A Multifunctional Liposome for Synergistic Chemotherapy with Ferroptosis Activation of Triple-Negative Breast Cancer.

There is an urgent need to develop efficient treatments for highly invasive triple-negative breast cancer (TNBC) with a high rate of postoperative. Baicalin (BA) has shown inhibitory effects on several tumor cells and could activate ferroptosis in some tumor cells by producing reactive oxygen species (ROS). For overcoming the shortcomings of BA in clinical applications and enhancing the effect of ferroptosis in TNBC, herein, a multifunctional liposome (BA-Fe(III) coordination-polymer-loaded liposome, BA-Fe(III) Lipo) was developed for synergistic chemotherapy of TNBC with ferroptosis activation. Fe(III) released from BA-Fe(III) Lipo could be efficiently reduced to Fe(II) in the presence of high glutathione in tumor microenvironment, which in turn catalyzed the oxidation of unsaturated fats through lipid peroxidation for more ROS production. In addition, BA-Fe(III) Lipo activated tumor cell ferroptosis by down-regulating the enzymatic activity of ferritin heavy chain 1 protein and glutathione peroxidase. This study provided a novel therapeutic strategy for the treatment of TNBC by ingeniously combining chemotherapy with the activation of ferroptosis, which presented potential clinical applications.

Application of exosomes as nanocarriers in cancer therapy.

Cancer remains the most common lethal disease in the world. Although the treatment choices for cancer are still limited, significant progress has been made over the past few years. By improving targeted drug therapy, drug delivery systems promoted the therapeutic effects of anti-cancer medications. Exosome is a kind of natural nanoscale delivery system with natural substance transport properties, good biocompatibility, and high tumor targeting, which shows great potential in drug carriers, thereby providing novel strategies for cancer therapy. In this review, we present the formation, distribution, and characteristics of exosomes. Besides, extraction and isolation techniques are discussed. We focus on the recent progress and application of exosomes in cancer therapy in four aspects: exosome-mediated gene therapy, chemotherapy, photothermal therapy, and combination therapy. The current challenges and future developments of exosome-mediated cancer therapy are also discussed. Finally, the latest advances in the application of exosomes as drug delivery carriers in cancer therapy are summarized, which provide practical value and guidance for the development of cancer therapy.

Pan-cancer analysis identified OAS1 as a potential prognostic biomarker for multiple tumor types.

Background: 2',5'-oligoadenylate synthetase 1 (OAS1), has been reported as a tumor driver gene in breast carcinoma and pancreatic carcinoma. However, the role of OAS1 in most tumors has not been reported. Methods: The original data of 35 tumor types were down load from the TCGA (The Cancer Genome Atlas) database and Human Protein Atlas (HPA) database. TIMER2, Kmplot, UALCAN, and TISIDB tools were used to investigate the expression and function of OAS1, and the role of OAS1 in prognosis, diagnostic value, and immune characteristics of pan-cancer. LUAD and PRAD cell lines, A549, H1975, PC-3 and C4-2 were utilized to perform cell function tests. Results: OAS1 expression was up-regulated in 12 tumor types and down-regulated in 2 tumor types. High OAS1 expression was correlated with poor prognosis in 6 tumor types, while high OAS1 expression was correlated with good prognosis in 2 tumor types. OAS1 was correlated with molecular subtypes in 8 tumor types and immune subtypes in 12 tumor types. OAS1 was positively associated with the expression of numerous immune checkpoint genes and tumor mutational burden (TMB). OAS1 had potential diagnostic value in 15 tumor types. Silence of OAS1 significantly inhibited the cell proliferation ability, and promoted G2/M cell cycle arrest of LUAD and PRAD cells. Meanwhile, silence of OAS1 enhanced cisplatin-induced apoptosis of LUAD and PRAD cells, but weakened cell migration. Conclusion: This pan-cancer study suggests that OAS1can be used as a molecular biomarker for prognosis in pan-cancer and may play an important role in tumor immune response.

Zn-Alloying Sites with Self-Adsorbed Molecular Crowding Layer as a Stable Interfacial Structure of Zn Electrodes.

Rechargeable aqueous zinc (Zn) metal batteries (ZMBs) have gained tremendous attention because of their intrinsic safety and low cost. However, the lifespan of ZMBs is seriously limited by severe Zn dendritic growth in aqueous electrolytes. Despite the feasibility of Zn deposition regulation by introducing Zn-alloying sites at the Zn plating surface, the activity of the Zn-alloying sites can be seriously reduced by side reactions in the aqueous environment. Here, we propose a facile but efficacious strategy to reinforce the activity of the Zn-alloying sites by introducing a low quantity of polar organic additive in the electrolyte that can be self-adsorbed on the Zn-alloying sites to form a molecular crowding layer against the parasitic water reduction during Zn deposition. As a consequence, stable cycling of the Zn anode can be maintained at such a multifunctional interfacial structure, arising from the synergism between the seeded low-overpotential Zn deposition on the stabilized Zn-alloying sites and a Zn2+ redistributing feature of the self-adsorbed molecular crowding layer. The interfacial design principle here can be widely employed due to the great variety of Zn-alloy and polar organic materials and potentially be applied to improve the performance of other aqueous metal batteries.

Carbon monoxide therapy: a promising strategy for cancer.

Cancer is one of the acute life-threatening diseases endangering the whole of humanity. The treatment modalities for cancer are various. However, in most cases, a single treatment choice provides multiple side effects, poor targeting, and ineffective treatment. In recent years, the physiological regulatory function of carbon monoxide (CO) in the cancer process has been reported gradually, and CO-related nano-drugs have been explored. It shows better application prospects in cancer treatment and provides new ideas for treatment. The present review introduces the pathophysiological role of CO. The recent advances in cancer therapy, such as CO-mediated gas therapy, combined application of CO chemotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), and immunotherapy, are described. Current challenges and future developments in CO-based treatment are also discussed. This review provides comprehensive information on recent advances in CO therapy and also some valuable guidance for promoting the progress of gas therapy nanomedicine.

Comparison of outcomes of monochorionic twin pregnancies conceived by assisted reproductive technology vs. spontaneous conceptions: A systematic review and meta-analysis.

Background: This review aimed to assess if monochorionic twin pregnancies conceived by assisted conception have worse maternal and neonatal outcomes as compared to those conceived naturally. Methods: Datasets of PubMed, ScienceDirect, CENTRAL, Embase, and Google Scholar were searched for studies comparing maternal and neonatal outcomes of monochorionic twin pregnancies conceived by assisted vs. spontaneous methods. Results: Eight studies comparing 337 assisted with 2,711 spontaneously conceived monochorionic twin pregnancies were included. Meta-analysis revealed that the mode of conception of monochorionic twin pregnancies had no impact on the risk of hypertensive disorders of pregnancy (HDP) (OR: 1.36 95% CI, 0.73, 2.54 I 2 = 9% p = 0.03), twin-twin transfusion syndrome (TTTS) (OR: 0.83 95% CI, 0.52, 1.31 I 2 = 0% p = 0.42), and very preterm delivery (OR: 1.18 95% CI, 0.74, 1.88 I 2 = 41% p = 0.49). We noted no statistically significant difference in the mean birth weights (MD: -17.66 95% CI, -157.23, 121.91 I 2 = 82% p = 0.80), risk of intra-uterine death (OR: 0.90 95% CI, 0.51, 1.60 I 2 = 36% p = 0.73) and small for gestational age between the two groups (OR: 0.92 95% CI, 0.67, 1.26 I 2 = 0% p = 0.59). There was an increased risk of caesarean sections (OR: 1.34 95% CI, 1.00, 1.80 I 2 = 0% p = 0.05) and neonatal death with assisted conceptions as compared to spontaneous conceptions (OR: 2.35 95% CI, 1.11, 5.01 I 2 = 37% p = 0.03). Conclusion: Monochorionic twin pregnancies conceived via assisted reproductive technology have a heightened risk of cesarean section and neonatal deaths. However, there is a need for further studies to supplement current evidence.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=325133, identifier: CRD42022325133.

GRAP2 is a prognostic biomarker and correlated with immune infiltration in lung adenocarcinoma.

BACKGROUND: GRAP2 is an adaptor protein involved in leukocyte signal activation; however, the prognostic value of GRAP2 and its correlation with immune infiltration in lung adenocarcinoma (LUAD) are unclear. METHODS: Original data were downloaded from the TCGA database and Gene Expression Omnibus (GEO) database. GRAP2 expression was analyzed with the TCGA and TIMER databases. We evaluated the influence of GRAP2 on clinical prognosis using the Kaplan-Meier plotter, GEO, and GEPIA database. The TIMER and TISIDB databases were used to investigate correlations between GRAP2 expression and cancer immune characteristics. Finally, we confirmed the expression of GRAP2 in LUAD by immunohistochemistry staining. RESULTS: The transcription levels of GRAP2 were significantly lower in several human cancer types, including LUAD, than in adjacent normal tissues. Immunohistochemistry staining confirmed that LUAD tumor tissues had lower GRAP2 protein expression levels than adjacent normal tissues. GRAP2 downregulation was associated with poorer overall survival, pathologic stage, T stage, N stage, and primary therapy outcome in LUAD. Mechanistically, we found a hub gene set that included a total of 91 genes coexpressed with GRAP2, which were closely related to the immune response in LUAD. The expression levels of GRAP2 were positively correlated with the infiltration levels of multiple immune cells and the cumulative survival time of a few immune cells. GRAP2 expression was found to be positively correlated with that of multiple immune markers, chemokines, chemokine receptors, and MHC molecules in LUAD. CONCLUSIONS: GRAP2 can be used as a biomarker for assessing prognosis and immune infiltration levels in LUAD.

Clinical Characteristics and Mortality of Non-tuberculous Mycobacterial Infection in Immunocompromised vs. Immunocompetent Hosts.

Immunosuppression and host vulnerability play a key role in non-tuberculous mycobacteria (NTM) pathogenesis. The objective of this study was to compare the clinical characteristics and mortality of NTM infections in immunocompromised and immunocompetent patients. We used a retrospective dataset obtained from our large, tertiary, urban, teaching hospital which is the medical records of hospitalized patients with NTM infections between January 1, 2013 to December 31, 2020. The information including clinical manifestations, imaging, and NTM etiological data were obtained from the hospital's clinical data system. A total of 480 patients with NTM infections completed species identification. 118 hospitalized NTM patients who met ATS/IDSA NTM diagnostic criteria and had complete medical records were included in the study. The average age was 49.4 years, 57 (48.3%) were female, and 64 (54.2%) were immunosuppressed hosts. In our study, the most common species in order of frequency were: M. intracellulare, M. abscessus, M. avium, and M. kansasii among NTM patients. The most common comorbidity was history of previous tuberculosis (30.5%). Besides malignancy, the most common immunodeficiencies were adult-onset immunodeficiency induced by anti-interferon-gamma autoantibody, SLE, and vasculitis. The immunocompromised patients with NTM had more clinical symptoms, comorbidities and lower lymphocyte counts compared to immunocompetent patients. The mortality we observed in immunocompromised patients of NTM disease was significantly higher than that of immunocompetent patients (HR 3.537, 95% CI 1.526-8.362). Immunosuppressed NTM patients with lower B and CD4+ T lymphocyte counts may more frequently present with disseminated NTM infections, clinical exacerbations, and higher mortality than immunocompetent patients.

Wogonin reduces cardiomyocyte apoptosis from mitochondrial release of cytochrome c to improve doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) has powerful anticancer properties, but its clinical application is affected by its serious cardiotoxicity. Wogonin (WG) has been shown to have marked cardiovascular protection potential. However, it is not known whether this potential can protect the heart from DOX damage. The aim of the present study was to investigate whether WG could ameliorate the cardiotoxicity of DOX. DOX and WG were used to establish a model of cardiac damage. Echocardiography, brain natriuretic peptide, creatine kinase MB and cardiac troponin T were used to detect the degree of cardiac damage. The levels of superoxide dismutase, malondialdehyde, glutathione and catalase in serum were measured to observed oxidative stress state. The mRNA levels of cyclophilin D, voltage-dependent anion-selective channel 1 and adenine nucleotide transporter 1 were detected by reverse transcription-quantitative PCR. Western blotting was used to detect the expression of cytochrome c in mitochondria and cytoplasm and cleaved-caspase-9 and pro/cleaved-caspase-3 in cytoplasm in cardiac tissue and primary cardiomyocytes to verify the related signaling pathways. DOX rats showed a series of cardiac damage. However, these damages were alleviated following WG treatment. Further studies showed that WG antagonized DOX cardiotoxicity through inhibiting the release of cytochrome c. WG protected rat heart from DOX damage. The mechanism may be closely related to inhibiting the release of cytochrome c from mitochondria and reducing cardiomyocyte apoptosis caused by caspase activation.

Development of an intensive simulating training program in emergency medicine for medical students in China.

BACKGROUND: A national standardized emergency medicine (EM) curriculum for medical students, including specific competencies in procedural skills, are absent in many countries. The development of an intensive simulating training program in EM, based on a tight schedule, is anticipated to enhance the competency of medical students. METHODS: A 3-day intensive EM training program, consisting of four procedural skills and 8-hour case-based learning (CBL), was developed by experienced physicians from the EM department in Peking Union Medical College Hospital (PUMCH). Medical students from Peking Union Medical College (PUMC) and Tsinghua University (THU) participated in the training. Three written tests were cautiously designed to examine the short-term (immediately after the program) and long-term (6 months after the program) efficacy of the training. After completion of the training program, an online personal appraisal questionnaire was distributed to the students on WeChat (a mobile messaging App commonly used in China) to achieve anonymous self-evaluation. RESULTS: Ninety-seven out of 101 students completed the intensive training and took all required tests. There was a significant increase in the average score after the intensive simulating training program (pre-training 13.84 vs. 15.57 post-training, P<0.001). Compared with the pre-training test, 63 (64.9%) students made progress. There was no significant difference in scores between the tests taken immediately after the program and 6 months later (15.57±2.22 vs. 15.38±2.37, P=0.157). Students rated a higher score in all diseases and procedural skills, and felt that their learning was fruitful. CONCLUSIONS: The introduction of a standardized intensive training program in EM focusing on key competencies can improve clinical confidence, knowledge, and skills of medical students toward the specialty. In addition, having such a program can also enhance student's interest in EM as a career choice which may enhance recruitment into the specialty and workplace planning.

Safety and immunogenicity of an inactivated COVID-19 vaccine, BBIBP-CorV, in people younger than 18 years: a randomised, double-blind, controlled, phase 1/2 trial.

BACKGROUND: Although SARS-CoV-2 infection often causes milder symptoms in children and adolescents, young people might still play a key part in SARS-CoV-2 transmission. An efficacious vaccine for children and adolescents could therefore assist pandemic control. For further evaluation of the inactivated COVID-19 vaccine candidate BBIBP-CorV, we assessed the safety and immunogenicity of BBIBP-CorV in participants aged 3-17 years. METHODS: A randomised, double-blind, controlled, phase 1/2 trial was done at Shangqiu City Liangyuan District Center for Disease Control and Prevention in Henan, China. In phases 1 and 2, healthy participants were stratified according to age (3-5 years, 6-12 years, or 13-17 years) and dose group. Individuals with a history of SARS-CoV-2 or SARS-CoV infection were excluded. All participants were randomly assigned, using stratified block randomisation (block size eight), to receive three doses of 2 µg, 4 µg, or 8 µg of vaccine or control (1:1:1:1) 28 days apart. The primary outcome, safety, was analysed in the safety set, which consisted of participants who had received at least one vaccination after being randomly assigned, and had any safety evaluation information. The secondary outcomes were geometric meant titre (GMT) of the neutralising antibody against infectious SARS-CoV-2 and were analysed based on the full analysis set. This study is registered with www.chictr.org.cn, ChiCTR2000032459, and is ongoing. FINDINGS: Between Aug 14, 2020, and Sept 24, 2020, 445 participants were screened, and 288 eligible participants were randomly assigned to vaccine (n=216, 24 for each dose level [2/4/8 µg] in each of three age cohorts [3-5, 6-12, and 13-17 years]) or control (n=72, 24 for each age cohort [3-5, 6-12, and 13-17 years]) in phase 1. In phase 2, 810 participants were screened and 720 eligible participants were randomly assigned and allocated to vaccine (n=540, 60 for each dose level [2/4/8 µg] in each of three age cohorts [3-5, 6-12, and 13-17 years]) or control (n=180, 60 for each age cohort [3-5, 6-12, and 13-17 years]). The most common injection site adverse reaction was pain (ten [4%] 251 participants in all vaccination groups of the 3-5 years cohort; 23 [9·1%] of 252 participants in all vaccination groups and one [1·2%] of 84 in the control group of the 6-12 years cohort; 20 [7·9%] of 252 participants in all vaccination groups of the 13-17 years cohort). The most common systematic adverse reaction was fever (32 [12·7%] of 251 participants in all vaccination groups and six [7·1%] of 84 participants in the control group of the 3-5 years cohort; 13 [5·2%] of 252 participants in the vaccination groups and one [1·2%] of 84 in the control group of the 6-12 years cohort; 26 [10·3%] of 252 participants in all vaccination groups and eight [9·5%] of 84 in the control group of the 13-17 years cohort). Adverse reactions were mostly mild to moderate in severity. The neutralising antibody GMT against the SARS-CoV-2 virus ranged from 105·3 to 180·2 in the 3-5 years cohort, 84·1 to 168·6 in the 6-12 years cohort, and 88·0 to 155·7 in the 13-17 years cohort on day 28 after the second vaccination; and ranged from 143·5 to 224·4 in the 3-5 years cohort, 127 to 184·8 in the 6-12 years cohort, and 150·7 to 199 in the 13-17 years cohort on day 28 after the third vaccination. INTERPRETATION: The inactivated COVID-19 vaccine BBIBP-CorV is safe and well tolerated at all tested dose levels in participants aged 3-17 years. BBIBP-CorV also elicited robust humoral responses against SARS-CoV-2 infection after two doses. Our findings support the use of a 4 µg dose and two-shot regimen BBIBP-CorV in phase 3 trials in the population younger than 18 years to further ascertain its safety and protection efficacy against COVID-19. FUNDING: National Program on Key Research Project of China, National Mega projects of China for Major Infectious Diseases, National Mega Projects of China for New Drug Creation, and Beijing Science and Technology Plan. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Blood eosinophil count-guided corticosteroid therapy and as a prognostic biomarker of exacerbations of chronic obstructive pulmonary disease: a systematic review and meta-analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and dyspnea, as well as an increase in the number of leukocytes in the airways, lungs, and pulmonary vessels. A 'One size fits all' approach to COPD patients with different clinical features may be considered outdated. The following are the two major objectives of this meta-analysis: the first is to determine if blood eosinophil counts (BEC) can serve as a prognostic biomarker of COPD outcomes, and the second is to determine which level of BEC is effective for inhaled corticosteroid (ICS) treatment. METHODS: We searched articles published before 15 May 2021 in the following four electronic databases: Web of Science, Cochrane Library, EMBASE, and PubMed. RESULTS: A total of 42 studies, comprising a sampling of 188,710 subjects, were summarized and compared in this meta-analysis. The rate ratio (RR) of exacerbations of COPD (ECOPD) between ICS and non-ICS treatment was statistically significant for the COPD patients with a baseline BEC ⩾ 2% or ⩾ 200 cells/µl, RR = 0.82 (0.73, 0.93) or 0.79 (0.70, 0.89) respectively, while the RR of ECOPD between ICS and non-ICS treatment was statistically insignificant for the COPD patients with baseline BEC < 2% or <200 cells/µl, RR = 0.97 (0.87, 1.08) or 0.97 (0.86, 1.08), suggested that ICS therapy was beneficial to the improvement of ECOPD in patients with a baseline BEC ⩾ 2% or BEC ⩾ 200 cells/µl. CONCLUSION: Our research shows that a BEC ⩾ 200 cells/µl or ⩾2% is likely to become the cutoff value of ICS treatment for ECOPD. Moreover, we believe that the baseline BEC can be used as a biomarker for predicting ECOPD. The stability of BEC requires special attention.

The Impact of N2-Assisted High-Pressure Processing on the Microorganisms and Quality Indices of Fresh-Cut Bell Peppers.

This work aimed to evaluate the effects of N2-assisted high-pressure processing (HPP, 400 MPa/7.5 min and 500 MPa/7.5 min) on the microorganisms and physicochemical, nutritional, and sensory characteristics of fresh-cut bell peppers (FCBP) during 25 days of storage at 4 °C. Yeasts and molds were not detected, and the counts of total aerobic bacteria were less than 4 log10 CFU/g during storage at 4 °C. The total soluble solids and L* values were maintained in HPP-treated FCBP during storage. After the HPP treatment, an 18.7-21.9% weight loss ratio and 54%-60% loss of hardness were found, and the polyphenol oxidase (PPO) activity was significantly inactivated (33.87-55.91% of its original activity). During storage, the weight loss ratio and PPO activity of the samples increased significantly, but the hardness of 500 MPa/7.5 min for treated FCBP showed no significant change (9.79-11.54 N). HPP also effectively improved the total phenol content and antioxidant capacity of FCBP to 106.69-108.79 mg GAE/100 g and 5.76-6.55 mmol Trolox/L; however, a non-negligible reduction in total phenols, ascorbic acid, and antioxidant capacity was found during storage. Overall, HPP treatments did not negatively impact the acceptability of all sensory attributes during storage, especially after the 500 MPa/7.5 min treatment. Therefore, N2-assisted HPP processing is a good choice for the preservation of FCBP.

Emodin enhances cisplatin sensitivity in non-small cell lung cancer through Pgp downregulation.

Cisplatin resistance is one of the main causes of chemotherapy failure and tumor progression in non-small cell lung cancer (NSCLC). Emodin has been demonstrated to induce NSCLC cell apoptosis and act as a potential cancer therapeutic agent. However, whether emodin could affect NSCLC cell sensitivity toward cisplatin remains unclear. The present study aimed to determine the effect of emodin and cisplatin combination on the chemosensitivity of NSCLC cells. A549 and H460 cells were treated with different concentrations of cisplatin and/or emodin. Cell Counting Kit-8, fluorescence microscopy, immunofluorescence assays and flow cytometry were used to determine cell proliferation, drug efflux, DNA damage level and cell apoptosis, respectively. P-glycoprotein (Pgp) and multidrug resistance-associated protein 1 (MRP1) expression was detected by western blotting. The results demonstrated that emodin and cisplatin inhibited the proliferation of A549 and H460 cells. Furthermore, emodin inhibited the drug efflux in A549 and H460 cells in a dose-dependent manner. In addition, emodin enhanced cisplatin-induced apoptosis and DNA damage in A549 and H460 cells. Emodin also decreased Pgp expression in A549 and H460 cells in a dose-dependent manner; however, it had no effect on MRP1 expression. Taken together, the results from the present study demonstrated that emodin can increase A549 and H460 cell sensitivity to cisplatin by inhibiting Pgp expression. Emodin may therefore be considered as an effective adjuvant for cisplatin treatment.

Curcumin potentiates laryngeal squamous carcinoma radiosensitivity via NF-ΚB inhibition by suppressing IKKγ expression.

Context: Curcumin has shown efficacy in promoting radiosensitivity combined with radiotherapy. However, the role and mechanism of curcumin on radiosensitivity in laryngeal squamous cell cancer (LSCC) is largely unknown.Objective: The aim of our study is to explore the role of IKKγ-NF-κB signaling in curcumin enhancing LSCC cell radiosensitivity in vitro.Materials and methods: Curcumin and X-ray were used to induce cell DNA damage and apoptosis, or inhibit cell clone formation. IKKγ siRNA and plasmid were used to change IKKγ expression. The CCK8 assay was used to detect cell viability. Clone formation ability was analyzed using a clonogenic assay, cell apoptosis was examined using flow cytometry, an immunofluorescence assay was used to detect DNA damage, while mRNA and protein levels were assayed using real time PCR and western blotting, respectively.Results: Curcumin significantly enhanced irradiation-induced DNA damage and apoptosis, while weakening clone-forming abilities of LSCC cell line Hep2 and Hep2-max. Compared to Hep2 cells, Hep2-max cells are more sensitive to curcumin post-irradiation. Curcumin suppressed irradiation-induced NF-κB activation by suppressing IKKγ expression, but not IKKα and IKKß. Overexpression of IKKγ decreased irradiation-induced DNA damage and apoptosis, while promoting clone-forming abilities of Hep2 and Hep2-max cells. IKKγ overexpression further increased expression of NF-κB downstream genes, Bcl-XL, Bcl-2, and cyclin D1. Conversely, IKKγ silencing enhanced irradiation-induced DNA damage and apoptosis, but promoted clone formation in Hep2 and Hep2-max cells. Additionally, IKKγ silencing inhibited expression of Bcl-XL, Bcl-2, and cyclin D1.Conclusions: Curcumin enhances LSCC radiosensitivity via NF-ΚB inhibition by suppressing IKKγ expression.

Enhanced Transport of Shape and Rigidity-Tuned α-Lactalbumin Nanotubes across Intestinal Mucus and Cellular Barriers.

Mucus is a viscoelastic biological hydrogel that protects the epithelial surface from penetration by most nanoparticles, which limits the efficiency of oral drug delivery. Pursuing highly efficient, biocompatible, and biodegradable oral drug vehicles is of central importance to the development of promising nanomedicine. Here, we prepared five peptosomes (PSs) with various sizes, shapes, and rigidities based on self-assembly of amphiphilic α-lactalbumin (α-lac) peptides from partial enzymolysis and cross-linking. The mucus permeation of α-lac PSs and release of curcumin (Cur) encapsulated in these PSs were evaluated. Compared with a long nanotube, big nanosphere, small nanosphere, and cross-linked short nanotube, we demonstrated that a short nanotube (SNT) exhibits excellent permeability in mucus, which enables it to arrive at epithelial cells quickly. Besides, SNT exhibits the highest cellular uptake and transmembrane permeability on Caco-2/HT29-MTX (E12) 3D coculture model. In vivo pharmacokinetic evaluation revealed that SNT formulation shows the highest curcumin bioavailability, which is 6.85-folds higher than free Cur. Most importantly, Cur loaded in SNT exhibits the optimum therapeutic efficacy for in vivo treatment of dextran sulfate sodium (DSS)-induced ulcerative colitis. In the end, the mechanism of the high permeability of SNTs through mucus was explained by coarse-grained molecular dynamics simulations, which indicated that short time scale jiggling and flying across pores of mucus network played key roles. These findings revealed the tubular α-lac PSs could be a promising oral drug delivery system targeted to mucosal for improving absorption and bioavailability of hydrophobic bioactive ingredients.

The delivery of sensitive food bioactive ingredients: Absorption mechanisms, influencing factors, encapsulation techniques and evaluation models.

Food-sourced bioactive compounds have drawn much attention due to their health benefits such as anti-oxidant, anti-cancer, anti-diabetes and cardiovascular disease-preventing functions. However, the poor solubility, low stability and limited bioavailability of sensitive bioactive compounds greatly limited their application in food industry. Therefore, numbers of carriers were developed for improving their dispersibility, stability and bioavailability. This review addresses the digestion and absorption mechanisms of bioactive compounds in epithelial cells based on several well-known in vitro and in vivo models. Factors such as environmental stimuli, stomach conditions and mucus barrier influencing the utilization efficacy of the bioactive compounds are discussed. Delivery systems with enhanced utilization efficacy, such as complex coacervates, cross-linked polysaccharides, self-assembled micro-/nano-particles and Pickering emulsions are compared. It is a comprehensive multidisciplinary review which provides useful guidelines for application of bioactive compounds in food industry.

Identification of Integrin ß1 as a Novel PAG1-Interacting Protein Involved in the Inherent Radioresistance of Human Laryngeal Carcinoma.

Inherent radioresistance plays a crucial role in the failure of radiotherapy. Using the inherent radioresistant (Hep-2max) and radiosensitive (Hep-2min) cell lines established from the parental cell line Hep-2, we previously reported that phosphoprotein associated with glycosphingolipid-enriched microdomains 1(PAG1) overexpression in laryngeal carcinoma cells was correlated with inherent radioresistant phenotypes. However, the underlying mechanisms of this effect remain unknown. In the present study, we performed a proteomic screen to investigate the interactome of PAG1 in Hep-2max cells resulting in the identification of several interaction partners. Bioinformatic analysis and immunofluorescence experiments indicated the integrin ß1 to be a crucial interaction partner of PAG1. PAG1 was also highly expressed in laryngeal carcinoma radioresistant tissues and showed co-localization with integrin ß1. In addition, we demonstrated that integrin ß1's binding to PAG1 could be interrupted by MßCD, an inhibitor of lipid rafts formation. Moreover, knockdown of integrin ß1 by RNA interference sensitized radioresistant cells to irradiation. Importantly, we identified 2 potential interaction sites (Pro216-Arg232 and Asn356-Gly377) in the cytoplasmic domain of PAG1 using high throughput peptide arrays. Taken together, these results suggest that the binding of PAG1 to integrin ß1 in lipid rafts is essential for inherent radioresistance of human laryngeal carcinoma.

PAG1 promotes the inherent radioresistance of laryngeal cancer cells via activation of STAT3.

Phosphoprotein associated with glycosphingolipid-enriched microdomains 1(PAG1) is a ubiquitous protein that is essential for the development and progression of various malignancies. A previous study in our laboratory confirmed that PAG1 plays an important role in modulating the inherent radioresistance of laryngeal cancer cells, but the underlying mechanisms are still poorly defined. In this study, we found that PAG1 was significantly increased in laryngeal cancer tissues compared to adjacent non-tumor tissues (P < 0.05). The expression of PAG1 was positively correlated with lymph node metastasis (P < 0.05) and TNM stage (P < 0.05). High expression of PAG1 also predicted a poor prognosis in patients with laryngeal cancer. Moreover, gain-of-function and loss-of-function studies showed that PAG1 overexpression was able to promote growth, increase migration and invasion, and enhance inherent radioresistance of laryngeal cancer cells. Mechanistic investigations revealed that the activation of STAT3 was required for PAG1-mediated inherent radioresistance of laryngeal cancer. Inhibition of STAT3 activity with a chemical inhibitor sensitized radioresistant cells to radiation. Importantly, PAG1-integrin ß1 complex was involved in the regulation of STAT3 activation. In addition, downregulation of PAG1 could suppress tumor growth and reverse inherent radioresistance in the nude mouse xenograft model. Taken together, these results suggested that PAG1 conferred inherent radioresistance by activating STAT3, which provided a novel therapeutic strategy for laryngeal cancer.

Hirsutella sinensis Attenuates Aristolochic Acid-Induced Renal Tubular Epithelial-Mesenchymal Transition by Inhibiting TGF-ß1 and Snail Expression.

OBJECTIVE: To investigate the inhibitory effect of Hirsutella sinensis (HS) on epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells induced by aristolochic acid (AA) and its possible mechanism. METHODS: 18 male Sprague-Dawley rats were randomly and equally divided into the following 3 groups: AA group, AA+HS group and control group. Urinary protein excretion and creatinine clearance (CCr) were measured. All rats were sacrificed at the end of 12th week. The pathological examination of renal tissue was performed and the mRNA and protein expression of transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), cytokeratin-18 and Snail in renal cortex were determined by real time quantitative PCR and immunohistochemical staining respectively. In addition, human renal proximal tubule epithelial cells line (HKC) was divided into the following 4 groups: AA group, AA+HS group, HS control group and control group. The above mRNA and protein expression in HKC was determined by real time quantitative PCR and Western blot respectively. RESULTS: (1) CCr was significantly decreased, and the urinary protein excretion and relative area of renal interstitial fibrosis were significantly increased in the rats of AA and AA+HS group compared to those in control group (P<0.05 or P<0.01); all the above abnormalities significantly lightened in the rats of AA+HS group compared to those in AA group (P<0.05). (2) The mRNA and protein expression of TGF-ß1, α-SMA and Snail was significantly up-regulated and the expression of cytokeratin-18 was significantly down-regulated in the rat renal cortex as well as in the cultured HKC cells in AA and AA+HS groups compared to those in control group (P<0.05 or P<0.01); all the above abnormalities significantly alleviated in AA+HS group compared to those in AA group (P<0.05 or P<0.01). (3) Knockdown endogenous Snail expression by siRNA could ameliorate AA-induced EMT of HKC cells, while overexpression of Snail by plasmid transfection diminished the antagonistic effect of HS on AA-induced EMT. These results suggest Snail might be a potential target of HS effect. CONCLUSION: HS is able to antagonize, to some extent, tubular EMT and renal interstitial fibrosis caused by AA, which might be related to its inhibitory effects on the TGF-ß1 and Snail expression.