Quercetin, a bioflavonoid derived from vegetables and fruits, exerts anti-inflammatory effects in various diseases. Our previous study revealed that quercetin could suppress the expression of matrix ...metalloprotease-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1) to achieve anti-inflammatory effects in tumor necrosis factor-α (TNF-α)-stimulated human retinal pigment epithelial (ARPE-19) cells. The present study explored whether quercetin can inhibit the interleukin-1β (IL-1β)-induced production of inflammatory cytokines and chemokines in ARPE-19 cells. Prior to stimulation by IL-1β, ARPE-19 cells were pretreated with quercetin at various concentrations (2.5-20 µM). The results showed that quercetin could dose-dependently decrease the mRNA and protein levels of ICAM-1, IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1). It also attenuated the adherence of the human monocytic leukemia cell line THP-1 to IL-1β-stimulated ARPE-19 cells. We also demonstrated that quercetin inhibited signaling pathways related to the inflammatory process, including phosphorylation of mitogen-activated protein kinases (MAPKs), inhibitor of nuclear factor κ-B kinase (IKK)α/β, c-Jun, cAMP response element-binding protein (CREB), activating transcription factor 2 (ATF2) and nuclear factor (NF)-κB p65, and blocked the translocation of NF-κB p65 into the nucleus. Furthermore, MAPK inhibitors including an extracellular signal-regulated kinase (ERK) 1/2 inhibitor (U0126), a p38 inhibitor (SB202190) and a c-Jun N-terminal kinase (JNK) inhibitor (SP600125) decreased the expression of soluble ICAM-1 (sICAM-1), but not ICAM-1. U0126 and SB202190 could inhibit the expression of IL-6, IL-8 and MCP-1, but SP600125 could not. An NF-κB inhibitor (Bay 11-7082) also reduced the expression of ICAM-1, sICAM-1, IL-6, IL-8 and MCP-1. Taken together, these results provide evidence that quercetin protects ARPE-19 cells from the IL-1β-stimulated increase in ICAM-1, sICAM-1, IL-6, IL-8 and MCP-1 production by blocking the activation of MAPK and NF-κB signaling pathways to ameliorate the inflammatory response.
Tumor microenvironment heterogeneity (TMH) remains a challenge in cancer treatment. Nanocarrier prodrugs based on small‐molecular drug or macromolecular drug conjugates emerge as an efficient ...approach for multidrug delivery at tumor sites and activating the prodrugs by endogenous stimuli resulting from TMH. Herein, a redox/pH dual‐sensitive micelle conjugated is developed via disulfide linkage with naphthalimide‐based prodrug (PNA), assigned as PDM to encapsulate hypoxia‐activated prodrug, banoxantrone (AQ4N), for combination therapy. These micelles have several interesting features, including sufficiently stable with less drug release under physiological conditions and dual stimuli‐triggered intracellular release, high drug loading content, and negligible cytotoxicity. More importantly, in vitro cytotoxicity of AQ4N‐loaded PDM micelles exhibits a combinational anticancer efficacy between chemotherapy of PNA and hypoxia‐activated chemotherapy of AQ4N under hypoxic conditions. Moreover, the developed PNA as a new chemotherapeutic drug displays good therapeutic efficiency and fluorescent properties, which can be used for monitoring drug release in real time. This study not only offers an attractive strategy for an effective combination of traditional chemotherapy and hypoxia‐activated chemotherapy, but also provides an important concept to develop dual stimuli‐sensitive prodrug nanoplatform targeting for endogenous TMH.
A pH/redox dual‐responsive and dual chemotherapeutic PNA and hypoxia‐activated AQ4N prodrug micelle is developed for targeting endogenous tumor microenvironment heterogeneity. This new micelle system provides an effective strategy to increase the drug stability and reduce toxicity or side effects under physiological conditions, trigger intracellular release of potent drugs as well as enhance the therapeutic efficiency via combined chemotherapy and hypoxia‐activated cancer treatment.
ABSTRACT
Adequate physical activity is associated with improved sleep in adults. Such associations, however, vary greatly across studies in pediatric populations, with no studies involving infants ...found in the literature. This prospective observational study was designed, therefore, to examine the association between physical activity and sleep patterns in infants. A total of 183 healthy infants aged 6 months wore an actigraph for 7 days to measure physical activity and sleep. Parents and caregivers completed a sleep‐activity diary over the same period documenting the different types of infant activities. Daily mean time spent in screen‐time‐or‐limited physical activity, including screen‐based (e.g., watching television or other electronic devices) and non‐screen based activity (e.g., quiet play or restricted infant movement when carried by caregivers or seated in high chairs, swings, or bouncer seats), was 6.68 hr (SD = 1.99), which represented 47.50% of daytime waking hours (SD = 13.73). We found that 65 (35.5%) infants engaged in some screen time during the study, with 10 (5.5%) infants having an average daily screen time >30 min. In our multivariate linear regression model, more hours of screen‐time‐or‐limited physical activity per day were significantly associated with a decrease in total daily 24 hr sleep duration (p < 0.01). Findings from our study suggest that reducing screen‐time‐or‐limited physical activity might be an approach for promoting adequate sleep and lengthening infant daily sleep duration.
Abstract
Background
Virtual reality and arm cycling have been reported as effective treatments for improving upper limb motor recovery in patients with stroke. Intermittent theta burst stimulation ...(iTBS) can increase ipsilesional cortical excitability, and has been increasingly used in patients with stroke. However, few studies examined the augmented effect of iTBS on neurorehabilitation program. In this study, we investigated the augmented effect of iTBS on virtual reality-based cycling training (VCT) for upper limb function in patients with stroke.
Methods
In this randomized controlled trial, 23 patients with stroke were recruited. Each patient received either 15 sessions of iTBS or sham stimulation in addition to VCT on the same day. Outcome measures were assessed before and after the intervention. Primary outcome measures for the improvement of upper limb motor function and spasticity were Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and Modified Ashworth Scale Upper-Extremity (MAS-UE). Secondary outcome measures for activity and participation were Action Research Arm Test (ARAT), Nine Hole Peg Test (NHPT), Box and Block Test (BBT) and Motor Activity Log (MAL), and Stroke Impact Scale (SIS). Wilcoxon signed-rank tests were performed to evaluate the effectiveness after the intervention and Mann–Whitney U tests were conducted to compare the therapeutic effects between two groups.
Results
At post-treatment, both groups showed significant improvement in FMA-UE and ARAT, while only the iTBS + VCT group demonstrated significant improvement in MAS-UE, BBT, NHPT, MAL and SIS. The Mann–Whitney U tests revealed that the iTBS + VCT group has presented greater improvement than the sham group significantly in MAS-UE, MAL-AOU and SIS. However, there were no significant differences in the changes of the FMA-UE, ARAT, BBT, NHPT and MAL-QOM between groups.
Conclusions
Intermittent TBS showed augmented efficacy on VCT for reducing spasticity, increasing actual use of the affected upper limb, and improving participation in daily life in stroke patients. This study provided an integrated innovative intervention, which may be a promising therapy to improve upper limb function recovery in stroke rehabilitation. However, this study has a small sample size, and thus a further larger-scale study is warranted to confirm the treatment efficacy.
Trial registration
This trial was registered under ClinicalTrials.gov ID No. NCT03350087, retrospectively registered, on November 22, 2017
Metastasis is responsible for most cancer mortality, but its molecular mechanism has not been completely understood. In addition to coding genes and miRNAs, the contribution of long noncoding RNAs ...(lncRNAs) to tumor metastatic dissemination and the mechanisms controlling their expression are areas of intensive investigation. Here, we show that lncRNA NORAD is downregulated in lung and breast cancers, and that NORAD low expression in these cancer types is associated with lymph node metastasis and poor prognosis. NORAD is transcriptionally repressed by the Hippo pathway transducer YAP/TAZ-TEAD complex in conjunction with the action of NuRD complex. Functionally, NORAD elicits potent inhibitory effects on migration and invasion of multiple lung and breast cancer cell lines, and repression of NORAD expression participates in the migration- and invasion-stimulatory effects of the YAP pathway. Mechanistically, NORAD exploits its multiple repeated sequences to function as a multivalent platform for binding and sequestering S100P, thereby suppressing S100P-elicited pro-metastatic signaling network. Using cell and mouse models, we show that the S100P decoy function of NORAD suppresses lung and breast cancer migration, invasion, and metastasis. Together, our study identifies NORAD as a novel metastasis suppressor, elucidates its regulatory and functional mechanisms, and highlights its prognostic value.
Objective
T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Serum‐derived exosomes are increased in SLE patients and are correlated with disease severity. This ...study was undertaken to investigate whether T cell–derived exosomal proteins play a role in SLE pathogenesis.
Methods
We characterized proteins in T cell–derived exosomes from SLE patients and healthy controls by MACSPlex exosome analysis and proteomics. To study the potential pathogenic functions of the exosomal protein identified, we generated and characterized T cell–specific transgenic mice that overexpressed that protein in T cells.
Results
We identified eosinophil cationic protein (ECP, also called human RNase III) as overexpressed in SLE T cell–derived exosomes. T cell–specific ECP–transgenic mice (n = 5 per group) displayed early induction of serum interferon‐γ (IFNγ) levels (P = 0.062) and inflammation of multiple tissue types. Older T cell–specific ECP–transgenic mice (n = 3 per group) also displayed an increase in follicular helper T cell and plasma B cell numbers, and in autoantibody levels (P < 0.01). Single‐cell RNA sequencing showed the induction of IFNγ messenger RNA (P = 2.2 × 10‐13) and inflammatory pathways in ECP‐transgenic mouse T cells. Notably, adoptively transferred ECP‐containing exosomes stimulated serum autoantibody levels (P < 0.01) and tissue IFNγ levels in the recipient mice (n = 3 per group). The transferred exosomes infiltrated into multiple tissues of the recipient mice, resulting in hepatitis, nephritis, and arthritis.
Conclusion
Our findings indicate that ECP overexpression in T cells or T cell–derived exosomes may be a biomarker and pathogenic factor for nephritis, hepatitis, and arthritis associated with SLE.
All‐inorganic CsPbX3 (X=I, Br, Cl) perovskite quantum dots (PQDs) have been investigated because of their optical properties, such as tunable wavelength, narrow band, and high quantum efficiency. ...These features have been used in light emitting diode (LED) devices. LED on‐chip fabrication uses mixed green and red quantum dots with silicone gel. However, the ion‐exchange effect widens the narrow emission spectrum. Quantum dots cannot be mixed because of anion exchange. We address this issue with a mesoporous PQD nanocomposite that can prevent ion exchange and increase stability. We mixed green quantum‐dot‐containing mesoporous silica nanocomposites with red PQDs, which can prevent the anion‐exchange effect and increase thermal and photo stability. We applied the new PQD‐based LEDs for backlight displays. We also used PQDs in an on‐chip LED device. Our white LED device for backlight display passed through a color filter with an NTSC value of 113 % and Rec. 2020 of 85 %.
Points of light: Green CsPbBr3 perovskite quantum dots (PQDs), embedded in mesoporous silica (MP), were mixed with red CsPb(Br0.4I0.6)3 quantum dots in a silicone resin and placed on an InGaN blue chip. The green and red QDs were excited by blue light with λ=450 nm. The resulting PQD white light emitting diode (LED) exhibits a wide color gamut because of its narrow emission wavelength.
Hypoxic microenvironment and limited penetration of photosensitizers within solid tumors are two crucial factors that restrict photodynamic therapy (PDT) efficacy. Herein, a new fluorinated mixed ...micelle (M60@PFC‐Ce6) is developed as a tumor‐penetrating and oxygen‐enriching nanoplatform, which consists of chlorin e6 (Ce6) and perfluorocarbons (PFCs) co‐loaded into fluorinated micelles to relieve hypoxia conditions as well as folate as targeting ligand that facilitates the selective biodistribution within tumor solids. The incorporation of fluorinated copolymers into mixed micelles exhibits not only a great increase in the oxygen‐loading capacity, but also improves the stability of liquid PFCs emulsion within micelles without leakage. M60@PFC‐Ce6 shows excellent oxygen delivery capability, good intracellular reactive oxygen species (ROS) generation, and superior phototoxicity in vitro for both 2D monolayer of cells and 3D multicellular spheroid model. These results indicate the enriched oxygen delivery and increased cellular uptake resulting from folate‐targeted ability to enhance ROS production and PDT efficacy. The penetration study of M60@PFC‐Ce6 into a 3D spheroid confirms that small micellar size and folate‐conjugation are beneficial for micelles to penetrate and accumulate within spheroids. Thus, a new nanoplatform with enriched oxygen‐carrying amounts, better drug penetration, and stable micellar properties that relieve tumor hypoxia and improve PDT efficacy is provided.
Herein, a simple strategy is designed by using a mixed micelle with targeting function as an oxygen‐efficient fluorinated nanoplatform to not only stably deliver oxygen to alleviate the hypoxia condition of cancer cells, but also enable drugs to penetrate deep into solid tumors to achieve better photodynamic therapeutic performance.
A productive and novel method for fabricating stretchable transparent heaters with recognised thermochromic properties using commercially available thermochromic ink (TM-55-blue) and silver nanowire ...(AgNW)-coated polydimethylsiloxane (PDMS) is proposed. Lower resistance, elevated heat generation, and higher transparencies were the expected essential prerequisites for the fabrication of items such as smart windows and window defrosters. AgNW-coated PDMS (hereafter PH devices) satisfied the essential prerequisites but did not produce sufficient color change. In addition to the appreciable electrical and optical characteristics and mechanical robustness, observable color changes represent a critical factor in effortless temperature monitoring by the heating device. Blending TM-55-blue thermochromic ink with PDMS (PBH device) improves the heating rate and color transformation and promotes the ultralow response time appreciably. More notably, it produces a visible transformation from blue to colorless. Color changes visible to the naked eye, ultralow response time, and heating rate represent valuable features for deploying the PBH devices as window defrosters and in smart window applications.
The as-designed heaters proved to be excellent candidates for employment in window defrosters, as they satisfy the essential prerequisites such as lower sheet resistance, high transparency, mechanical robustness and good stability to tensile strain.
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