Designing Microneedle Patch for Prophylaxis of Postoperative Atrial Fibrillation.

Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery, which often occurs within 30 postoperative days, especially peaking at 2-3 days. Antiarrhythmic medications such as amiodarone are recommended in clinical practice for the prophylaxis and treatment of POAF. However, conventional oral administration is hindered due to delayed drug action and high risks of systemic toxicity, and emerging localized delivery strategies suffer from a limited release duration (less than 30 days). Herein, we develop a microneedle (MN) patch for localized delivery of amiodarone to the atria in a "First Rapid and Then Sustained" dual-release mode. Specifically, this patch is composed of a needle array integrated with an amiodarone-loaded reservoir for a sustained and steady release for over 30 days; and an amiodarone-containing coating film deposited on the needle surface via the Langmuir-Blodgett technique for a rapid release at the first day. Upon this design, only one MN patch enables a higher drug accumulation in the atrial tissue at the first day than oral administration and simultaneously remains therapeutical levels for over 30 days, despite at a significantly reduced drug dosage (5.08 mg in total versus ∼10 mg per day), thereby achieving ideal preventive effects and safety in a rat model. Our findings indicate that this MN device provides a robust and efficient delivery platform for long-term prophylaxis of POAF.

A Diketopyrrolopyrrole-Based All-in-One Nanoplatform for Self-Reinforcing Mild Photothermal Therapy Cascade Immunotherapy for Tumors.

Mild photothermal therapy (PTT) has attracted attention for effectively avoiding the severe side effects associated with high-temperature tumor ablation. However, its progress is hindered by the limited availability of high-performance photothermal agents (PTAs) and the thermoresistance of cancer cells induced by heat shock reactions. Herein, this work proposes a new strategy to expand the library of high-performance organic small-molecule PTAs and utilize it to construct a multifunctional nano-theranostic platform. By incorporating additional acceptors and appropriate π-bridges, a diketopyrrolopyrrole-based dye BDB is developed, which exhibits strong absorption and bright fluorescence emission in the near-infrared (NIR) region. Subsequently, BDB is co-coated with the heat shock protein (HSP) inhibitor tanespimycin (17-AAG) using the functional amphiphilic polymers DSPE-Hyd-PEG2000-cRGD to form an all-in-one nanoplatform BAG NPs. As a result, BAG NPs can precisely target tumor tissue, guide the treatment process in real-time through NIR-II fluorescence/photoacoustic/photothermal imaging, and release 17-AAG on demand to enhance mild PTT. Additionally, the mild PTT has been demonstrated to induce immunogenic cell death (ICD) and activate a systemic anti-tumor immune response, thereby suppressing both primary and distant tumors. Overall, this study presents a multifunctional nanoplatform designed for precise mild PTT combined with immunotherapy for effective tumor treatment.

Pro-inflammation and pro-atherosclerotic responses to short-term air pollution exposure associated with alterations in sphingolipid ceramides and neutrophil extracellular traps.

Air pollution has been associated with the development of atherosclerosis; however, the pathophysiological mechanisms underlying pro-atherosclerotic effects of air pollution exposure remain unclear. We conducted a prospective panel study in Beijing and recruited 152 participants with four monthly visits from September 2019 to January 2020. Linear mixed-effect models were applied to estimate the associations linking short-term air pollution exposure to biomarkers relevant to ceramide metabolism, pro-inflammation (neutrophil extracellular traps formation and systemic inflammation) and pro-atherosclerotic responses (endothelial stimulation, plaque instability, coagulation activation, and elevated blood pressure). We further explored whether ceramides and inflammatory indicators could mediate the alterations in the profiles of pro-atherosclerotic responses. We found that significant increases in levels of circulating ceramides of 9.7% (95% CIs: 0.7, 19.5) to 96.9% (95% CIs: 23.1, 214.9) were associated with interquartile range increases in moving averages of ambient air pollutant metrics, including fine particulate matter (PM2.5), black carbon, particles in size fractions of 100-560 nm, nitrogen dioxide, carbon monoxide and sulfur dioxide at prior up to 7 days. Higher air pollution levels were also associated with activated neutrophils (increases in citrullinated histone H3, neutrophil elastase, double-stranded DNA, and myeloperoxidase) and exacerbation of pro-atherosclerotic responses (e.g., increases in vascular endothelial growth factor, lipoprotein-associated phospholipase A2, matrix metalloproteinase-8, P-selectin, and blood pressure). Mediation analyses further showed that dysregulated ceramide metabolism and potentiated inflammation could mediate PM2.5-associated pro-atherosclerotic responses. Our findings extend the understanding on potential mechanisms of air pollution-associated atherosclerosis, and suggest the significance of reducing air pollution as priority in urban environments.

The Transcription Factor RUNX1 Aggravates Hypoxia-Induced Human Retinal Microvascular Endothelial Cell Dysfunction by Negatively Regulating TFF1 Promoter.

OBJECTIVE: As a retinal vaso-proliferative disorder, retinopathy of prematurity (ROP) is characterized by neovascularization and angiogenesis, causing irreversible retinal damage and even visual loss among premature infants. Trefoil factor 1 (TFF1) has been identified as a key regulator in mediating retinal angiogenesis in diabetic retinopathy. However, whether TFF1 can mediate the angiogenic process in ROP remains unknown. Here, we aimed to investigate the regulatory function of TFF1 and its underlying mechanisms in hypoxia-exposed human retinal vascular endothelial cells (HRVECs) in vitro. METHODS: HRVECs were exposed to hypoxia condition to establish the in vitro ROP models. HRVEC viability was validated using CCK-8 assay. The migratory and angiogenic capacities of HRVECs were assessed by wound healing and tube formation assays, respectively. RT-qPCR was performed to detect gene levels. Western blotting was used to measure the protein levels of TFF1 and Runt-related transcription factor 1 (RUNX1). The binding relationship between RUNX1 to TFF1 promoter was confirmed by chromatin immunoprecipitation and luciferase reporter assays. RESULTS: Hypoxia downregulated TFF1 expression and elevated RUNX1 expression in HRVECs. Moreover, hypoxic condition increased HRVEC viability and accelerated HRVEC migration and angiogenesis, which were antagonized by TFF1 elevation or RUNX1 knockdown. RUNX1 as a transcription factor bound to TFF1 promoter and transcriptionally repressed TFF1 expression in HRVECs. In rescue assays, overexpression of TFF1 counteracted the promotive effect of RUNX1 overexpression on the viability, migratory and angiogenic abilities of HRVECs under hypoxia. CONCLUSIONS: RUNX1 transcriptionally suppresses TFF1 expression to aggravate hypoxia-induced HRVEC dysfunction.

Placental Barrier on Cadmium Transfer from Mother to Fetus in Related to Pregnancy Complications.

Purpose: As two of the most severe and common medical disorders during pregnancy, gestational diabetes mellitus (GDM) and hypertensive disorder complicating pregnancy (HDCP) cause adverse effects on placental barrier function and thus may lead to a high risk of intrauterine exposure to toxic metals from mother to fetus. This study investigates the impact of the placental barrier on the transfer of cadmium (Cd) from mother to fetus and the relationship between pregnancy complications. Methods: A total of 107 pairs of samples were collected in Kunming, China; 29 were from healthy pregnant women, and 78 were from patients with pregnancy complications. Cd was measured in each mother's placenta and maternal and umbilical cord blood. The expressions of MT and Cd-MT complex in blood and placental tissue samples were determined by enzyme-linked immunosorbent assay (ELISA). Results: The cesarean section rate in the whole pathological group (60.7%) was higher than that in the normal group (20.7%), and the ratio of the effective barrier (ratio of maternal blood to umbilical cord blood>1) in the pathological group (74%) was lower than that in the normal group (79%). In addition, the proportion of practical placental barriers in women aged 20-25 years was 83.3%, 76.3% in women aged 26-30 years, 74.3% in women aged 31-35 years, 70% in women aged 36-40 years, and 71% in women aged 40-45 years. The Cd content in the placenta of the three pathological groups was significantly higher than that in maternal and umbilical cord blood (P<0.05), and the distribution of Cd was the same as that in the normal group. However, there was no significant difference between maternal and umbilical cord blood Cd concentrations in the pathological group. The Cd concentration in the normal group's maternal blood was significantly higher than that in cord blood (P<0.05). In addition, the expression levels of both metallothionein (MT) and Cd-MT complex in placenta is much higher than in maternal and umbilical blood, and which in normal group are significantly higher than those in pathological group. Conclusion: Both mothers and fetuses are at increased health risk for pregnancy disorders when maternal age, BMI, or body weight increases. Increased maternal age increases the likelihood of Cd transfer from the mother to the fetus. Pregnancy complications may induce lower expression of MT, thus reducing the Cd-MT complex in the placenta, weakening the placental barrier, and increasing the risk of Cd transfer and exposure to the fetus.

An excipient-free "sugar-coated bullet" for the targeted treatment of orthotopic hepatocellular carcinoma.

Several components of traditional nanoformulations that result in structural heterogeneity, poor reproducibility, excipient-trigged biotoxicity, and low retention of antitumor drugs in neoplastic foci are important barriers limiting clinical translation. We report an excipient-free nanoformulation prepared by a reactive oxygen species (ROS)-responsive amphiphilic prodrug (Gal-MB-DOX) for the targeted treatment of orthotopic hepatocellular carcinoma (HCC). Gal-MB-DOX can form monocomponent nanoparticles with a galactose-rich surface similar to a "sugar-coated bullet" through self-assembly in aqueous solution. This nanoformulation can be decomposed quickly by ROS and release free hydrophobic drugs that further precipitate into larger particles, potentially promoting the retention of drugs in tumor cells. These sugar-coated bullets selectively target tumor cells through passive and active targeting, resulting in high in vivo therapeutic efficacy in an orthotopic HCC mouse model. This monocomponent nanomedicine system provides a simple but effective strategy for the treatment of tumors.

Cyclopiazonic Acid and Okaramine Analogues, Including Chlorinated Compounds, from Chrysosporium undulatum YT-1.

Eight new cyclopiazonic acid (1-8) and five new okaramine (9-13) alkaloids together with 13 known compounds were isolated from the fungus Chrysosporium undulatum YT-1. Compounds 2, 4, 5, 7, 10, 11, and 13 were chlorinated indole alkaloids. The structures of compounds 1-13 were elucidated by HRESIMS and NMR spectroscopic data. Their relative and absolute configurations were established by J-based configuration analysis, NOESY, NOEDIFF experiments, ECD spectroscopic data, and biogenetic considerations. Compound 4 inhibited the growth of Bacillus subtilis with an MIC value of 6.3 µg/mL. Compounds 9-11 exhibited strong insecticidal capacity against the third instar larvae of silkworm and cotton bollworm (LD50: ≤7.56 µg/g). At 40 µM, compound 1 showed obvious neuroprotection to the PC12 cells with 6-OHDA treatment.

Analysis of metabolites of fungal balls in the paranasal sinuses.

Fungal ball sinusitis is characterized by complex fungus infections with non-invasive inflammation. But no research reported fungal ball composition and metabolic-related product types currently. 12 patients with chronic rhinosinusitis who underwent surgery and 9 healthy control were enrolled in this study. Samples from both groups were analyzed for high-throughput metabolites by UPLC-MS. OsiriX software was applied to perform imaging measurements on sinus CT. 2138 and 394 metabolites were screened from cationic and anionic modes. There was a significant difference in the abundance of glycerophospholipid metabolism and sphingolipid metabolism between the two groups, with the experimental group showing an increased trend related to the sphingolipid metabolic pathway, including sphingosine 1-phosphate (S1P) and related products, diacylglycerol, sphingomyelin (SM), suggesting that its metabolites are associated with mucosal and bony inflammation. Imaging measurements showed a median sinus CT value (median (P25, P75) of 351(261.4, 385.8) HU and a median sinus wall thickness (median (P25, P75) of 2.31(1.695, 3.718) mm, which correlated with the levels of glycerophospholipid metabolites and sphingolipid metabolites (P < 0.03). Dysfunctional glycerophospholipid and sphingolipid metabolism is present in the lesion of fungal ball sinusitis. Glycerophospholipid and sphingolipid metabolism plays a significant role in the progression of mucosal and osteitis produced by fungal ball sinusitis.

circEPSTI1 promotes tumor progression and cisplatin resistance via upregulating MSH2 in cervical cancer.

CircRNAs (circRNAs) are a kind of non-coding RNAs which are extensively distributed in tissues. Previous investigations reported that circRNAs harbor indispensable roles in modulating the progress of multiple cancers. Nevertheless, the function along with the molecular mechanism of most circRNAs in cervical cancer progression was still not clear. Herein, we illustrated that circEPSTI1 is a remarkably upregulated circRNA, which we validated in tissues with cervical cancer along with cell lines. The biological role of circEPSTI1 in the advancement of cervical cancer was probed via loss-of function assessments. Silencing circEPSTI1 could diminish the proliferative capacity of the cervical cancer cells to spread. In cervical cancer cells, silencing circEPSTI1 dramatically elevated drug responsivity to cisplatin. Mechanically, RNA immuno-precipitation experiments and dual luciferase enzyme reporter experiments were conducted to reveal the molecular mechanism of circEPSTI1 in cervical cancer. In conclusion, this research premise identified the biological function of circEPSTI1-miR-370-3p-MSH2 axis in cervical cancer progression. Our result is significant for slowing the progress of and overcoming drug resistance of cervical cancer.

A Smart Theranostic Prodrug System Activated by Reactive Oxygen Species for Regional Chemotherapy of Metastatic Cancer.

Metastatic cancer is difficult to cure because of its uncontrollable nature and side effects during treatment. We constructed a reactive oxygen species (ROS)-activated smart theranostic prodrug system based on an ROS active site linked with both a targeting group and an anticancer drug for efficient regional chemotherapy of metastatic cancers. The optimized prodrug (Bio-(8)-MB-CPT) with biotin as the targeting group displayed high sensitivity towards ROS and selectively targeting ability towards cervical cancer cells, showing highly efficient drug release (up to 92 %) in vitro. Bio-(8)-MB-CPT thus exerted strong toxicity towards cervical cancer cells, but unlike the parent drug (camptothecin), showed no toxicity towards normal cells. Moreover, the prodrug displayed significantly enhanced antitumor efficacy in vivo and eradicated the tumor with no obvious side effects (inhibition of the tumor reached up to 99.9 %).

Pregnancy complications effect on the nickel content in maternal blood, placenta blood and umbilical cord blood during pregnancy.

BACKGROUND: Nickel (Ni) may accumulate in the human body and has biological toxicity and carcinogenicity. Ni has an extensive impact on the health of pregnant women and fetuses during gestation. AIM: To evaluate Ni exposure in pregnant women in Kunming, Yunnan Province, China; to describe the distribution of Ni in the maternal-fetal system and placental barrier function; and to investigate the effect of Ni exposure on fetal health in mothers with pregnancy complications. METHODS: Seventy-two pregnant women were selected using a case-control design. The women were divided into two groups: The control group (no disease; n = 29) and the disease group [gestational diabetes (GDM), hypertensive disorder complicating pregnancy (HDCP), or both; n = 43]. The pregnant women in the disease group were further divided as follows: 14 cases with GDM (GDM group), 13 cases with HDCP (HDCP group) and 16 cases with both GDM and HDCP (disease combination group). Basic information on the pregnant women was collected by questionnaire survey. Maternal blood, placenta blood and cord blood were collected immediately after delivery. The Ni content in paired samples was determined using inductively coupled plasma mass spectrometry. RESULTS: Compared to the control group, age was higher and body mass index was greater in pregnant women in the disease groups (28.14 ± 2.54 vs 28.42 ± 13.89, P < 0.05; 25.90 ± 3.86 vs 31.49 ± 5.30, P < 0.05). The birth weights of newborns in the HDCP group and the control group were significantly different (2.52 ± 0.74 vs 3.18 ± 0.41, P < 0.05). The content of Ni in umbilical cord blood in the entire disease group was higher than that in the control group (0.10 ± 0.16 vs 0.05 ± 0.07, P < 0.05). CONCLUSION: In the maternal-fetal system of women with pregnancy complications, the barrier effect of the placenta against Ni is weakened, thus affecting healthy growth of the fetus in the uterus.

De novo design of self-assembly hydrogels based on Fmoc-diphenylalanine providing drug release.

Short peptides with self-assembled nanostructures are widely applied in the areas of drug delivery systems and biomaterials. In this article, we create a new peptide-based hydrogelator (Fmoc-FFRRVR) based on N-fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) through an approach to improve its hydrophilicity. Compared to Fmoc-FF, Fmoc-FFRRVR prefers to form a hydrogel under mild conditions, and the gelation time is only 2 s. Fmoc-FFRRVR self-assembles into organized arrays of ß-sheets in nanofibers via π-stacking of Fmoc-FF, which are supported by circular dichroism and fluorescence emission spectroscopy. Rheology results confirm that the hydrogel of Fmoc-FFRRVR is elastic, reversible and injectable. The newly discovered hydrogel not only retains some excellent performances of Fmoc-FF, but also can be used as a drug carrier for biomedical applications.

Blocking MCT4 SUMOylation inhibits the growth of breast cancer cells.

Monocarboxylate transporter 4 (MCT4) is highly expressed in various types of solid neoplasms including breast cancer (BC); however, the pro-tumor functions underlying its increased expression have not been explained. Here, we examined the roles of posttranslational modifications to MCT4 in BC, particularly SUMOylation. Our findings revealed that SUMOylation of MCT4 inhibited its degradation and stabilized MCT4 protein levels, while ubiquitination facilitated MCT4 degradation. The E3 ubiquitin ligases ß-TRCP and FBW7 interacted with MCT4 at the DSG-box and TPETS sequences, respectively, and Lys448 (K448) of MCT4 could be modified by SUMO chains. Our key finding was that K448 was crucial for MCT4 SUMOylation. Moreover, mutations of K448 abolished MCT4 expression, delaying the growth of BC. This study suggested that SUMOylation of K448 increased MCT4 levels, and mutations of K448 in MCT4 could have therapeutic significance in BC.

HOCl-Activated Aggregation of Gold Nanoparticles for Multimodality Therapy of Tumors.

Tumor microenvironment-responsive nanodrugs offer promising opportunities for imaging-guided precision therapy with reduced side effects. Considering that the antitumor effect is closely related to the size of the nanodrugs, it is particularly important to develop a therapeutic system with size adjustability in the tumor microenvironment, which is still a great challenge in the field of nanotheranostics. Herein, a reactive oxygen species (ROS)-activated aggregation strategy is reported for imaging-guided precision therapy of tumors. The ROS-activated nanoplatform is constructed based on gold nanoparticles (AuNPs) coated with an HOCl probe on its surface (namely, Au-MB-PEG NPs). The Au-MB-PEG NPs show high sensitivity toward HOCl, resulting in the modulation of surface charge and rapid aggregation of AuNPs, and simultaneous release of methylene blue as a photosensitizer for photodynamic therapy (PDT). In the tumor environment, the aggregated AuNPs ensure higher tumor accumulation and retention. Furthermore, the redshift of the absorption of aggregated AuNPs leads to activated photoacoustic imaging signals and photothermal therapy (PTT) under near-infrared irradiation. Au-MB-PEG NPs thus efficiently inhibit the tumor growth through combined PTT-PDT therapy. This work contributes to the design of stimuli-induced size-aggregation nanodrugs, thereby attaining advanced performance in cancer diagnosis and treatment.

Enhanced anticancer effect of doxorubicin by TPGS-coated liposomes with Bcl-2 siRNA-corona for dual suppression of drug resistance.

Multiple drug resistance (MDR) is a tough problem in developing hepatocellular carcinoma (HCC) therapy. Here, we developed TPGS-coated cationic liposomes with Bcl-2 siRNA corona to load doxorubicin (Dox) i.e., Bcl-2 siRNA/Dox-TPGS-LPs, to enhance anticancer effect of Dox in HCC-MDR. TPGS i.e., d-α-tocopheryl polyethylene glycol 1000 succinate, inhibited P-glycoprotein (P-gp) efflux pump and Bcl-2 siRNA suppressed anti-apoptotic Bcl-2 protein. The Bcl-2 siRNA loaded in the liposomal corona was observed under transmission electron microscopy. The stability and hemolysis evaluation demonstrated Bcl-2 siRNA/Dox-TPGS-LPs had good biocompatibility and siRNA-corona could protect the liposomal core to avoid the attachment of fetal bovine serum. In drug-resistant cells, TPGS effectively prolonged intracellular Dox retention time and siRNA-corona did improve the internalization of Dox from liposomes. In vitro and in vivo anticancer effect of this dual-functional nanostructure was examined in HCC-MDR Bel7402/5-FU tumor model. MTT assay confirmed the IC50 value of Dox was 20-50 fold higher in Bel7402/5-FU MDR cells than that in sensitive Bel7402 cells. Bcl-2 siRNA corona successfully entered the cytosol of Bel7402/5-FU MDR cells to downregulate Bcl-2 protein levels in vitro and in vivo. Bcl-2 siRNA/Dox-TPGS-LPs showed superior to TPGS- (or siRNA-) linked Dox liposomes in cell apoptosis and cytotoxicity assay in Bel7402/5-FU MDR cells, and 7-fold greater effect than free Dox in tumor growth inhibition of Bel7402/5-FU xenograft nude mice. In conclusion, TPGS-coated cationic liposomes with Bcl-2 siRNA corona had the capacity to inhibit MDR dual-pathways and subsequently improved the anti-tumor activity of the chemotherapeutic agent co-delivered to a level that cannot be achieved by inhibiting a MDR single way.

YAP activity protects against endotoxemic acute lung injury by activating multiple mechanisms.

The roles of the Hippo­Yes­associated protein (YAP) pathway in lung injury and repair remain elusive. The present study examined the effects of systemic inhibition or stimulation of YAP activity on lung injury, repair and inflammation in a mouse model of lipopolysaccharide (LPS)­induced lung injury. Mice were treated with or without YAP inhibitor, verteporfin, or with or without YAP stimulator, XMU­MP­1, and intraperitoneally injected with LPS (7.5 mg/kg). Lung injury and repair were evaluated by histological analysis and by testing for markers of lung injury. Lung inflammation was assessed by measuring tissue levels of inflammatory mediators. Lung injury was associated with a decreased, whereas lung repair was associated with an increased YAP activity evidenced by nuclear translocation. Lung injury was associated with a high level of lung inflammation and epithelial adherens junction disassembly, but not with cell proliferation or epithelial cell regeneration. The injury phase was defined as 0­48 h post­LPS injection, and the 48­168 h time period was considered the repair phase. Inhibition of YAP activity at the injury phase, using verteporfin, exacerbated, whereas its stimulation, using XMU­MP­1, alleviated lung injury, lung inflammation and epithelial adherens junction disassembly. Inhibition or stimulation of YAP activity at the injury phase had no effects on cell proliferation or epithelial regeneration. By contrast, lung repair was associated with inflammation resolution, increased cell proliferation, epithelial regeneration and reassembly of epithelial adherens junctions. Inhibition of YAP activity at the repair phase delayed inflammation resolution, impeded lung recovery, inhibited cell proliferation and epithelial regeneration, and inhibited epithelial adherens junction reassembly. Stimulation of YAP activity at the repair phase reversed all these processes. The results of the current study demonstrated that the Hippo­YAP activity serves a protective role against endotoxemic lung injury. The Hippo­YAP activity alleviated lung inflammation and injury at the injury phase and promoted inflammation resolution and lung repair at the repair phase.

Multifunctional Smart Yolk-Shell Nanostructure with Mesoporous MnO2 Shell for Enhanced Cancer Therapy.

Manganese dioxide (MnO2) nanostructures have aroused great interest among analytical and biological medicine researchers as a unique type of tumor microenvironment (TME)-responsive nanomaterial. However, reliable approaches for synthesizing yolk-shell nanostructures (YSNs) with mesoporous MnO2 shell still remain exciting challenges. Herein, a YSN (size, ∼75 nm) containing a mesoporous MnO2 shell and Er3+-doped upconversion/downconversion nanoparticle (UCNP) core with a large cavity is demonstrated for the first time. This nanostructure not only integrates diverse functional components including MnO2, UCNPs, and YSNs into one system but also endows a size-controllable hollow cavity and thickness-tunable MnO2 layers, which can load various guest molecules like photosensitizers, methylene blue (MB), and the anticancer drugs doxorubicin (DOX). NIR-II fluorescence and photoacoustic (PA) imaging from UCNP and MB, respectively, can monitor the enrichment of the nanomaterials in the tumors for guiding chemo-photodynamic therapy (PDT) in vivo. In the TME, degradation of the mMnO2 shell by H2O2 and GSH not only generates Mn2+ for tumor-specific T1-MR imaging but also releases O2 and drugs for tumor-specific treatment. The result confirmed that imaging-guided enhanced chemo-PDT combination therapy that benefited from the unique structural features of YSNs could substantially improve the therapeutic effectiveness toward malignant tumors compared to monotherapy.

The critical size of gold nanoparticles for overcoming P-gp mediated multidrug resistance.

Multidrug resistance (MDR) remains a huge obstacle during cancer treatment. One of the most studied MDR mechanisms is P-glycoprotein (P-gp) mediated drug efflux. Based on the three-dimensional structural characteristics of P-gp, gold nanoparticles (AuNPs) with average sizes of 4.1 nm and 5.4 nm were designed for the construction of nanodrug delivery systems (NanoDDSs), with the anticancer molecules 2-(9-anthracenylmethylene)-hydrazinecarbothioamide (ANS) and 6-mercaptopurine (6-MP) modified on the AuNP surfaces through the thiol group. In vitro cytotoxicity results suggested that the larger sized AuNPs can effectively decrease the drug resistance index of MCF-7/ADR cells to ∼2. Verapamil and P-gp antibody competitive experiments, combined with the cellular uptake of AuNPs, indicated that larger NanoDDSs were more conducive to intracellular drug accumulation and thus had improved anticancer activities, due to a size mismatch between the nanoparticles and the active site of P-gp, and, therefore, reduced drug efflux was seen. Measurements of ATPase activity and intracellular ATP levels indicated that the larger nanoparticles do not bind well to P-gp, thus avoiding effective recognition by P-gp. This was further evidenced by the observation that 4.1 nm and 5.4 nm NanoDDS-treated MCF-7/ADR cells showed remarkable differences in energy-related metabolic pathways. Therefore, the critical size of AuNPs for overcoming MDR was identified to be between 4.1 nm and 5.4 nm. This provides a more accurate description of the composite dimension requirements for NanoDDSs that are designed to overcome MDR.

pH-responsive Ag2S nanodots loaded with heat shock protein 70 inhibitor for photoacoustic imaging-guided photothermal cancer therapy.

Heat-treated cancer cells have thermo-resistance due to the up-regulated levels of heat shock proteins (HSP) resulting in low therapeutic efficiency and ineffective ablation of tumors. In this work, we report pH-responsive Ag2S nanodots (Ag2S NDs) loaded with HSP70 inhibitor (QE-PEG-Ag2S) for enhanced photothermal cancer therapy. QE-PEG-Ag2S was easily prepared via self-assembly of hydrophobic Ag2S NDs, amphiphilic pH-responsive PEG5k-PAE10k polymer, and an HSP70 inhibitor quercetin (QE). QE-PEG-Ag2S has ideal water-solubility and biocompatibility, can rapidly enter cells, and preferentially accumulate in cell lysosomes. The slightly acidic environment of tumor cells and the acidity of lysosomes as well as the high temperature generated by photothermal therapy under irradiation of NIR light (808 nm) promote the release of the inhibitor molecules to reduce the heat resistance of cancer cells and improve the in vivo photothermal therapy efficiency. Moreover, QE-PEG-Ag2S has good photoacoustic imaging (PAI) ability; this QE-PEG-Ag2S concentration dependent signal can precisely follow the accumulation of the nanomaterials in tumors and dictate the correct time for light therapy. As a result, QE-PEG-Ag2S achieved complete tumor ablation effect with no recurrence when only irradiated with NIR light for 10 min. This approach offers a new approach for the theranostic applications of Ag2S NDs. STATEMENT OF SIGNIFICANCE: In this work, pH-responsive Ag2S nanodots loaded with the heat shock protein inhibitor for enhanced photothermal cancer therapy have been simply prepared via self-assembly process. This nanoagent possesses ideal water-solubility and biocompatibility, can rapidly enter cells, and preferentially accumulate in cell lysosomes. The acidic environment of tumor cells and the acidity of lysosomes, as well as the high temperature generated by photothermal therapy under irradiation of NIR light promote the release of the inhibitor molecules from the nanoagent to improve the in vivo photothermal therapy efficiency. Moreover, the photoacoustic imaging (PAI) of the nanoagent can precisely follow the accumulation of the nanomaterials in tumors and dictate the light therapy time to guarantee the complete tumor ablation effect with no recurrence.

The Joubert Syndrome Gene arl13b is Critical for Early Cerebellar Development in Zebrafish.

Joubert syndrome is characterized by unique malformation of the cerebellar vermis. More than thirty Joubert syndrome genes have been identified, including ARL13B. However, its role in cerebellar development remains unexplored. We found that knockdown or knockout of arl13b impaired balance and locomotion in zebrafish larvae. Granule cells were selectively reduced in the corpus cerebelli, a structure homologous to the mammalian vermis. Purkinje cell progenitors were also selectively disturbed dorsomedially. The expression of atoh1 and ptf1, proneural genes of granule and Purkinje cells, respectively, were selectively down-regulated along the dorsal midline of the cerebellum. Moreover, wnt1, which is transiently expressed early in cerebellar development, was selectively reduced. Intriguingly, activating Wnt signaling partially rescued the granule cell defects in arl13b mutants. These findings suggested that Arl13b is necessary for the early development of cerebellar granule and Purkinje cells. The arl13b-deficient zebrafish can serve as a model organism for studying Joubert syndrome.