WAV E3 ubiquitin ligases mediate degradation of IAA32/34 in the TMK1-mediated auxin signaling pathway during apical hook development.

Auxin regulates plant growth and development through downstream signaling pathways, including the best-known SCFTIR1/AFB-Aux/IAA-ARF pathway and several other less characterized "noncanonical" pathways. Recently, one SCFTIR1/AFB-independent noncanonical pathway, mediated by Transmembrane Kinase 1 (TMK1), was discovered through the analyses of its functions in Arabidopsis apical hook development. Asymmetric accumulation of auxin on the concave side of the apical hook triggers DAR1-catalyzed release of the C-terminal of TMK1, which migrates into the nucleus, where it phosphorylates and stabilizes IAA32/34 to inhibit cell elongation, which is essential for full apical hook formation. However, the molecular factors mediating IAA32/34 degradation have not been identified. Here, we show that proteins in the CYTOKININ INDUCED ROOT WAVING 1 (CKRW1)/WAVY GROWTH 3 (WAV3) subfamily act as E3 ubiquitin ligases to target IAA32/34 for ubiquitination and degradation, which is inhibited by TMK1c-mediated phosphorylation. This antagonistic interaction between TMK1c and CKRW1/WAV3 subfamily E3 ubiquitin ligases regulates IAA32/34 levels to control differential cell elongation along opposite sides of the apical hook.

Quantum Griffiths Singularity in Ordered Artificial Superconducting-Islands-Array on Graphene.

Quantum Griffiths phase (QGP) is a novel quantum phenomenon of quantum phase transition in two-dimensional (2D) superconductors, and the emergence of inhomogeneous superconducting rare regions immersed in a metallic matrix is theoretically related to the quantum Griffiths singularity (QGS). However, the theoretical proposal of superconducting rare regions still lacks intuitive experimental verification. Here, we construct an artificial ordered superconducting-islands-array on monolayer graphene with the aid of an anodic aluminum oxide (AAO) membrane. The QGS under both in-plane and out-of-plane magnetic fields is evidenced by the divergent dynamical critical exponent and is in compliance with the direct activated scaling behavior. The phase diagram clearly shows that the QGP is indeed bred in the rare superconducting regions within isolated superconducting islands with a vanished quantum coherence. Our results reveal the universal features of QGP in artificial heterostructured systems and provide a visualized platform for the theoretical proposal of QGS.

Polyoxometalate-Intercalated Tremella-Like CoNi-LDH Nanocomposites for Electrocatalytic Nitrite-Ammonia Conversion.

The electrocatalytic reduction of NO2- (NO2RR) holds promise as a sustainable pathway to both promoting the development of emerging NH3 economies and allowing the closing of the NOx loop. Highly efficient electrocatalysts that could facilitate this complex six-electron transfer process are urgently desired. Herein, tremella-like CoNi-LDH intercalated by cyclic polyoxometalate (POM) anion P8W48 (P8W48/CoNi-LDH) prepared by a simple two-step hydrothermal-exfoliation assembly method is proposed as an effective electrocatalyst for NO2- to NH3 conversion. The introduction of POM with excellent redox ability tremendously increased the electrocatalytic performance of CoNi-LDH in the NO2RR process, causing P8W48/CoNi-LDH to exhibit large NH3 yield of 0.369 mmol h-1 mgcat-1 and exceptionally high Faradic efficiency of 97.0% at -1.3 V vs the Ag/AgCl reference electrode in 0.1 M phosphate buffer saline (PBS, pH = 7) containing 0.1 M NO2-. Furthermore, P8W48/CoNi-LDH demonstrated excellent durability during cyclic electrolysis. This work provides a new reference for the application of POM-based nanocomposites in the electrochemical reduction of NO2- to obtain value-added NH3.

Biomimetic MDSCs membrane coated black phosphorus nanosheets system for photothermal therapy/photodynamic therapy synergized chemotherapy of cancer.

Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4+, CD8+ T cells as well as CD103+ DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer.

Multitarget therapy with a corticosteroid, cyclosporine and mycophenolate mofetil for idiopathic membranous nephropathy: a prospective randomized controlled trial.

BACKGROUND: The effectiveness of multitarget combination therapy with a corticosteroid, cyclosporine and mycophenolate mofetil for idiopathic membranous nephropathy (IMN) is unclear. In the present study, we aimed to compare the efficacy and safety of multitarget therapy with a cyclical corticosteroid-cyclophosphamide regimen in patients with IMN. METHODS: This was a single-centre, prospective, randomized, controlled trial. We randomly assigned patients with IMN to receive multitarget therapy (a combination of prednisone, cyclosporine and mycophenolate mofetil) or 6-month cyclical treatment with a corticosteroid and cyclophosphamide. The study patients were followed up for 12 months. The primary outcome was a composite of complete or partial remissions at 12 months. Adverse events were also assessed. RESULTS: The study cohort comprised 78 patients, 39 of whom received multitarget therapy and the other 39 cyclical alternating treatment with a corticosteroid and cyclophosphamide. At 12 months, 31 of 39 patients (79%) in the multitarget therapy group and 34 of 39 (87%) in the corticosteroid-cyclophosphamide group had achieved complete or partial remissions (relative risk 0.93; 95% confidence interval 0.72-1.21; P = .85; log-rank test). The prevalence of adverse events was significantly lower in the multitarget therapy group than in the corticosteroid-cyclophosphamide group [46% (18 of 39) vs 74% (29 of 39); P < .05]. CONCLUSIONS: Multitarget therapy for IMN patients is noninferior to cyclical alternating treatment with corticosteroid and cyclophosphamide in inducing proteinuria remission and has a better safety profile than the corticosteroid-cyclophosphamide combination.

Effect of dialytic phosphate reduction rate on mortality in maintenance hemodialysis patients: a matched case-control study.

BACKGROUND: Phosphates, similar to urea, are small molecular substances that can be cleared during dialysis. Dialytic phosphate reduction rate (PRR) may, to some extent, be related to the relative amount of phosphates cleared during dialysis. However, few studies have evaluated the associations between PRR and mortality in maintenance hemodialysis (MHD) patients. In this study, we investigated the association between PRR and clinical outcomes in MHD patients. METHODS: This was a retrospective, matched case-control study. Data were collected from the Beijing Hemodialysis Quality Control and Improvement Center. Patients were divided into four groups according to PRR quartile. Age, sex, and diabetes were matched between the groups. The primary outcome was all-cause death, and the secondary outcome was cardiocerebrovascular death. RESULTS: The study cohort comprised 4063 patients who were divided into four groups according to the PRR quartile: group PRR1 (< 48.35%), group PRR2 (48.35% - 54.14%), group PRR3 (54.14% - 59.14%), and group PRR4 (≥ 59.14%). We enrolled 2172 patients (543 in each study group) by case-control matching. The all-cause death rates were as follows: group PRR1: 22.5% (122/543), group PRR2: 20.1% (109/543), group PRR3: 19.3% (105/543), and group PRR4: 19.3% (105/543). No significant differences in all-cause and cardiocerebrovascular death rates according to the Kaplan-Meier survival curves were found between the groups (log-rank test, P > 0.05). Multivariable Cox regression analysis revealed no significant differences in all-cause and cardiocerebrovascular death rates between the four groups (P = 0.461; adjusted hazard ratio, 0.99; 95% confidence interval, 0.97 - 1.02 versus P = 0.068; adjusted hazard ratio, 0.99; 95% confidence interval, 0.97 - 1.00, respectively). CONCLUSIONS: Dialytic PRR was not significantly associated with all-cause death and cardiocerebrovascular death in MHD patients.

Epidemiological analysis of death among patients on maintenance hemodialysis: results from the beijing blood purification quality Control and Improvement Center.

BACKGROUND: China has the largest number of patients on maintenance hemodialysis (MHD) worldwide. Despite continuous improvements in hemodialysis techniques, patients on MHD have a higher mortality rate than the general population. Understanding the characteristics of death in this population can better promote clinical practice, thereby improving patients' survival. METHODS: We collected demographic and clinical data for patients on MHD registered in the Beijing Blood Purification Quality Control and Improvement Center database from 2014 to 2020. The annual mortality rate was calculatedand the primary cause of end-stage renal disease (ESRD), dialysis vintage, and cause of death among deceased patients were analyzed. RESULTS: (1) 24,363 patients on MHD were included, of which 6,065 patients died from 2014 to 2020. The annual mortality rate fluctuated between 7.4% and 8.0%. The median age of death was 70.0 (60.8-79.0) years and the male to female ratio was 1.27:1 (2). The top three primary causes of ESRD in deceased patients were chronic glomerulonephritis (CGN), diabetic nephropathy (DN), and hypertensive nephropathy (HN). Comparison of the annual mortality rate showed DN > HN > CGN (3). The median dialysis vintage of deceased patients was 3.7 (1.8-6.9) years, which slowly increased annually. Patients with diabetes had a shorter dialysis vintage than patients without diabetes (3.4 vs. 4.1 years, Z = 8.3, P < 0.001) (4). The major causes of death were cardiovascular disease (20.2%), sudden death (18.1%), infection (17.9%), and cerebrovascular disease (12.6%). Proportions of death from cardiovascular disease, infection, and sudden death were higher in patients with diabetes (22.2%, 20.2%, and 20.0%) than patients without diabetes (18.4%, 15.8%, and 16.3%). Sudden death was the leading cause of death in young (18-44 years; 27.0%) and middle aged (45-64 years; 20.8%) patients, whereas infection was the leading cause of death in patients aged ≥ 75 years (24.5%). CONCLUSION: The annual mortality rate of patients on MHD in Beijing was relatively stable from 2014 to 2020. Sudden death was more likely to occur in young and middle-aged patients, and more patients aged ≥ 75 years died from infections.

Advanced materials and technologies for oral diseases.

Oral disease, as a class of diseases with very high morbidity, brings great physical and mental damage to people worldwide. The increasing burden and strain on individuals and society make oral diseases an urgent global health problem. Since the treatment of almost all oral diseases relies on materials, the rapid development of advanced materials and technologies has also promoted innovations in the treatment methods and strategies of oral diseases. In this review, we systematically summarized the application strategies in advanced materials and technologies for oral diseases according to the etiology of the diseases and the comparison of new and old materials. Finally, the challenges and directions of future development for advanced materials and technologies in the treatment of oral diseases were refined. This review will guide the fundamental research and clinical translation of oral diseases for practitioners of oral medicine.

[Conversion of traditional Chinese medicine (TCM) into nanomedicine:application of theory of unification of medicines and excipients].

In recent years, the use of active substances as excipients or as substitutes for other excipients in the design of modern drug delivery systems has received widespread attention, which has promoted the development of the theory of unification of medicines and excipients in the design of traditional Chinese medicine(TCM) preparations. Adopting the theory of unification of medicines and excipients to design drug delivery systems can reduce the use of excipients and thus the cost of preparations, reduce drug toxicity, increase drug solubility and biocompatibility, enhance synergistic effect, and realize targeted delivery and simultaneous delivery of multiple components. However, the research on the application of this theory in the modern drug delivery system of TCM preparations is still insufficient, with few relevant articles. In addition, the TCM active substances that can be used as the excipients remain to be catalogued. In this paper, we review the types and applications of the drug delivery systems with TCM active substances as excipients and describe their common construction methods and mechanisms, aiming to provide references for the in-depth research on the modern drug delivery systems for TCM preparations.

A genomic-augmented multivariate prognostic model for the survival of natural-killer/T-cell lymphoma patients from an international cohort.

With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK), and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; p < .001) and overall survival (OS, HR: 5.23, 95% CI 2.57-10.65; p = .001) with known risk-features of these indices. When we assign an additional risk-score to samples, which are mutant for the GPM, the Harrell's C-indices of GPM-augmented IPI, PINK, and PINK-E improved significantly (p < .001, χ2 test) for both PFS and OS. Thus, we report on how genomic mutational information could steer toward better prognostication of NKTCL patients.

HLA class I genes modulate disease risk and age at onset together with DR-DQ in Chinese patients with insulin-requiring type 1 diabetes.

AIMS/HYPOTHESIS: The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes. METHODS: A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing. RESULTS: The susceptible DR3 (ß = -0.09, p = 0.0009) and DR4-DQ8 (ß = -0.13, p = 0.0059) haplotypes were negatively associated with onset age, while the protective DR11 (ß = 0.21, p = 0.0314) and DR12 (ß = 0.27, p < 0.0001) haplotypes were positively associated with onset age. After adjustment for linkage disequilibrium with DR-DQ haplotypes, A*11:01:01 was positively associated with onset age (ß = 0.06, p = 0.0370), while the susceptible C*15:02:01 was negatively associated with onset age (ß = -0.21, p = 0.0050). The unit for ß was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition, B*46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A*24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B*54:01:01 (OR 3.96, 3.79; pc = 0.0018, 0.0004) were predisposing in both the <18 group and the ≥18 group compared with healthy control participants. In the context of DR4-DQ4, A*11:01:01 (61.29% vs 28.26%, pc = 0.0144) was increased while the predisposing A*24:02:01 (19.35% vs 47.83%, pc = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset <18 years. CONCLUSIONS/INTERPRETATION: In addition to DR-DQ haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies.

Correction: The bZIP Transcription Factor MoAP1 Mediates the Oxidative Stress Response and is Critical for Pathogenicity of the Rice Blast Fungus Magnaporthe oryzae.

[This corrects the article DOI: 10.1371/journal.ppat.1001302.].

Analysis of radiotherapy impact on survival in resected stage I/II pancreatic cancer patients: a population-based study.

BACKGROUND: The application of radiotherapy (RT) in pancreatic cancer remains controversial. AIM: The aim of the study was to evaluate the efficacy of radiotherapy (neoadjuvant and adjuvant radiotherapy) for resectable I/II pancreatic cancer. METHODS: Fourteen thousand nine hundred seventy-seven patients with pancreatic cancer were identified from SEER database from 2004 to 2015. Multivariate analyses were performed to determine factors including RT on overall survival. Overall survival and overall mortality among the different groups were evaluated using the Kaplan-Meier method and Gray's test. RESULTS: Patients were divided into groups according to whether they received radiotherapy or not. The median survival time of all 14,977 patients without RT was 20 months, neoadjuvant RT was 24 months and adjuvant RT was 23 months (p < 0.0001). Median survival time of 2089 stage I patients without RT was 56 months, significantly longer than those with RT regardless of neoadjuvant or adjuvant RT (no RT: 56 months vs adjuvant RT: 37 months vs neoadjuvant RT: 27 months, P = 0.0039). Median survival time of 12,888 stage II patients with neoadjuvant RT was 24 months, adjuvant RT 22 months, significantly prolonged than those without radiotherapy (neoadjuvant RT: 24 months vs adjuvant RT: 22 months vs no RT: 17 months, P<0.0001). Neoadjuvant RT (HR = 1.434, P = 0.023, 95% CI: 1.051-1.957) was independent risk factors for prognosis of stage I patients, and adjuvant RT (HR = 0.904, P < 0.001, 95% CI: 0.861-0.950) predicted better outcomes for prognosis of stage II patients by multivariate analysis. The risk of cancer-related death caused by neoadjuvant RT in stage I and no-RT in stage II patients were significantly higher. CONCLUSIONS: The study identified a significant survival advantage for the use of adjuvant RT over surgery alone or neoadjuvant RT in treating stage II pancreatic cancer. RT was not associated with survival benifit in stage I patients.

Long-Term Effect of Microwave Ablation on Patients Undergoing Hemodialysis for Moderate Secondary Hyperparathyroidism: A Retrospective Cohort Study.

OBJECTIVES: A previous 12-month study confirmed that microwave ablation (MWA) was effective for moderate secondary hyperparathyroidism (SHPT). A further analysis was performed in this study to evaluate the efficacy of MWA for moderate SHPT over an observational follow-up period of up to 60 months. METHODS: This was a retrospective cohort study of patients involved in a previous randomized controlled trial. Patients were divided into an MWA group (those who underwent MWA followed by drug therapy according to the patient's clinical situation) and a control group (those who received drug therapy only). The primary outcome was the composite endpoint. During the efficacy assessment phase, the two groups were compared in terms of the proportion of patients with intact parathyroid hormone (iPTH) levels <300 pg/ml and the differences in iPTH levels. RESULTS: Twenty-seven patients were included in this study: 13 in the MWA group and 14 in the control group. The median (interquartile range) follow-up periods of the MWA and control groups were 58 (54-60) and 58 (49-60) months, respectively. The proportion of patients with iPTH levels <300 pg/ml in the MWA group was slightly higher than that in the control group (6/13 [46.2%] versus 2/14 [14.3%], respectively; p = .08). Furthermore, iPTH levels in the MWA group were lower than in the control group during the efficacy assessment phase (411 ± 299 pg/ml versus 516 ± 369 pg/ml, respectively; p <.01). CONCLUSIONS: MWA helped to contain the necessary iPTH levels in patients undergoing hemodialysis for moderate SHPT in a 60-month timeframe.

In situ and rapid determination of acetamiprid residue on cabbage leaf using surface-enhanced Raman scattering.

BACKGROUND: Pesticide residues in agricultural products and foods pose a serious threat to human health, and therefore a simple, rapid and direct method is urgently needed for pesticide residue detection. In addition to realizing the detection of acetamiprid in cabbage extract solution, the main target of this study was to establish an in situ surface-enhanced Raman scattering (SERS) method, which could directly detect acetamiprid residue on cabbage leaf without the need for extraction. Acetamiprid was first used to contaminate the surface of fresh cabbage leaf, and then bimetallic silver-coated gold nanoparticles (Au@AgNPs) were added on the contaminated spots and dried for SERS measurement. RESULTS: Results suggested that acetamiprid can be detected in cabbage extract and on cabbage leaf surface in situ using the SERS method based on the Au@AgNPs substrate. The limit of detection was 0.08 µg mL-1 in cabbage extract and 0.14 mg kg-1 on cabbage leaf, the recovery ranged from 80.5% to 105.5% and the relative standard deviation was in the range 4.37-10.63%. CONCLUSIONS: The proposed SERS method provides an in situ, nondestructive and rapid way to detect acetamiprid residue on the surface of fruits and vegetables, which could serve as an auxiliary approach for early screening of contaminated produce in field or on site in the future. © 2020 Society of Chemical Industry.

Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations.

BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL. METHODS: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL. FINDINGS: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10-16; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10-26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants. INTERPRETATION: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention. FUNDING: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.

Intracellular Restructured Reduced Glutathione-Responsive Peptide Nanofibers for Synergetic Tumor Chemotherapy.

Self-assembled peptide nanofibers have been widely studied in cancer nanotherapeutics with their excellent biocompatibility and low toxicity of degradation products, showing the significant potential in inhibiting tumor progression. However, poor solubility prevents direct intravenous administration of nanofibers. Although water-soluble peptide precursors have been formed via the method of phosphorylation for intravenous administration, their opportunities for broad in vivo application are limited by the weak capacity of encapsulating drugs. Herein, we designed a novel restructured reduced glutathione (GSH)-responsive drug delivery system encapsulating doxorubicin for systemic administration, which achieved the intracellular restructuration from three-dimensional micelles into one-dimensional nanofibers. After a long blood circulation, micelles endocytosed by tumor cells could degrade in response to high GSH levels, achieving more release and accumulation of doxorubicin at desired sites. Further, the synergistic chemotherapy effects of self-assembled nanofibers were confirmed in both in vitro and in vivo experiments.

Bone marrow mesenchymal stem cell-derived exosomes alleviate high phosphorus-induced vascular smooth muscle cells calcification by modifying microRNA profiles.

Vascular calcification is a common complication in patients with chronic kidney disease (CKD). It is an important predictor of cardiovascular disease and all-cause mortality. Previous studies have confirmed that bone marrow mesenchymal stem cell (BMSC) therapy can reduce vascular calcification, but the specific mechanism is still controversial. In this study, we aimed to investigate the mechanisms of BMSC-derived exosomes (EXO) in improving vascular calcification. BMSCs were cultured and EXO were isolated using the Total Exosome Isolation Reagent. Human aortic vascular smooth muscle cells (HA-VSMCs) were cultured into three groups: control group, high phosphorus group, and high phosphorus plus EXO group. Then, indicators related to smooth muscle cell calcification and microRNA profiles were analyzed. BMSC-derived exosomes inhibited high phosphorus-induced calcification in HA-VSMCs. Besides, EXO treatment reduced calcium content and decreased the alkaline phosphatase (AKP) activity in high phosphorus co-incubated HA-VSMCs. MicroRNA (miRNA) and mRNA expression profiles analyses revealed that 63 miRNAs were significantly upregulated and 1424 genes were significantly downregulated in HA-VSMCs after EXO treatment. Functional miRNA-gene regulatory network revealed that mTOR, MAPK, and Wnt signaling pathway were involved in vascular calcification. BMSC-derived exosomes alleviated high phosphorus-induced calcification in HA-VSMC through modifying miRNA profiles.

Co-Delivery of Metformin Enhances the Antimultidrug Resistant Tumor Effect of Doxorubicin by Improving Hypoxic Tumor Microenvironment.

Doxorubicin (DOX) is a first-line chemo drug for cancer therapy, yet it fails to treat multi-drug-resistant tumors. Hypoxia is a major causative factor leading to chemotherapy failure. Particularly, hypoxia up-regulates its responsive transcription factor-hypoxia-inducible factors (HIF)-to induce the overexpression of drug resistant genes. Metformin (MET) is recently found to cooperate with DOX against multiple tumors. As a mitochondrial inhibitor, MET could suppress tumor oxygen consumption, and thereby modulate the hypoxic tumor microenvironment. In this study, we used cationic liposomes to codeliver both DOX and MET for treating multi-drug-resistant breast cancer cells-MCF7/ADR. Faster release of MET enhanced the cytotoxicity of DOX through attenuating hypoxic stress both in vivo and in vitro. MET diminished the cellular oxygen consumption and inhibited HIF1α and P-glycoprotein (Pgp) expression in vitro. In addition, the dual-drug-loaded liposomes increased tumor targeting and intratumoral blood oxygen saturation, which suggested that the tumor reoxygenation effect of MET facilitated the exertion of its synergistic activity with DOX against MCF7/ADR xenografts. In general, our study represents a feasible strategy to boost the therapeutic effect in treating multi-drug-resistant cancer by improving the hypoxic tumor microenvironment.

Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis.

BACKGROUND: Ceramide plays pathogenic roles in nonalcoholic fatty liver disease (NAFLD) via multiple mechanisms, and as such inhibition of ceramide de novo synthesis in the liver may be of therapeutically beneficial in patients with NAFLD. In this study, we aimed to explore whether inhibition of ceramide signaling by myriocin is beneficial in animal model of NAFLD via regulating autophagy. METHODS: Sprague Dawley rats were randomly divided into three groups: standard chow (n = 10), high-fat diet (HFD) (n = 10) or HFD combined with oral administration of myriocin (0.3 mg/kg on alternate days for 8 weeks) (n = 10). Liver histology and autophagy function were measured. HepG2 cells were incubated with fatty acid with or without myriocin treatment. Lipid accumulation and autophagy markers in the HepG2 cells were analyzed. Serum ceramide changes were studied in 104 subjects consisting healthy adults, liver biopsy-proven patients with NAFLD and liver biopsy-proven patients with chronic hepatitis B (CHB). RESULTS: Myriocin reversed the elevated body weight and serum transaminases and alleviated dyslipidemia in HFD fed rats. Myriocin treatment significantly attenuated liver pathology including steatosis, lobular inflammation and ballooning. By qPCR analysis, it was revealed that myriocin corrected the expression pattern of fatty acid metabolism associated genes including Fabp1, Pparα, Cpt-1α and Acox-2. Further, myriocin also restored the impaired hepatic autophagy function in rats with HFD-induced NASH, and this has been verified in HepG2 cells. Among the sphingolipid species that we screened in lipidomic profiles, significantly increased ceramide was observed in NASH patients as compared to the controls and non-NASH patients, regardless of whether or not they have active CHB. CONCLUSIONS: Ceramide may play an important regulatory role in the autophagy function in the pathogenesis of NASH. Hence, blockade of ceramide signaling by myriocin may be of therapeutically beneficial in NASH. TRIAL REGISTRATION: Registration ID: ChiCTR-DDT-13003983 . Data of registration: 13 May, 2013, retrospectively registered.