ABSTRACT
Pulmonary hypertension (PH) is an insidious pulmonary vasculopathy with high mortality and morbidity and its underlying pathogenesis is still poorly delineated. The hyperproliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) contributes to pulmonary vascular remodeling in pulmonary hypertension, which is closely linked to the downregulation of fork-head box transcriptional factor O1 (FoxO1) and apoptotic protein caspase 3 (Cas-3). Here, PA-targeted co-delivery of a FoxO1 stimulus (paclitaxel, PTX) and Cas-3 was exploited to alleviate monocrotaline-induced pulmonary hypertension. The co-delivery system is prepared by loading the active protein on paclitaxel-crystal nanoparticles, followed by a glucuronic acid coating to target the glucose transporter-1 on the PASMCs. The co-loaded system (170 nm) circulates in the blood over time, accumulates in the lung, effectively targets the PAs, and profoundly regresses the remodeling of pulmonary arteries and improves hemodynamics, leading to a decrease in pulmonary arterial pressure and Fulton's index. Our mechanistic studies suggest that the targeted co-delivery system alleviates experimental pulmonary hypertension primarily via the regression of PASMC proliferation by inhibiting cell cycle progression and promoting apoptosis. Taken together, this targeted co-delivery approach offers a promising avenue to target PAs and cure the intractable vasculopathy in pulmonary hypertension.
ABSTRACT
Atherosclerosis (AS) is a lipid-driven chronic inflammatory disease occurring at the arterial subendothelial space. Macrophages play a critical role in the initiation and development of AS. Herein, targeted codelivery of anti-miR 155 and anti-inflammatory baicalein is exploited to polarize macrophages toward M2 phenotype, inhibit inflammation and treat AS. The codelivery system consists of a carrier-free strategy (drug-delivering-drug, DDD), fabricated by loading anti-miR155 on baicalein nanocrystals, named as baicalein nanorods (BNRs), followed by sialic acid coating to target macrophages. The codelivery system, with a diameter of 150 nm, enables efficient intracellular delivery of anti-miR155 and polarizes M1 to M2, while markedly lowers the level of inflammatory factors and . In particular, intracellular fate assay reveals that the codelivery system allows for sustained drug release over time after internalization. Moreover, due to prolonged blood circulation and improved accumulation at the AS plaque, the codelivery system significantly alleviates AS in animal model by increasing the artery lumen diameter, reducing blood pressure, promoting M2 polarization, inhibiting secretion of inflammatory factors and decreasing blood lipids. Taken together, the codelivery could potentially be used to treat vascular inflammation.
ABSTRACT
@#Atherosclerosis is an inflammatory disease which mediated by the immune system of the arterial wall. Specific and non-specific immune systems of arterial wall showed positive immunore action with many endogenous and exogenous antigens.Studies have shown that the immune system promotes atherosclerosis on the one hand and delays atherosclerosis on the other. Therefore,the progress of atherosclerosis can be regulated through activating immune regulation. In this review,the double effects of specific and non-specific immune systems on the process of atherosclerosis were discussed. The studies of those antigen which have been made into vaccines and successfully delayed the process of atherosclerosis in laboratory models were introduced. And the prospects and challenges for future clinical application of atherosclerosis vaccines were discussed in this review.
ABSTRACT
Objective To investigate the expression of human ribonucleotide reductase large subunit M1 (RRM1) in the patients with gastric adenocarcinoma and its clinical significance.Methods The expressions of RRM1 were detected in 88 cases of gastric adenocarcinoma and 20 cases of nonnal gastric tissues by immunohistochemical method.The correlations between the expression of RRM1 and clinicopathological characteristics were analyzed.Results The positive expression rate of RRM1 in gastric adenocarcinoma was 83.0％(73/88).And RRM1 was negative in the entire normal gastric tissues.The positive expression of RRM1 was not associated with patient's age (x2 =0.352,P=0.553),gender (x2 =0.493,P=0.482),depth of tumor infiltration depth (x2 =0.007,P =0.933),lymph nodes metastasis (x2 =0.121,P =0.728) and distant metastasis (P =0.415).But it was related to the degree of tumor differentiation (x2 =7.740,P =0.021) and clinical stage (x2 =5.733,P =0.017).Conclusion The expression of RRM1 is positive expression in most gastric adenocarcinoma,and is associated with the degree of tumor differentiation and clinical stage.It is of great significance to detect the expression of RRM1 in gastric adenocarcinoma for confirming the diagnosis and judging malignant degree of the tumor.It also may have potential value in choosing the best therapeutic scheme and estimating prognosis.