Qingqing Xiao

The use of small interfering RNAs (siRNAs) has been under investigation for the treatment of several unmet medical needs, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS) wherein siRNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the mRNA level. The properties such as clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy. However, the translation of siRNA is restricted by the inefficient delivery of siRNA therapeutics to the target cells due to the properties of naked siRNA. Thus, this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable siRNA formulations for human use before siRNA therapeutics for ALI/ARDS become available in the clinic.

Treatment for metastatic cancer is a great challenge throughout the world. Commonly, directed inhibition of extracellular matrix metalloproteinases (MMPs) secreted by cancer cells can reduce metastasis. Here, a novel nanoplatform (HPMC NPs) assembled from hyaluronic acid (HA)-paclitaxel (PTX) prodrug and marimastat (MATT)/-casein (CN) complexes was established to cure a 4T1 metastatic cancer model via targeting CD44 and intracellular, rather than extracellular, MMPs. Methods: HPMC NPs were prepared by assembling the complexes and prodrug under ultrasonic treatment, which the interaction between them was evaluated by frster resonance energy transfer, circular dichroism and fluorescence spectra. The developed nanoplatform was characterized via dynamic light scattering and transmission electron microscopy, and was evaluated in terms of MMP-sensitive release and stability. Subsequently, the cellular uptake, trafficking, and in vitro invasion were studied by flow cytometry, confocal laser microscopy and transwell assay. MMP expression and activity was determined by western blotting and gelatin zymography. Finally, the studies of biodistribution and antitumor efficacy in vivo were performed in a mouse 4T1 tumor breast model, followed by in vivo safety study in normal mouse.

Atherosclerosis is a chronic disease comprising intima malfunction and arterial inflammation. Recent studies have demonstrated that autophagy could inhibit inflammatory response in atherosclerosis and exert subsequent atheroprotective effects. Our previous study also demonstrated the role of autophagy in the inhibition of inflammation by atorvastatin in vitro. Therefore, in the present study, we aimed to determine whether atorvastatin could upregulate autophagy to inhibit inflammatory cytokines secretion, lipid accumulation, and improve vulnerable plaque stability, both in vitro and in vivo. First, we established a vulnerable atherosclerotic plaque mouse model through partial ligation of left common carotid artery and left renal artery to explore the effect of atorvastatin on vulnerable plaques. The results showed that atorvastatin could enhance the stability of vulnerable atherosclerotic plaques and reduce the lesion area in the aorta. Atorvastatin could also inhibit NLRP3 inflammasome activation and inflammatory cytokines, such as IL-1β, TNF-α and IL-18 secretion in vivo. Atorvastatin treatment upregulated the expression of autophagy-related protein microtubule-associated protein light chain (LC3B) and downregulated the expression of SQSTM1/p62, which suggested that autophagy was activated in vulnerable plaques. Transmission electron microscopy further demonstrated the atorvastatin-induced increase in autophagy activity in vulnerable atherosclerotic plaques. We employed oxidized low-density lipoprotein (ox-LDL) to stimulate RAW264.7 cells with atorvastatin, which showed that atorvastatin could attenuate lipid deposition, ameliorate inflammation, inhibit NLRP3 inflammasome activation, and enhance autophagy in vitro. All these beneficial effects were abolished by 3-methyladenine treatment, an autophagy inhibitor. Atorvastatin also significantly inhibited the phosphorylation of mTOR, which strongly suggested the involvement of the mTOR pathway. Our study proposed a new role for atorvastatin as an autophagy inducer to exert anti-inflammatory and atheroprotective effects, to stabilize vulnerable atherosclerotic plaques.

BACKGROUND: The relationship between vitamin D status and mortality in patients with osteoarthritis (OA) is unknown. This study investigated the associations of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cause-specific mortality among American adults with OA. METHODS: This study included 2556 adults with OA from the National Health and Nutrition Examination Survey (2001-2014). Death outcomes were ascertained by linkage to National Death Index (NDI) records through 31 December 2015. Cox proportional hazards model and two-piecewise Cox proportional hazards model were used to elucidate the nonlinear relationship between serum 25(OH)D concentrations and mortality in OA patients, and stratified analyses were performed to identify patients with higher mortality risk. RESULTS: During 16,606 person-years of follow-up, 438 all-cause deaths occurred, including 74 cardiovascular disease (CVD)-related and 78 cancer deaths. After multivariable adjustment, lower serum 25(OH)D levels were significantly and nonlinearly associated with higher risks of all-cause and CVD mortality among participants with OA. Furthermore, we discovered L-shaped associations between serum 25(OH)D levels and all-cause and CVD mortality, with mortality plateauing at 54.40 nmol/L for all-cause mortality and 27.70 nmol/L for CVD mortality. Compared to participants with 25(OH)D levels below the inflection points, those with higher levels had a 2% lower risk for all-cause mortality (hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.96-0.99) and 17% lower risk for CVD mortality (HR 0.83, 95% CI 0.72-0.95). CONCLUSIONS: Nonlinear associations of serum 25(OH)D levels with all-cause and CVD mortality were observed in American patients with OA. The thresholds of 27.70 and 54.40 nmol/L for CVD and all-cause mortality, respectively, may represent intervention targets for lowering the risk of premature death and cardiovascular disease, but this needs to be confirmed in large clinical trials.

Metastasis is a major cause of chemotherapeutic failure and death. Degradation of a specific component of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) affects the physical barrier of the tumor microenvironment (TME) and induces metastasis. Here, lysolipid-containing thermosensitive liposomes (LTSLs) were prepared to deliver an MMP inhibitor, marimastat (MATT), to the TME to inhibit MMP activity and expression. LTSLs rapidly released their payloads at 42 °C. Compared with the saline control, MATT-LTSLs exhibited enhanced accumulation in the tumor and a 20-fold decrease in tumor growth in 4T1 tumor-bearing mice; moreover, MATT-LTSLs reduced MMP-2 and MMP-9 activity by 50% and 43%, respectively, and downregulated MMP-2 and MMP-9 expression in vivo by 30% and 43%, respectively. Most importantly, MATT-LTSL treatment caused a 7-fold decrease in metastatic lung nodules and a 6-fold reduction in microvessels inside the tumor. We believe this study provides an effective approach for the suppression of metastasis, and the use of a cytotoxic agent in combination with MATT is a potential strategy for metastatic cancer treatment.