Sonodynamic therapy has shown promise as an effective alternative to conventional photodynamic therapy owing to its ability to treat deep-seated tumors. However, the development of stimuli-responsive ...sonosensitizers with high biocompatibility faces a significant challenge.
In this study, we developed dual stimuli-responsive sonosensitizers with desirable biosafety using extracellular vesicles (EVs), a class of naturally occurring nanoparticles. Indocyanine green (ICG), which functions as both a sonosensitizer and photoacoustic (PA) imaging agent, was loaded into EVs, together with paclitaxel (PTX) and sodium bicarbonate (SBC), to achieve pH-responsive PA imaging-guided chemo-sonodynamic combination therapy.
The EVs significantly improved the cellular uptake of ICG, thus triggering enhanced sonodynamic effects in breast cancer cells. SBC-, ICG-, and PTX-loaded EV SBC-EV(ICG/PTX) efficiently released the PTX in response to acidic pH in the endo/lysosomes because CO
bubbles generated from the SBC caused the EV membranes to burst. The drug release was further facilitated by ultrasound (US) treatment, demonstrating dual pH/US-responsive drug release. The ICG- and PTX-loaded EVs exhibited efficient anticancer activity against breast tumor cells owing to the combination of chemo-sonodynamic therapy. High-resolution PA imaging visualized the preferential tumor accumulation of SBC-EV(ICG/PTX) in tumor-bearing mice. Notably, a single intravenous injection of SBC-EV(ICG/PTX) with US irradiation significantly suppressed tumor growth in mice without systemic toxicity.
Our findings demonstrate that dual stimuli-responsive SBC-EV(ICG/PTX) are promising sonotheranostic nanoplatforms for safe and efficient chemo-sonodynamic combination cancer therapy and photoacoustic imaging.
Receptor activator of NF-kB ligand (RANKL) generates intracellular reactive oxygen species (ROS), which increase RANKL-mediated signaling in osteoclast (OC) precursor bone marrow macrophages (BMMs). ...Here we show that a ROS scavenging protein DJ-1 negatively regulates RANKL-driven OC differentiation, also called osteoclastogenesis. DJ-1 ablation in mice leads to a decreased bone volume and an increase in OC numbers. In vitro, the activation of RANK-dependent signals is enhanced in DJ-1-deficient BMMs as compared to wild-type BMMs. DJ-1 suppresses the activation of both RANK-TRAF6 and RANK-FcRγ/Syk signaling pathways because of activation of Src homology region 2 domain-containing phosphatase-1, which is inhibited by ROS. Ablation of DJ-1 in mouse models of arthritis and RANKL-induced bone disease leads to an increase in the number of OCs, and exacerbation of bone damage. Overall, our results suggest that DJ-1 plays a role in bone homeostasis in normal physiology and in bone-associated pathology by negatively regulating osteoclastogenesis.
Biologically produced reactive oxygen species (ROS) are important signaling molecules in the human body. Despite their importance under normal conditions, abnormal overproduction of ROS under ...unbalanced or irregular homeostasis can cause severe inflammatory diseases. Various antioxidants have been developed in the biomedical field to resolve high levels of ROS; however, high doses of natural antioxidants such as polyphenol can induce side effects on health. Further, synthetic antioxidants are still controversial in regards to their safety and their complicated synthesis. Inspired from our previous work, a nitric oxide-scavenging nanogel designed for treating rheumatoid arthritis, we report herein a biocompatible tannic acid (TA)-based nanogel as an effective ROS scavenger. A polymeric phenylboronic acid-tannic acid nanogel (PTNG) was prepared by simply mixing through to the formation of phenylboronic ester bonds between polymeric phenylboronate and TA. We focused on the reaction of phenylboronic ester with H
2
O
2
, which readily consumes H
2
O
2
molecules, and applied it as an antioxidant. In addition, TA is a well-known antioxidant, specifically a free radical scavenger; thus, we expected combinatory ROS scavenging effects for PTNG. Various ROS scavenging assays revealed the significant antioxidant effects of PTNG. Under an induced inflammation model
in vitro
, our PTNG showed high biocompatibility as well as strong anti-inflammatory effects. Furthermore, in the zymosan-induced peritonitis mouse model, a representative acute inflammation model
in vivo
, PTNG reduced significant neutrophil recruitment and pro-inflammatory cytokines, indicating successful alleviation of inflammation. On the basis of these results, we suggest that PTNG has great potential as an antioxidant and should find application in the treatment of further ROS-overproducing inflammatory diseases.
Biologically produced reactive oxygen species (ROS) are important signaling molecules in the human body.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Our previous study reported novel loci as genetic markers associated with increased susceptibility to CML. The present study ...conducted an expression quantitative trait loci (eQTL) analysis to confirm that the single nucleotide polymorphisms (SNPs) at these loci affect the expression of candidate CML-susceptible genes. We identified that three SNPs (rs963193, rs6931104, and rs9371517) were related to the gene expression pattern of RMND1 (Required For Meiotic Nuclear Division 1 Homolog) in both granulocytes and mononuclear cells from 83 healthy donors. Furthermore, reduced expression of RMND1 expression was noted in CML patients compared with that in healthy individuals. We used the eQTL browsing tool to assess the regulatory information on the three associated significant SNPs, out of which rs6931104 showed strong evidence of regulatory effects. Chromatin immunoprecipitation (ChIP) assays demonstrated that A alleles of rs6931104 could significantly change the binding affinity of transcription factor (TF) RFX3 compared to the G alleles. Then, we performed in vitro experiments on BCR-ABL1-positive (BCR-ABL1+) cell lines. We found that expression of the CML-susceptible gene RMND1 is affected by the binding affinity of TF RFX3, suggesting that RFX3 plays a role in RMND1 expression. Our findings suggest potential target genes for associations of genetic susceptibility risk loci and provide further insights into the pathogenesis and mechanism of CML.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
tRNA-derived RNA fragments (tRFs) have emerged as a new class of functional RNAs implicated in cancer, metabolic and neurological disorders, and viral infection. Yet our understanding of ...their biogenesis and functions remains limited. In the present study, through analysis of small RNA profile we have identified a distinct set of tRFs derived from pre-tRNA 3′ trailers in the hepatocellular carcinoma cell line Huh7. Among those tRFs, tRF_U3_1, which is a 19-nucleotide-long chr10.tRNA2-Ser(TGA)-derived trailer, was expressed most abundantly in both Huh7 and cancerous liver tissues, being present primarily in the cytoplasm. We show that genetic loss of tRF_U3_1 does not affect cell growth and it is not involved in Ago2-mediated gene silencing. Using La/SSB knockout Huh7 cell lines, we demonstrate that this nuclear-cytoplasmic shuttling protein directly binds to the 3′ U-tail of tRF_U3_1 and other abundantly expressed trailers and plays a critical role in their stable cytoplasmic accumulation. The pre-tRNA trailer-derived tRFs capable of sequestering the limiting amounts of La/SSB in the cytoplasm rendered cells resistant to various RNA viruses, which usurp La/SSB with RNA chaperone activity for their gene expression. Collectively, our results establish the trailer-derived tRF-La/SSB interface, regulating viral gene expression.
Abstract
To increase mechanical strength of porous ceramics, here, an effective two‐step sintering (TSS) technique capable of producing highly porous alumina with enhanced mechanical strength is ...suggested. Based on the sintering theories, here, a significantly lower activation energy for densification at low temperature region allowed a beneficial temperature range for the TSS to be deduced. With a specific TSS regime (
T
1
= 1550°C and
T
2
= 1400°C), significantly higher compressive strength levels (8.00–15.24 MPa) were measured with an apparent porosity of 56.49% compared to conventional sintering (1.03–1.86 MPa) with similar apparent porosity of 57.84%. Specifically, another TSS regime (
T
1
= 1550°C and
T
2
= 1380°C) left submicron‐sized open pores within the lamellar walls, providing a hierarchical porous structure with enhanced mechanical strength. An evaluation of the mechanical stability by a finite element analysis indicated outstanding compressive strength even with small pores in the lamella walls.
This study aimed to investigate the prevalence and clinical significance of lead-related tricuspid regurgitation (TR) in patients with permanent pacemaker (PM). A total of 2,533 patients who ...underwent permanent PM implantation between January 2008 and December 2017 in a single center were retrospectively reviewed. Among them, 429 patients who underwent transthoracic echocardiography within 90 days before implantation and were followed up at least 3 months after PM implantation were included. Patients who had pre-existing grade 3 or 4 TR, had a single atrial lead, or had undergone tricuspid valve surgery before PM implantation were excluded. Occurrence of PM-related TR (PMTR) was defined as worsening of TR by at least 2 grades on follow-up echocardiography. Cardiovascular outcomes were defined as the composite of cardiovascular death and hospitalization for heart failure. During the median follow-up of 855 days, 42 (9.8%) patients had PMTR and 86 (20.0%) presented with cardiovascular outcomes. In the multivariate logistic regression analysis, the presence of atrial fibrillation (hazard ratio HR: 2.07, 95% confidence interval CI: 1.27-4.09, p = 0.037) and history of open-heart surgery (HR: 3.34, 95% CI: 1.68-6.68, p0.001) were independently associated with PMTR. Patients with PMTR showed significantly higher cardiovascular events than those without (45.2 vs. 17.3%, log-rank p0.001). Furthermore, PMTR was independently associated with the primary outcome (HR: 2.45, 95% CI: 1.43-4.22, p = 0.001). In conclusion, the occurrence of TR in patients with permanent PM is not uncommon. PMTR is associated with atrial fibrillation, the history of open-heart surgery, and poorer cardiovascular outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several studies have demonstrated chemopreventive effects of aspirin against hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).
To investigate the associations of aspirin use ...with risks of HCC, liver-related mortality, and major bleeding according to metabolic risk factor burden among non-cirrhotic patients with CHB METHODS: Using the Korean National Health Insurance Service database, we identified 282,611 non-cirrhotic adults with CHB. Data on obesity, diabetes, high blood pressure, and hypercholesterolemia were collected. Subjects were stratified into lower and higher metabolic risk groups (≤2 and ≥3 risk factors, respectively). Propensity score-matched cohorts of aspirin users and non-users were generated. Risks of HCC, liver-related death and major bleeding were analyzed.
During the median follow-up of 7.4 years, positive associations between metabolic risk factor burden and outcomes were verified (all p
< 0.001). In the lower metabolic risk group (13,104 pairs), the association between aspirin use and HCC risk was not significant after multivariable adjustment (adjusted subdistribution hazard ratio aSHR: 0.93; 95% CI: 0.84-1.03); however, aspirin use was associated with elevated major bleeding risk (aSHR: 1.22; 95% CI: 1.08-1.39). In the higher metabolic risk group (2984 pairs), aspirin use was associated with reduced risks of HCC (aSHR: 0.72; 95% CI: 0.57-0.91) and liver-related mortality (aSHR: 0.69; 95% CI: 0.50-0.96) without an increase in risk of major bleeding (aSHR: 1.02; 95% CI: 0.79-1.32).
Aspirin therapy was associated with reduced risks of HCC and liver-related death without excess risk of major bleeding, in non-cirrhotic patients with CHB who had a higher metabolic risk factor burden.
We report a highly versatile and one-pot microwave route to the mass production of three-dimensional graphene-carbon nanotube-iron oxide nanostructures for the efficient removal of arsenic from ...contaminated water. The unique three-dimensional nanostructure shows that carbon nanotubes are vertically standing on graphene sheets and iron oxide nanoparticles are decorated on both the graphene and the carbon nanotubes. The material with iron oxide nanoparticles shows excellent absorption for arsenic removal from contaminated water, due to its high surface-to-volume ratio and open pore network of the graphene-carbon nanotube-iron oxide three-dimensional nanostructures.
An in-depth analysis on the load transient operation of a buck converter with auxiliary current control is presented in this article. The analysis quantifies the effects of nonideal characteristics, ...such as the equivalent series resistance, inductor current and output voltage ripples, time delay, and slew rate of the load current, on the fluctuation of the output voltage in a practical implementation. The analysis results reveals that some of the non-idealities may cancel each other out and become negligible in the implementation. A design considering the nonidealities can achieve the transient-wise capacitor charge balance of the output capacitor and minimize the output voltage deviation during the load transient. The agreement between the simulation and experimental results validates the effectiveness and precision of the proposed analysis and design.
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