclicAMP and cyclicGMP. CONCLUSION Inhibitors targeting specific family of PDE may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions,while drug discovery efforts focusing on PDE2 are not as advanced as those for PDE4,some selective inhibitors are being developed and evaluated.

Biophotons Contribute to Retinal Dark Noise

The discovery of dark noise in retinal photoreceptors resulted in a long-lasting controversy over its origin and the underlying mechanisms.Here,we used a novel ultra-weak biophoton imaging system（UBIS） to detect biophotonic activity（emission） under dark conditions in rat and bullfrog（Rana catesbeiana） retinas in vitro.We found a significant temperature-dependent increase in biophotonic activity that was completely blocked either by removing intracellular and extracellular Ca^（2＋）together or inhibiting phosphodiesterase 6.These findings suggest that the photon-like component of discrete dark noise may not be caused by a direct contribution of the thermal activation of rhodopsin,but rather by an indirect thermal induction of biophotonic activity,which then activates the retinal chromophore of rhodopsin.Therefore,this study suggests a possible solution regarding the thermal activation energy barrier for discrete dark noise,which has been debated for almost half a century.