Solid lipid nanoparticles loading with curcumin and dexanabinol to treat major depressive disorder

Dexanabinol(HU-211)is an artificially synthesized cannabinoid derivative that exerts neuroprotective effects through anti-inflammatory and antioxidant effects.Curcumin exhibits antidepressant effects in the treatment of major depressive disorder.To investigate the antidepressant effects of solid lipid nanoparticles loaded with both curcumin and dexanabinol,and the underlying mechanisms associated with this combination,we established wild-type(CBR1~(+/+))and cannabinoid receptor 1(CBR1)knockout(CBR1~(–/–))mouse models of major depressive disorder,through the intraperitoneal injection of corticosterone,for 3 successive days,followed by treatment with intraperitoneal injections of solid lipid nanoparticles loading with curcumin(20 mg/kg)and dexanabinol(0.85 mg/kg),for 2 successive days.Our results revealed that solid lipid nanoparticle loading with curcumin and dexanabinol increased the m RNA and protein expression levels of the mature neuronal markers neuronal nuclei,mitogen-activated protein 2,and neuron-specific beta-tubulin III,promoted the release of dopamine and norepinephrine,and increased the m RNA expression of CBR1 and the downstream genes Rasgef1c and Egr1,and simultaneously improved rat locomotor function.However,solid lipid nanoparticles loaded with curcumin and dexanabinol had no antidepressant effects on the CBR1~(–/–)mouse models of major depressive disorder.This study was approved by the Institutional Ethics Committee of Tongji Hospital of Tongji University,China(approval No.2017-DW-020)on May 24,2017.

Synergistic induction of mitotic pyroptosis and tumor remission by inhibiting proteasome and WEE family kinases

Mitotic catastrophe(MC),which occurs under dysregulated mitosis,represents a fascinating tactic to specifically eradicate tumor cells.Whether pyroptosis can be a death form of MC remains unknown.Proteasome-mediated protein degradation is crucial for M-phase.Bortezomib(BTZ),which inhibits the 20S catalytic particle of proteasome,is approved to treat multiple myeloma and mantle cell lymphoma,but not solid tumors due to primary resistance.To date,whether and how proteasome inhibitor affected the fates of cells in M-phase remains unexplored.Here,we show that BTZ treatment,or silencing of PSMC5,a subunit of 19S regulatory particle of proteasome,causes G2-and M-phase arrest,multi-polar spindle formation,and consequent caspase-3/GSDME-mediated pyroptosis in M-phase(designated as mitotic pyroptosis).Further investigations reveal that inhibitor of WEE1/PKMYT1(PD0166285),but not inhibitor of ATR,CHK1 or CHK2,abrogates the BTZ-induced G2-phase arrest,thus exacerbates the BTZ-induced mitotic arrest and pyroptosis.Combined BTZ and PD0166285 treatment(named BP-Combo)selectively kills various types of solid tumor cells,and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 monotreatment.Studies using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment,and no obvious toxicity is observed in BP-Combo-treated mice.These findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase,characterize pyroptosis as a new death form of mitotic catastrophe,and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.