Near-Infrared Persistent Luminescence Nanoprobe for Early Detection of Atherosclerotic Plaque.

Atherosclerosis (AS) is a crucial contributor to various cardiovascular diseases (CVDs), which seriously threaten human life and health. Early and accurate recognition of AS plaques is essential for the prevention and treatment of CVD. Herein, we introduce an AS-targeting nanoprobe based on near-infrared (NIR) persistent luminescence nanoparticles (PLNPs), developing a highly sensitive NIR persistent luminescence (PersL) AS plaque imaging technique and successfully realizing early AS plaque detection. The nanoprobe exhibits good monodispersity and regular spherical morphology and also owns exceptional NIR PersL performance upon repetitive irradiation by biological window light. The surface-conjugated antibody (anti-osteopontin) endowed nanoprobe excellent targeting ability to foam cells within plaques. After intravenously injected nanoprobe into AS model mice, the highly sensitive PersL imaging technique can accurately detect AS plaques prior to ultrasonography (US) and magnetic resonance imaging (MRI). Specifically, the NIR PersL imaging reveals AS plaques at the earliest within 2 weeks, with higher signal-to-background ratio (SBR) up to 5.72. Based on this technique, the nanoprobe has great potential for applications in the prevention and treatment of CVD, the study of AS pathogenesis, and the screening of anti-AS drugs.

Persistent luminescent nanoparticles for plant imaging: toward exploring the distribution of nanoparticles in plants.

Nanotoxicology on plants has raised great concerns about the prevalence of nanoparticles (NPs) in ecosystems, and the most fundamental aspect is to assess the fate of NPs in plants. Nonetheless, the lack of high-sensitivity tracking techniques in vivo constraints intensive research on NP distribution in plants. Herein, we have overcome this limitation by first introducing persistent luminescent nanoparticles (PLNPs) as an imaging probe, which can detect the distribution of NPs in whole plants with high sensitivity by completely eliminating interference from autofluorescence. We synthesized two differently surface-charged PLNPs with excellent biosafety and then exposed these NPs to plants in the hydroponic medium. Persistent luminescence (PersL) images visually showed the disparate accumulation of PLNPs in plants. PersL signals of positively charged PLNPs were observed in the whole exposed portion of the plant roots, while negatively charged PLNPs were mainly in the root collars instead of the exposed portion. With prolonged exposure, the presence of PersL signals in leaves indicated the long-distance translocation of differently charged PLNPs from roots to leaves via hypocotyls. For further confirmation of imaging results, the distribution of NPs in plants was investigated using electron microscopy. Based on their unique optical properties, PLNPs provide a promising strategy for tracking NP's fate in plants.

Dual-Triggered Near-Infrared Persistent Luminescence Nanoprobe for Autofluorescence-Free Imaging-Guided Precise Therapy of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a common, chronic, and highly disabling autoimmune disease characterized by difficult treatment, long disease duration, and easy recurrence. The development and application of high-sensitivity theranostic probes for RA that will facilitate precise monitoring of disease progression and enable effective treatment are currently hotspots in the field of RA theranostics. In this study, mZMI@HA, a dual-triggered theranostics nanoprobe, is constructed based on near-infrared persistent luminescence nanoparticles (NIR-PLNPs) for precise RA treatment and therapeutic evaluation. This is the first reported use of high-sensitivity autofluorescence-free imaging based on NIR-PLNPs for precise RA treatment and therapeutic evaluation. Compared with the NIR fluorescence imaging probe-indocyanine green, the signal-to-background ratio of persistent luminescence (PersL) imaging is improved nearly 14-fold. Using PersL imaging to guide photothermal therapy and controllable drug release through NIR/pH-responsiveness, the progress of collagen-induced RA is relieved. Additionally, the therapeutic evaluation of RA by PersL imaging is consistent with clinical micro-computed tomography and histological analyses. This study demonstrates the potential of NIR-PLNPs for high-sensitivity imaging-guided RA treatment, providing a new strategy for RA precise theranostics.

A dual-functional nanoplatform based on NIR and green dual-emissive persistent luminescence nanoparticles for X-ray excited persistent luminescence imaging and photodynamic therapy.

Persistent luminescence nanoparticles (PLNPs) possess advantages for high-sensitivity bioimaging and continuous photodynamic therapy (PDT) because they can emit persistent luminescence (PerL) after excitation ceases. However, PLNPs are limited to single-wavelength emission, which can only efficiently realize one of the functions of bioimaging or PDT. In addition, most PLNPs are excited by shallow tissue penetrating excitation light, which makes it difficult to achieve repeatable in vivo applications with high efficiency. Herein, X-ray-excited PLNPs (Zn3Ga2Ge2O10:Cr3+,Mn2+, ZGGCM) with dual emission for in vivo X-rays repeatedly activated PerL imaging and tumor PDT are reported for the first time. ZGGCM exhibits dual-emission peaks after X-ray excitation/re-excitation, located at 698 nm and 532 nm, respectively. Additionally, ZGGCM is modified with the photosensitizer rose bengal (RB) to construct a dual-functional nanoplatform based on PerL imaging and PDT. The results indicate that the PerL emission peak (698 nm) of Cr3+ ions in ZGGCM possesses excellent near-infrared (NIR) PerL imaging performance, and the green PerL emission peak (532 nm) of Mn2+ ions can activate RB effectively and generate reactive oxygen species (ROS), thereby causing a significant antitumor effect. This unique dual-functional nanoplatform is expected to further promote the application of PLNPs in the integration of efficient tumor diagnosis and treatment.

Smart Manganese Dioxide-Based Lanthanide Nanoprobes for Triple-Negative Breast Cancer Precise Gene Synergistic Chemodynamic Therapy.

Small interfering RNA (siRNA)-based gene therapy has been widely studied as a promising treatment for malignant triple-negative breast cancer (TNBC), but efficient delivery of siRNA still remains a challenge. In this study, a smart manganese dioxide (MnO2)-based lanthanide nanoprobe therapeutic nanoplatform (ErNPs@MnO2-siS100A4-RGD) was developed for tumor imaging and precise stimuli-responsive S100A4 siRNA (siS100A4)-mediated gene therapy in synergism with chemodynamic therapy (CDT) of TNBC. ErNPs@MnO2-siS100A4-RGD has a tumor microenvironment-responsive capability attributed to the presence of MnO2, which can be degraded by glutathione (GSH) in the tumor region while releasing siRNA and generating Mn2+ to achieve precise gene therapy and a Fenton-like reaction-mediated CDT effect on TNBC. Subsequently, the lanthanide nanoprobes (ErNPs) are exposed to the second near-infrared region (NIR-II) fluorescence emission to realize the precise tumor location. Both the in vitro and in vivo results demonstrated that the smart nanoplatform possessed high siRNA delivery efficiency and GSH-responsive precise siRNA releasing ability, and compared with individual gene therapy, the GSH-depletion-enhanced CDT effect further reinforced TNBC inhibition, demonstrating excellent GSH-responsive-enhanced NIR-II precise tumor imaging therapy. These results indicate that the nanoplatform provides a crucial foundation for further research on theranostic systems of TNBC.

Polydopamine-doped virus-like structured nanoparticles for photoacoustic imaging guided synergistic chemo-/photothermal therapy.

The therapeutic diagnosis effect of cancer commonly depends on the cellular uptake efficiency of nanomaterials. However, the morphology of nanomaterials significantly affects cellular uptake capability. Herein, we designed a polydopamine-doped virus-like structured nanoparticle (GNR@HPMO@PVMSN) composed of a gold nanorod (GNR) core, hollow periodic mesoporous organosilica (HPMO) shell and polydopamine-doped virus-like mesoporous silica nanoparticle (PVMSN) outer shell. Compared with conventional gold nanorod@hollow periodic mesoporous organosilica core-shell nanoparticles (GNR@HPMO), GNR@HPMO@PVMSN with its virus-like structure was proved to enhance the efficiency of cellular uptake. GNR@HPMO@PVMSN with the virtues of high photothermal conversion efficiency and good photoacoustic imaging (PAI) ability was expected to be a promising nanotheranostic agent for imaging guided cancer treatment. The experiments in vitro and in vivo proved that GNR@HPMO@PVMSN had good biocompatibility as well as photothermal conversion ability. In addition, DOX loading and pH-/NIR-response DOX release abilities of GNR@HPMO@PVMSN were also verified in vitro. Therefore, the GNR@HPMO@PVMSN offers a promising strategy for PAI directed synergistic chemo-/photothermal therapy, which improves the therapeutic effect of the nanomaterial on tumors. This work explores the effects of rough surfaces on cellular uptake and provides a versatile theranostic platform for biomedical applications.

Comparison of the Therapeutic Effects of Gold Nanoclusters and Gold Nanoparticles on Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and progressive cartilage and bone damage. In our previous studies, we found that Au clusters using glutathione as a template (GACs) produced profound anti-inflammatory effects in vitro on lipopolysaccharide (LPS)-induced inflammation in mouse macrophage RAW 264.7 cells and type II collagen-induced rat RA in vivo. In this study, we examined whether the template for Au clusters synthesis has an effect on its anti-inflammatory effect and whether Au nanoparticles with larger particle diameter produce the same anti-inflammatory effect. We synthesized Au clusters with bovine serum albumin (BSA) as a template (BACs), Au clusters with glutathione (GSH) as a template (GACs), and Au nanoparticles with glutathione as a template (GANs) and compared their anti-inflammatory effects in vitro and in vivo. These three Au nanomaterials can inhibit the production of lipopolysaccharide (LPS)-induced proinflammatory mediators and ameliorate type II collagen-induced rat RA. However, although the three Au nanomaterials produced similar anti-inflammatory effects, the GANs with larger particle sizes were less stable in vivo and accumulated in the peritoneum after intraperitoneal injection, resulting in poor absorption in vivo. The BACs showed relatively high liver accumulation due to the larger molecular weight of the outer shell. Therefore, we believe that the GACs are potential reliable nanodrugs for the treatment of RA.

Surface-Functionalized Modified Copper Sulfide Nanoparticles Enhance Checkpoint Blockade Tumor Immunotherapy by Photothermal Therapy and Antigen Capturing.

Nanomaterial-based tumor photothermal therapy (PTT) has attracted increasing attention and been a promising method for cancer treatment because of its low level of adverse effects and noninvasiveness. However, thermotherapy alone still cannot control tumor metastasis and recurrence. Here, we developed surface-functionalized modified copper sulfide nanoparticles (CuS NPs). CuS NPs can not only be used as photothermal mediators for tumor hyperthermia but can adsorb tumor antigens released during hyperthermia as an antigen-capturing agent to induce antitumor immune response. We selected maleimide polyethylene glycol-modified CuS NPs (CuS NPs-PEG-Mal) with stronger antigen adsorption capacity, in combination with an immune checkpoint blocker (anti-PD-L1) to evaluate the effect of hyperthermia, improving immunotherapy in a 4T1 breast cancer tumor model. The results showed that hyperthermia based on CuS NPs-PEG-Mal distinctly increased the levels of inflammatory cytokines in the serum, leading to a tumor immunogenic microenvironment. In cooperation with anti-PD-L1, PTT mediated by CuS NPs-PEG-Mal enhanced the number of tumor-infiltrating CD8+ T cells and inhibited the growth in primary and distant tumor sites of the 4T1 tumor model. The therapeutic strategies provide a simple and effective treatment option for metastatic and recurrent tumors.

Mother-to-child transmission prevention of human immunodeficiency virus, syphilis and hepatitis B virus.

BACKGROUND: China is the first country to initiate a nationwide program for prevention of mother-to-child transmission of human immunodeficiency virus, syphilis and hepatitis B virus by an integrated approach. However, the progress of this program remains unreported at national or local level for China. Therefore, we performed a hospital-based longitudinal study to assess the integrated prevention effect in Hunan, South-central China. METHODS: This study was conducted at 123 counties in Hunan and covered all local hospitals providing midwifery and antenatal care services from 2010 to 2016. We used the Cochran-Armitage test to examine the temporal changes of the indicators related with prevention of mother-to-child transmission. Besides, we used Spearman rank correlation analysis to assess the association between mother-to-child transmission rates and the process indicators related with prevention of mother-to-child transmission. RESULTS: After implementation of integrated prevention program, the indicators related with prevention of mother-to-child transmission are moving in the right direction. From 2010 to 2016, mother-to-child transmission rates significantly decreased from 19.4% to 9.6% for human immunodeficiency virus, and from 116.3 to 13.6 cases per 100,000 live births for syphilis. The proportion of children receiving hepatitis B immunoglobulin injection within 24h after birth increased from 95.2% to 98.9% among exposed neonates. Mother-to-child transmission rates were negatively associated with the process indicators related with prevention of mother-to-child transmission (all P<0.05). CONCLUSIONS: Our prevention program of mother-to-child transmission for three diseases by an integrated approach proved to be viable and effective. Our model may be of interest to other countries.

Fenofibrate Increases Heme Oxygenase 1 Expression and Astrocyte Proliferation While Limits Neuronal Injury During Intracerebral Hemorrhage.

Peroxisome proliferator-activated receptors alpha (PPARα) is a therapy target in atherosclerosis and cardiovascular diseases. However, anti-inflammatory effects of PPARα in intracerebral hemorrhage (ICH) remain unknown. We investigated the anti-inflammatory effects of fenofibrate, a ligand of PPARα, in ICH rat model. We found that engagement of fenofibrate increased nissl body and astrocytes, and reduced the neuronal damage, which was observed in paraffin section of ICH rat brain. Fenofibrate also promoted the proliferation of astrocytes that were isolated from adult rat brain. Fenofibrate significantly upregulated heme oxygenase 1 (HO-1) at protein and mRNA levels in human glioblastoma LN-18 cells and rat brain astrocytes respectively, but nuclear factor kappalight- chain-enhancer of activated B cells (NFκB) was downregulated after fenofibrate treatment. Results showed that fenofibrate-induced upregulation of HO-1 expression were inhibited after LN-18 cells were transfected with 50nM small interfering RNA (siRNAs) for 48 hours to knockdown PPARα. Further studies in rat astrocytes confirmed the rescue effects of PPARα silence against fenofibrate induced upregulation of HO-1 expression. Our data indicated that fenofibrate benefits neuronal protection through increasing HO-1 expression level and decreasing NFκB expression in PPARα-dependent manner. In conclusion, PPARα and HO-1 may function as significant targets to protect the brain during ICH.

A new benzopyrans derivatives from a mangrove-derived fungus Penicillium citrinum from the South China Sea.

One new benzopyran derivative (2R(*),4R(*))-3,4-dihydro-5-methoxy-2-methyl-2H-1-benzopyran-4-ol (1), together with five known compounds (2-6), were obtained from the EtOAc extract of the endophytic fungus Penicillium citrinum HL-5126 isolated from the mangrove Brguiera sexangula var. rhynchopetala collected in the South China Sea. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. All compounds were evaluated for their antibacterial activities. Compound 6 exhibited potent inhibitory activity against Bacillus subtilis, Bacillus cereus and Micrococcus tetragenus with the same MIC values of 6.94 µM.

The effectiveness of insulin initiation regimens in patients with type 2 diabetes mellitus: a large national medical records review study comparing a basal insulin analogue to premixed insulin.

OBJECTIVES: The objective of the study was to compare the level of HbA(1c) reduction between a once-daily basal insulin analogue (glargine, GLG) and two twice-daily premixed insulin analogue formulations (premixed insulin lispro 75/25, PIL; premixed human insulin 70/30, PHI) in patients with type 2 diabetes mellitus (T2DM) initiating insulin therapy. RESEARCH DESIGN AND METHODS: Data were extracted from a US national medical records database for this retrospective, 18-month, observational, cohort study. Patients with T2DM were initiated on GLG (n = 3624), PIL (n = 895) or PHI (n = 3647). A combined premixed insulin group (CPI; n = 4542) was formed for data analyses. Propensity score methods were used to adjust for 19 baseline characteristics. MAIN OUTCOME MEASURES: Adjusted and unadjusted reductions in HbA(1c) at six time points post-insulin initiation for a period of 18 months. RESULTS: Reductions in mean HbA(1c) relative to baseline were demonstrated by all cohorts for all treatment periods. After adjusting for baseline differences, the CPI cohort consistently demonstrated greater reductions in HbA(1c) (0.04-0.14%; p < 0.05), compared to the GLG cohort. The PIL cohort consistently demonstrated the greatest reductions in HbA(1c) (0.26-0.65%; p < 0.05), compared to the GLG cohort. LIMITATIONS: Retrospective study design and vulnerabilities to patient drop-outs. CONCLUSIONS: In clinical practice settings, greater reductions in HbA(1c) were found in patients with premixed insulin than with a basal insulin analogue with the greatest reduction observed with premixed insulin lispro 75/25, confirming the observations of randomized, controlled trials.