Hyaluronic acid-coated liposomes for enhanced in vivo efficacy of neogambogic acid via active tumor cell targeting and prolonged systemic exposure.

Neogambogic acid (NGA), which possesses a variety of anticancer activities, is visualized as an anticancer bioactive ingredient. However, the huge vascular stimulation, poor aqueous solubility, and short half-life restricted its clinical use. In this work, an effective nanocarrier was explored to reduce toxicity and enhance the tumor-targeted delivery. Two liposomal formulations, neogambogic acid liposomes (NGA-L), and hyaluronic acid-coated neogambogic acid liposomes (HA-NGA-L) were prepared and characterized with high encapsulation efficiency, slow pattern of drug release, narrow size distribution and higher stability. The cytotoxicity and cellular uptake of HA-NGA-L were higher than those of NGA-L in MDA-MB-231 cells (high CD44 expression), while no obvious differences in MCF-7 cells with (low CD44 expression), suggesting the CD44-mediated cellular internalization of hyaluronic acid-modified liposomes enhanced the cytotoxicity. Mechanistically, elevation of Bax and caspase-3 as well as downregulation of Bcl-2 led to cell apoptosis. Besides, the vascular stimulation and the hemolysis test indicated good safety of HA-NGA-L. In addition, HA-NGA-L was the effective nanocarrier to repress tumor proliferation in MDA-MB-231 tumor xenograft mouse through CD44 mediated active targeting without any obvious histopathological abnormities on major organs. Immunohistochemistry analysis revealed the enhanced elevation of Bax and caspase-3, and reduced expression of Bcl-2 contribute to apoptosis in tumors. Meanwhile, HA-NGA-L increased the AUC and t1/2 by 5.34-fold and 3.94-fold, respectively. In summary, the present study shows that HA-NGA-L may be safe and effective for the tumor-targeted delivery of neogambogic acid.

Ptpn23 Controls Cardiac T-Tubule Patterning by Promoting the Assembly of Dystrophin-Glycoprotein Complex.

BACKGROUND: Cardiac transverse tubules (T-tubules) are anchored to sarcomeric Z-discs by costameres to establish a regular spaced pattern. One of the major components of costameres is the dystrophin-glycoprotein complex (DGC). Nevertheless, how the assembly of the DGC coordinates with the formation and maintenance of T-tubules under physiological and pathological conditions remains unclear. METHODS: Given the known role of Ptpn23 (protein tyrosine phosphatase, nonreceptor type 23) in regulating membrane deformation, its expression in patients with dilated cardiomyopathy was determined. Taking advantage of Cre/Loxp, CRISPR/Cas9, and adeno-associated virus 9 (AAV9)-mediated in vivo gene editing, we generated cardiomyocyte-specific Ptpn23 and Actn2 (α-actinin-2, a major component of Z-discs) knockout mice. We also perturbed the DGC by using dystrophin global knockout mice (DmdE4*). MM 4-64 and Di-8-ANEPPS staining, Cav3 immunofluorescence, and transmission electron microscopy were performed to determine T-tubule structure in isolated cells and intact hearts. In addition, the assembly of the DGC with Ptpn23 and dystrophin loss of function was determined by glycerol-gradient fractionation and SDS-PAGE analysis. RESULTS: The expression level of Ptpn23 was reduced in failing hearts from dilated cardiomyopathy patients and mice. Genetic deletion of Ptpn23 resulted in disorganized T-tubules with enlarged diameters and progressive dilated cardiomyopathy without affecting sarcomere organization. AAV9-mediated mosaic somatic mutagenesis further indicated a cell-autonomous role of Ptpn23 in regulating T-tubule formation. Genetic and biochemical analyses showed that Ptpn23 was essential for the integrity of costameres, which anchor the T-tubule membrane to Z-discs, through interactions with α-actinin and dystrophin. Deletion of α-actinin altered the subcellular localization of Ptpn23 and DGCs. In addition, genetic inactivation of dystrophin caused similar T-tubule defects to Ptpn23 loss-of-function without affecting Ptpn23 localization at Z-discs. Last, inducible Ptpn23 knockout at 1 month of age showed Ptpn23 is also required for the maintenance of T-tubules in adult cardiomyocytes. CONCLUSIONS: Ptpn23 is essential for cardiac T-tubule formation and maintenance along Z-discs. During postnatal heart development, Ptpn23 interacts with sarcomeric α-actinin and coordinates the assembly of the DGC at costameres to sculpt T-tubule spatial patterning and morphology.

Revealing the contradiction between DLVO/XDLVO theory and membrane fouling propensity for oil-in-water emulsion separation.

Oil fouling is the crucial issue for the separation of oil-in-water emulsion by membrane technology. The latest research found that the membrane fouling rate was opposite to the widely used theoretical prediction by Derjaguin-Landau-Verwey-Overbeek (DLVO) or extended DLVO (XDLVO) theory. To interpret the contradiction, the molecular dynamics was adopted to explore the molecular behavior of oil and emulsifier (Tween 80) at membrane interface with the assistance of DLVO/XDLVO theory and membrane fouling models. The decreased flux attenuation and fitting of fouling models proved that the existence of Tween 80 effectively alleviated membrane fouling. Conversely, DLVO/XDLVO theory predicted that the membrane fouling should be exacerbated with the increase of Tween 80 concentration in O/W emulsion. This contradiction originated from the different interaction energy between oil/Tween 80 molecules and polyether sulfone (PES) membrane. The favorable free energy of Tween 80 was resulted from the sulfuryl groups in PES and hydrogen bonds (O-H…O) formation further strengthened the interaction. Therefore, Tween 80 could preferentially adsorb on membrane surface and form an isolation layer by demulsification and steric hindrance and resist the aggregation of oil, which effectively alleviated membrane fouling. This study provided a new insight in the interpretation of interaction in O/W emulsion.

Effect of Cinobufacini plus platinum-based chemotherapy regimen on the immune function of patients with non-small-cell lung cancer: A meta-analysis.

Background: Cinobufacini is a Chinese medicinal preparation extracted from the traditional Chinese medicine toad skin and is commonly used clinically as an adjuvant treatment for malignant tumours. Purpose: To systematically evaluate the effects of Cinobufacini combined with a first-line platinum-based chemotherapy regimen in patients with non-small-cell lung cancer (NSCLC), especially in terms of immune function. Materials and methods: Eight electronic databases were searched for randomised controlled trials (RCTs) investigating Cinobufacini in conjunction with platinum-based chemotherapy for NSCLC (stage III-IV) published from 2012 to the present. GRADE Pro GDT was used to assess RCT quality and meta-analysis was performed mainly using Review Manager version 5.4, with the assistance of Stata version 16.0 (StataCorp LLC, College Station, TX, USA), and trial sequential analysis software. Results: A total of 35 studies were included. Meta-analysis revealed that the combination therapy group exhibited a better disease control rate (DCR) [OR = 2.63, 95%CI (2.15, 3.21), P < 0.00001], with a higher one-year [OR = 2.41,95% CI (1.75,3.33), P < 0.00001], and two-year [OR = 2.28, 95% CI (1.56,3.33), P < 0.00001] survival rate, plus lower leukocyte toxicity [OR = 0.40, 95%CI (0.33,0.49), P < 0.00001]. For immune function, the combination of chemotherapy with Cinobufacini effectively increased the proportion of CD3+ [SMD = 1.15, 95% CI (0.89,1.42), P < 0.00001], CD4+ [SMD = 1.60, 95%CI (1.26,1.94), P < 0.00001] and the CD4+/CD8+ ratio [SMD = 2.15, 95% CI (1.45,2.86), P < 0.00001] in peripheral blood. Conclusion: The addition of Cinobufacini to platinum-based chemotherapies for advanced NSCLC significantly improved clinical efficacy, enhanced immune function, and reduced chemotherapeutic toxicity, irrespective of administration and treatment duration.

Iron Single-Atom Catalyst-Enabled Peroxydisulfate Activation Enhances Cathodic Electrochemiluminescence of Tris(bipyridine)ruthenium(II).

The tris(bipyridine)ruthenium(II) (Ru(bpy)32+)-tripropylamine anodic electrochemiluminescence (ECL) system has been widely applied in commercial bioanalysis. However, the presence of amine compounds in the biological environment results in unavoidable anodic interference signals, which hinder further extensive use of the system. In contrast, the cathodic Ru(bpy)32+ ECL system can overcome these limitations. The Ru(bpy)32+/peroxydisulfate (S2O82-, PDS) ECL system has been extensively employed due to its ability to produce a sulfate radical anion (SO4•-) with strong oxidation ability, which enhances the ECL signal. However, the symmetrical molecular structure of PDS makes it challenging to be activated and causes low luminescence efficiency. To address this issue, we propose an efficient Ru(bpy)32+-based ternary ECL system that uses the iron-nitrogen-carbon single-atom catalyst (Fe-N-C SAC) as an advanced accelerator. Fe-N-C SAC can efficiently activate PDS into reactive oxygen species at a lower voltage, which significantly boosts the cathodic ECL emission of Ru(bpy)32+. Benefiting from the outstanding catalytic activity of Fe-N-C SAC, we successfully established an ECL biosensor that detects alkaline phosphatase activity with high sensitivity, demonstrating the feasibility of practical application.

Enhanced pH-Responsive Chemo/Chemodynamic Synergistic Cancer Therapy Based on In Situ Cu2+ Di-Chelation.

Considering the chemodynamic therapy and chemotherapy independent of external stimulus witnessing great advantage in the clinical translation, developing a smart nanoplatform that can realize enhanced chemo/chemodynamic synergistic therapy in the tumor microenvironment (TME) is of great significance. Herein, we highlight the enhanced pH-responsive chemo/chemodynamic synergistic cancer therapy based on in situ Cu2+ di-chelation. The alcohol-withdrawal drug disulfiram (DSF) and chemotherapeutic drug mitoxantrone (MTO) were embedded into PEGylated mesoporous CuO (denoted as PEG-CuO@DSF@MTO NPs). The acidic TME triggered the collapse of CuO and the concurrent release of Cu2+, DSF, and MTO. Then, the in situ complexation between Cu2+ and DSF, as well as the coordination between Cu2+ and MTO not only prominently enhanced the chemotherapeutic performance but also triggered the chemodynamic therapy. In vivo mouse model experiments demonstrated that the synergistic therapy can remarkably eliminate tumors. This study provides an interesting strategy to design intelligent nanosystems, which could proceed to clinical translations.

Insights into effects of operating temperature on the removal of pharmaceuticals/pesticides/synthetic organic compounds by membrane bioreactor process.

In this study, the removal efficiency and mechanism of 8 kinds of typical micropollutants by membrane bioreactor (MBR) at different temperatures (i.e. 15, 25 and 35 °C) were investigated. MBR exhibited the high removal rate (>85%) for 3 kinds of industrial synthetic organic micropollutants (i.e. bisphenol A (BPA), 4-tert-octylphenol (TB) and 4-n-nonylphenol (NP)) with similar functional groups, structures and high hydrophobicity (Log D > 3.2). However, the removal rates of ibuprofen (IBU), carbamazepine (CBZ) and sulfamethoxazole (SMX) with pharmaceutical activity showed great discrepancy (i.e. 93%, 14.2% and 29%, respectively), while that of pesticides (i.e. acetochlor (Ac) and 2,4-dichlorophenoxy acetic acid (2,4-D) were both lower than 10%. The results showed that the operating temperature played a significant role in microbial growth and activities. High temperature (35 °C) led to a decreased removal efficiency for most of hydrophobic organic micropollutants, and was also not conducive for refractory CBZ due to the temperature sensitivity. At lower temperature (15 °C), a large amount of exopolysaccharides and proteins were released by microorganisms, which caused the inhibited microbial activity, poor flocculation and sedimentation, resulting in the polysaccharide-type membrane fouling. It was proved that dominant microbial degradation of 61.01%-92.73% and auxiliary adsorption of 5.29%-28.30% were the main mechanisms for micropollutant removal in MBR system except for pesticides due to the toxicity. Therefore, the removal rates of most micropollutants were highest at 25 °C due to the high activity sludge so as to enhance microbial adsorption and degradation.

The mitochondrial protein YME1 Like 1 is important for non-small cell lung cancer cell growth.

The expression and biological function of the mitochondrial inner membrane protease YME1L (YME1 Like 1 ATPase) in NSCLC are tested here. Bioinformatical analyses and results from local human tissues show that YME1L expression is elevated in NSCLC tissues. YME1L upregulation was observed in primary and immortalized NSCLC cells. In NSCLC cells, shRNA-mediated silence of YME1L or dCas9/sgRNA-induced knockout (KO) of YME1L robustly suppressed cell growth and migration, and provoking apoptosis. YME1L shRNA/KO resulted in mitochondrial dysfunctions in NSCLC cells, leading to mitochondrial depolarization, ROS accumulation and ATP depletion. Conversely, ectopic YME1L overexpression augmented NSCLC cell proliferation and motility. Akt-S6K1 phosphorylation was reduced after YME1L shRNA/KO in primary NSCLC cells, but augmented after YME1L overexpression. Importantly, YME1L KO-caused anti-NSCLC cell activity was attenuated by a constitutively-activate Akt1 (S473D) construct. In vivo, subcutaneous NSCLC xenograft growth was remarkably slowed following intratumoral YME1L shRNA AAV injection in nude mice. YME1L knockdown, Akt-mTOR inactivation and ATP reduction were detected in YME1L-silenced NSCLC xenografts. Taken together, overexpressed YME1L in NSCLC exerts pro-tumorigenic function.

Toxicities of polystyrene microplastics (MPs) and hexabromocyclododecane (HBCD), alone or in combination, to the hepatopancreas of the whiteleg shrimp, Litopenaeus vannamei.

The hepatopancreas is one of the largest organs playing crucial roles in metabolism and detoxification in crustacean invertebrates. Although toxicities have been increasingly documented for the two ubiquitous pollutants, hexabromocyclododecane (HBCD) and microplastics (MPs), in model animals, little is known about their impacts on the hepatopancreas of crustaceans. To fill this knowledge gap, the effects of MPs and HBCD, alone or in combination, on the hepatopancreas were evaluated in a commercially important crustacean species (the whiteleg shrimp) by histological observation as well as quantification of hepatic lesion-, metabolism-, and detoxification-related parameters. In addition, to reveal potential mechanisms underlying the hepatoxicity observed, the accumulation of HBCD in the shrimp and the status of oxidative stress were also investigated. Our results demonstrated that exposure of the whiteleg shrimp to MPs and HBCD for 4 weeks resulted in evident histological injury in the hepatopancreas and marked elevation in hepatic lesion markers (alanine aminotransferase and aspartate aminotransferase) in the hemolymph. Moreover, both metabolism (activity of phosphofructokinase, contents of lactic acid and adenosine triphosphate, and expression of metabolism-related genes) and detoxification (contents of cytochrome P450, UDP-glucuronosyltransferase, and glutathione, activity of glutathione S-transferase, and expression of detoxification-related genes) were found to be disrupted by the pollutants tested. In addition, exposure to MPs and HBCD also led to alterations in the contents and/or activities of antioxidant enzymes and resulted in oxidative damage to the hepatopancreas (indicated by marked elevation in malondialdehyde content). Furthermore, a significant amount of HBCD accumulated in shrimp treated with HBCD-containing seawater. The data also illustrated that HBCD-MP coexposure was more toxic than single exposure to these pollutants. These findings suggest that MPs and HBCD may exert hepatotoxic impacts on whiteleg shrimp by accumulating in vivo and inducing oxidative stress, which could pose a severe threat to the health of this important crustacean species.

Divide and Conquer: A Flexible Deep Learning Strategy for Exploring Metabolic Heterogeneity from Mass Spectrometry Imaging Data.

Research on metabolic heterogeneity provides an important basis for the study of the molecular mechanism of a disease and personalized treatment. The screening of metabolism-related sub-regions that affect disease development is essential for the more focused exploration on disease progress aberrant phenotypes, even carcinogenesis and metastasis. The mass spectrometry imaging (MSI) technique has distinct advantages to reveal the heterogeneity of an organism based on in situ molecular profiles. The challenge of heterogeneous analysis has been to perform an objective identification among biological tissues with different characteristics. By introducing the divide-and-conquer strategy to architecture design and application, we establish here a flexible unsupervised deep learning model, called divide-and-conquer (dc)-DeepMSI, for metabolic heterogeneity analysis from MSI data without prior knowledge of histology. dc-DeepMSI can be used to identify either spatially contiguous regions of interest (ROIs) or spatially sporadic ROIs by designing two specific modes, spat-contig and spat-spor. Comparison results on fetus mouse data demonstrate that the dc-DeepMSI outperforms state-of-the-art MSI segmentation methods. We demonstrate that the novel learning strategy successfully obtained sub-regions that are statistically linked to the invasion status and molecular phenotypes of breast cancer as well as organizing principles during developmental phase.

Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy: Longitudinal Evaluation in Age-Related Macular Degeneration.

PURPOSE: To examine the association between incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) on OCT imaging and the subsequent risk of developing geographic atrophy (GA) defined on conventional color fundus photography (CFP) and to compare this with the specific features that define nascent GA (nGA). DESIGN: Retrospective analysis of data from a longitudinal study. PARTICIPANTS: A total of 280 eyes from 140 participants with bilateral large drusen without specific nGA-defining features or late age-related macular degeneration (AMD) at baseline. METHODS: OCT imaging and CFP were performed at baseline and then at 6-month intervals for up to 36 months. Eyes that developed neovascular AMD were censored on the day it was detected. OCT volume scans were graded for the presence of iRORA and nGA separately, and CFP images were graded for the presence of GA. MAIN OUTCOME MEASURES: Association with and variance explained in time to GA development. RESULTS: A total of 58 eyes (21%) from 46 participants (33%) had iRORA at baseline, and a further 87 eyes (31%) developed iRORA over the follow-up period. Time-to-event analyses demonstrated that prevalent or incident iRORA was associated with an increased rate of GA development (adjusted hazard ratio [HR], 12.1; P = 0.021), as was incident nGA (adjusted HR, 78.6; P < 0.001). However, only the specific nGA features (adjusted P < 0.001), and not iRORA (adjusted P = 0.520), were associated with an increased rate of GA development when both features were included in the same multivariable model. The proportion of variance explained in the time to GA development by iRORA itself (R2 = 43%) was significantly lower than explained by nGA alone (R2 = 91%; P = 0.010). CONCLUSIONS: In this cohort, iRORA is a significant risk factor for GA development, but its association with GA development appears to be accounted for by the development of the specific features that define nGA. Although requiring replication, these findings provide useful guidance on the relative utility of nGA and iRORA as risk factors for GA and as potential surrogate end points for future interventional studies in the early stages of AMD.

Key-point estimation of knee X-ray images using a parallel fusion decoding network.

BACKGROUND: High tibial osteotomy (HTO) is a knee preservation procedure used to treat osteoarthritis of the knee. Identifying the hinge point, surgical point, and Fujisawa point in the patient's knee X-ray before surgery is a critical task. The aim of this study was to propose an artificial intelligence-based method to effectively help surgeons select the location of these landmark points, which provides important reference for subsequent surgery. METHODS: We proposed PFDNet (parallel fusion decoding network), a novel convolutional neural network for key-point estimation of knee X-rays. PFDNet employs Res2Net for feature extraction in the network encoding phase and two partial decoders connected in parallel in the network decoding phase to finely aggregate the multiscale feature information produced by Res2Net. A total of 1842 knee X-ray images were trained, validated and predicted by PFDNet to determine whether the network could accurately detect key-points in the HTO surgical plan. RESULTS: At the hinge point, surgical point, and Fujisawa point, the average error and standard deviation from the calibration value in the PFDNet test results were 2.06 ± 1.165 mm, 2.713 ± 1.457 mm, and 2.015 ± 1.304 mm, respectively. This method exhibits superior performance compared with four convolutional neural network models that are also based on encoding and decoding frameworks: U-Net, ResUnet, SegNet, and FCN. CONCLUSION: The hinge point, surgical point, and Fujisawa point can be clearly selected by PFDNet from knee X-ray images and is locked to the millimeter level. The results show that the proposed artificial intelligence-based strategy can be instrumental in preoperative HTO planning.

Tuning iron spin states in single-atom nanozymes enables efficient peroxidase mimicking.

The large-scale application of nanozymes remains a significant challenge owing to their unsatisfactory catalytic performances. Featuring a unique electronic structure and coordination environment, single-atom nanozymes provide great opportunities to vividly mimic the specific metal catalytic center of natural enzymes and achieve superior enzyme-like activity. In this study, the spin state engineering of Fe single-atom nanozymes (FeNC) is employed to enhance their peroxidase-like activity. Pd nanoclusters (PdNC) are introduced into FeNC, whose electron-withdrawing properties rearrange the spin electron occupation in Fe(ii) of FeNC-PdNC from low spin to medium spin, facilitating the heterolysis of H2O2 and timely desorption of H2O. The spin-rearranged FeNC-PdNC exhibits greater H2O2 activation activity and rapid reaction kinetics compared to those of FeNC. As a proof of concept, FeNC-PdNC is used in the immunosorbent assay for the colorimetric detection of prostate-specific antigen and achieves an ultralow detection limit of 0.38 pg mL-1. Our spin-state engineering strategy provides a fundamental understanding of the catalytic mechanism of nanozymes and facilitates the design of advanced enzyme mimics.

Harnessing Nickel Phthalocyanine-Based Electrochemical CNT Sponges for Ammonia Synthesis from Nitrate in Contaminated Water.

Electrochemical reduction of nitrate to ammonia is of great interest in water treatment with regard to the conversion of contaminants to value-added products, which requires the development of advanced electrodes to achieve high selectivity, stability, and Faradaic efficiency (FE). Herein, nickel phthalocyanine was homogeneously doped into the fiber of a carbon nanotube (CNT) sponge, enabling the production of an electrode with high electrochemical double-layer capacitance (CDL) and a large electrochemically active surface area (ECSA). The as-prepared NiPc-CNT sponge could achieve 97.6% nitrate removal, 88.4% ammonia selectivity, and 86.8% FE at a nitrate concentration of 50 mg-N L-1 under an optimized potential of -1.2 V (vs Ag/AgCl). Meanwhile, the ammonia selectivity could be further improved at the high nitrate concentration. Density functional theory calculations showed that the exposure of Ni-N4 active sites could effectively suppress the hydrogen evolution reaction and dinitrogen generation, enhancing the ammonia selectivity and Faradaic efficiency. Overall, this work sheds light on the conversion of nitrate to ammonia on the metal phthalocyanine-based electrode, offering a novel strategy for managing nitrate in wastewater.

Population genomics of an icefish reveals mechanisms of glacier-driven adaptive radiation in Antarctic notothenioids.

BACKGROUND: Antarctica harbors the bulk of the species diversity of the dominant teleost fish suborder-Notothenioidei. However, the forces that shape their evolution are still under debate. RESULTS: We sequenced the genome of an icefish, Chionodraco hamatus, and used population genomics and demographic modelling of sequenced genomes of 52 C. hamatus individuals collected mainly from two East Antarctic regions to investigate the factors driving speciation. Results revealed four icefish populations with clear reproduction separation were established 15 to 50 kya (kilo years ago) during the last glacial maxima (LGM). Selection sweeps in genes involving immune responses, cardiovascular development, and photoperception occurred differentially among the populations and were correlated with population-specific microbial communities and acquisition of distinct morphological features in the icefish taxa. Population and species-specific antifreeze glycoprotein gene expansion and glacial cycle-paced duplication/degeneration of the zona pellucida protein gene families indicated fluctuating thermal environments and periodic influence of glacial cycles on notothenioid divergence. CONCLUSIONS: We revealed a series of genomic evidence indicating differential adaptation of C. hamatus populations and notothenioid species divergence in the extreme and unique marine environment. We conclude that geographic separation and adaptation to heterogeneous pathogen, oxygen, and light conditions of local habitats, periodically shaped by the glacial cycles, were the key drivers propelling species diversity in Antarctica.

Molecular Tailoring Based on Forster Resonance Energy Transfer for Initiating Two-Photon Theranostics with Amplified Reactive Oxygen Species.

The fabrication of multifunctional photosensitizers (PSs) with abundant Type I/II ROS for efficient theranostics in the "therapeutic window" (700-900 nm) is an appealing yet significantly challenging task. We herein report a molecular tailoring strategy based on intramolecular two-photon Forster Resonance Energy Transfer (TP-FRET) to obtain a novel theranostic agent (Lyso-FRET), featuring the amplified advantage of energy donor (NH) and acceptor (COOH), because of the reuse of fluorescence energy with high efficiency of FRET (∼83%). Importantly, under the excitation by the near-infrared (840 nm) window, Lyso-FRET can not only penetrate the deeper tissue with a higher resolution for fluorescence imaging due to the nonlinear optical (NLO) nature, but also generate more Type I (superoxide anion) and Type II (singlet oxygen) reactive oxygen species for hypoxic PDT. Moreover, Lyso-FRET targeting lysosomes further promotes the effect of treatment. The experiments in vitro and in vivo also verify that the developed TP-FRET PS is conducive to treating deep hypoxic tumors. This strategy provides new and significant insights into the design and fabrication of advanced multifunctional PSs.

The sodium/myo-inositol co-transporter SLC5A3 promotes non-small cell lung cancer cell growth.

Identification of novel molecular signaling targets for non-small cell lung cancer (NSCLC) is important. The present study examined expression, functions and possible underlying mechanisms of the sodium/myo-inositol co-transporter SLC5A3 in NSCLC. The Cancer Genome Atlas (TCGA) database and local NSCLC tissue results demonstrated that SLC5A3 expression in NSCLC tissues (including patient-derived primary NSCLC cells) was significantly higher than that in normal lung tissues and lung epithelial cells. In primary NSCLC cells and immortalized lines, SLC5A3 depletion, using small hairpin RNA (shRNA) and CRSIRP/Cas9 methods, robustly impeded cell proliferation and migration, simultaneously provoking cell cycle arrest and apoptosis. Conversely, ectopic overexpression of SLC5A3 further enhanced proliferation and migration in primary NSCLC cells. The intracellular myo-inositol contents and Akt-mTOR activation were largely inhibited by SLC5A3 silencing or knockout (KO), but were augmented following SLC5A3 overexpression in primary NSCLC cells. Significantly, SLC5A3 KO-induced anti-NSCLC cell activity was largely ameliorated by exogenously adding myo-inositol or by a constitutively-active Akt construct. By employing the patient-derived xenograft (PDX) model, we found that the growth of subcutaneous NSCLC xenografts in nude mice was largely inhibited by intratumoral injection SLC5A3 shRNA adeno-associated virus (AAV). SLC5A3 silencing, myo-inositol depletion, Akt-mTOR inactivation and apoptosis induction were detected in SLC5A3 shRNA virus-injected NSCLC xenograft tissues. Together, elevated SLC5A3 promotes NSCLC cell growth possibly by maintaining myo-inositol contents and promoting Akt-mTOR activation.

Propofol Prevents the Growth, Migration, Invasion, and Glycolysis of Colorectal Cancer Cells by Downregulating Lactate Dehydrogenase Both In Vitro and In Vivo.

Colorectal cancer (CRC) is one of the most frequently diagnosed gastrointestinal malignancies worldwide and has high rates of morbidity and mortality. Propofol has been reported to have certain anticancer properties. However, the role and mechanism of propofol in CRC are not entirely clear. CRC cells were treated with propofol and/or LDH-overexpression plasmids, and a mouse xenograft model of CRC was also established and treated with propofol. Cell viability, migration, and invasion were evaluated by CCK-8, wound healing, and transwell assays; the expression of related proteins was confirmed by western blotting; indexes of the glycolytic pathway were analyzed using specialized kits; tumor growth in mice was measured; pathological tissue structure was assessed by H&E staining; and 8-OHDG expression was determined by an immunochemistry assay. Our results verified that propofol could effectively prevent the malignant behaviors of CRC cells by suppressing cell viability, migration, and invasion and accelerating apoptosis. We also discovered that propofol could attenuate the glycolytic pathway in CRC cells. Moreover, we proved that lactate dehydrogenase (LDH) was required for the inhibitory effects of propofol on the growth of CRC cells, including glycolysis in CRC cells. Furthermore, our results showed that propofol could not only significantly inhibit tumor growth and glycolysis, but also ameliorate the pathological structure of CRC tumors. The current results proved that propofol could attenuate the malignant progression of CRC by preventing LDH activity, suggesting that propofol might be an effective therapeutic agent for CRC.