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1.
Colloids Surf B Biointerfaces ; 183: 110448, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31472387

RESUMO

High mechanical property especially the exorbitant elastic modulus is the common complication of the clinical polymethylmethacrylate (PMMA) bone cement which will generate the fracture of the adjacent bone and even aseptic loosening, other side effects including excess thermal temperature and low efficiency of the drug release bother the development of the PMMA bone cement. The present study aims to investigate the optimum dosage of gelatin as the porogen, which reduced the elastic modulus of the bone cement to the relatively close level of the cancellous bone. Meanwhile, better antibiotic release profile was introduced by enhancing the specific surface area and interconnectivity than the neat PMMA bone cement. Compared to the PMMA bone cement, the mechanical and thermal property was successfully reduced by the porous structure, the component with 200-400 µm gelatin has the better porosity which resulted in the increasing drug release amount and rate than that of the PMMA bone cement. Furthermore, data analysis and fitting curve could guide experiments, in turn, to obtain the PMMA bone cement with specific requirements of the mechanical properties by the addition of gelatin as the pore-forming agent, and in some cases for predictive purposes, to estimate how a change of gelatin may affect the porosity, mechanical properties, and drug release profiles.

2.
J Colloid Interface Sci ; 556: 492-502, 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31473539

RESUMO

Given the complexity of pollutants in wastewater, development of facile and effective multifunctional materials, which can not only kill bacteria but also remove dyes from wastewater, is in high demand. Herein, a facile strategy for the preparation of positively-charged nanofibrous membranes (NFMs) is reported via the combination of electrospinning and in-situ cross-linked polymerization of poly ([2-(methacryloyloxy)-ethyl] trimethyl ammonium chloride) (PMETAC) in poly (ether sulfone) (PES) solution. The quaternary ammonium salt polymer of PMETAC enabled the NFMs with positive charge to kill bacteria and remove anionic dyes. The antibacterial tests including agar plate counting and live/dead staining indicate that the NFMs show strong antibacterial ability with bacterial killing ratios of nearly 99% for both Escherichia coli and Staphylococcus aureus, as well as remarkable recyclability towards killing bacteria. The dyes adsorption experiments show that the NFMs exhibit high adsorption capacity for anionic dyes up to 208 mg g-1 for Congo Red (CR) and good reusability toward CR. Impressively, the membrane adsorption column test indicates that the CR dye removal ratio is up to 100% for the first time, and that is still as high as 96.5% for the third time with a fresh dye solution. Given the above advantages, such fascinating NFMs may provide new perspectives in the exploitation of multifunctional membrane materials for complex water remediation.

3.
Nanotechnology ; 30(46): 465703, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476137

RESUMO

The Fe3O4@Au core-shell nanocomposites, as the multifunctional magnetic surface enhanced Raman scattering (SERS) substrates, were fabricated successfully by the seeds growth method based on the Fe3O4-Au core-satellite nanocomposites. The SERS properties of the Fe3O4-Au core-satellite nanocomposites and the Fe3O4@Au core-shell nanocomposites were compared using 4-aminothiophenol (4-ATP) as the probe molecule. It was found that Fe3O4@Au core-shell nanocomposites showed better SERS performance than Fe3O4-Au core-satellite nanocomposites. The Au shell provided an effectively large surface area for forming sufficient plasmonic hot spots and capturing target molecules. The integration of magnetic core and plasmonic Au nanocrystals endowed the Fe3O4@Au core-shell nanocomposites with highly efficient magnetic separation and enrichment ability and abundant interparticle hot spots. The Fe3O4@Au core-shell nanocomposites could be easily recycled because of the intrinsic magnetism of the Fe3O4 cores and had good reproducibility of the SERS signals. For practical application, the Fe3O4@Au core-shell nanocomposites were also used to detect thiram. There was a good linear relationship between the SERS signal intensity and the concentration of thiram from 1 × 10-3 to 1 × 10-8 M and the limit of detection was 7.69 × 10-9 M. Moreover, residual thiram on apple peel was extracted and detected with a recovery rate range of 99.3%. The resulting substrate with high SERS activity, stability and strong magnetic responsivity makes the Fe3O4@Au core-shell nanocomposites a perfect choice for practical SERS detection applications.

4.
Int J Mol Sci ; 20(17)2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31480430

RESUMO

Breast cancer is regarded worldwide as a severe human disease. Various genetic variations, including hereditary and somatic mutations, contribute to the initiation and progression of this disease. The diagnostic parameters of breast cancer are not limited to the conventional protein content and can include newly discovered genetic variants and even genetic modification patterns such as methylation and microRNA. In addition, breast cancer detection extends to detailed breast cancer stratifications to provide subtype-specific indications for further personalized treatment. One genome-wide expression-methylation quantitative trait loci analysis confirmed that different breast cancer subtypes have various methylation patterns. However, recognizing clinically applied (methylation) biomarkers is difficult due to the large number of differentially methylated genes. In this study, we attempted to re-screen a small group of functional biomarkers for the identification and distinction of different breast cancer subtypes with advanced machine learning methods. The findings may contribute to biomarker identification for different breast cancer subtypes and provide a new perspective for differential pathogenesis in breast cancer subtypes.

5.
Hum Mol Genet ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31384951

RESUMO

Germ cell-derived genomic structure variants not only drive the evolution of species but also induce developmental defects in offspring. The genomic structure variants have different types, but most of them are originated from DNA double-strand breaks (DSBs). It is still not well known whether DNA DSBs exist in adult mammalian oocytes and how the growing and fully-grown oocytes repair their DNA DSBs induced by endogenous or exogenous factors. In this study we detected the endogenous DNA DSBs in the growing and fully-grown mouse oocytes, and found that the DNA DSBs mainly localized at the centromere-adjacent regions which are also copy number variation hotspots. When the exogenous DNA DSBs were introduced by Etoposide, we found that Rad51-mediated homologous recombination (HR) was used to repair the broken DNA. However, the HR repair caused the chromatin intertwined and impaired the homologous chromosome segregation in oocytes. Although we hadn't detected the indication about HR repair of endogenous centromere-adjacent DNA DSBs, we found that Rad52 and RNA:DNA hybrids colocalized with these DNA DSBs, indicating a Rad52 dependent DNA repair might exist in oocytes. In summary, our results not only demonstrated an association between endogenous DNA DSBs with genomic structure variants, but also revealed one specific DNA DSB repair manner in oocytes.

6.
Mikrochim Acta ; 186(8): 593, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31372825

RESUMO

A heterojunction microcomposite was synthesized that consists of ZnO nanoparticles (ZnO NPs) anchored on MoS2 microflowers (MoS2 MFs). The material is shown to enable trace level detection of the pollutant bisphenol A (BPA). The microcomposite was characterized by XRD, XPS, SEM and TEM. In addition, coupling reaction between phenolic estrogens and Pauly's reagents was adopted to greatly enhance the SERS signal. BPA display a characteristic Raman band at 1592 cm-1 which can be used for its selective detection. The assay is highly sensitive and has a 1 nM detection limit which is the lowest among the reported semiconductor substrates. Graphical abstract MoS2/ZnO MCs SERS substrate broke through the application barrier of semiconductor composite materials in SERS substrates. It also sheds light on a deeper understanding of the charge-transfer based enhancement mechanism.

7.
Cell Immunol ; : 103958, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31376919

RESUMO

T cell immunoglobulin and ITIM domain (TIGIT) is a novel immune checkpoint receptor and plays critical roles in cancer immunity. Adult acute lymphoblastic leukemia (ALL) remains a treatment challenge despite years of research. In this study, we analyzed the status of TIGIT expression in circulating T cells from patients with adult ALL. Compared to the data in healthy controls, the expression of TIGIT in CD4+CD25- T cells and CD8+ T cells in adult ALL patients presented a small but significant upregulation. Stimulation via the CD3/CD28 route increased TIGIT mRNA expression at 24 h, which peaked at 48 h and was maintained at 72 h post-stimulation. The frequency of TIGIT+ cells, on the other hand, consistently increased over time. ALL protein lysate or Wilms' Tumor 1 peptide could significantly increase the expression of TIGIT in ALL, but not healthy control T cells. Compared to TIGIT- cells, the TIGIT+ cells presented significantly higher PD-1 and Tim-3 expression directly ex vivo, and significantly lower IL-2, IFN-γ, and TNF-α after CD3/CD28 stimulation. The high inhibitory molecule and low cytokine expression signature was especially pronounced in ALL TIGIT+ CD4+CD25- T cells and TIGIT+ CD8+ T cells. Blocking TIGIT alone could minimally increase cytokine expression independent of PD-1 and Tim-3 blocking, whereas blocking TIGIT, PD-1, and Tim-3 altogether was significantly more effective. Together, these data demonstrated that TIGIT regulated T cell function in adult ALL patients, and may serve as a treatment target for ALL.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31365289

RESUMO

Orexin is a peptide neurotransmitter released in the globus pallidus. Morphological evidence reveals that both orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) exist in the globus pallidus. Here we showed that bilateral microinjection of both orexin-A and orexin-B into the globus pallidus alleviated motor deficits in MPTP-induced parkinsonian mice. Further in vivo extracellular single unit recording revealed that the basal spontaneous firing rate of the globus pallidus neurons in MPTP parkinsonian mice was slower than that of normal mice. Application of orexin-A or orexin-B significantly increased the spontaneous firing rate of pallidal neurons. The influx of Ca2+ through L-type Ca2+ channel is involved in orexin-induced excitation in the globus pallidus. Orexin-A-induced increase in firing rate of pallidal neurons in MPTP parkinsonian mice was stronger than that of normal mice. Orexin-A exerted both the electrophysiological and behavioral effects mainly via OX1R, and orexin-B exerted the effects via OX2R. Endogenous orexins modulated the excitability of globus pallidus neurons mainly through OX1R. The present behavioral and electrophysiological results suggest that orexins ameliorate parkinsonian motor deficits through increasing the spontaneous firing of globus pallidus neurons.

9.
Cells ; 8(9)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461851

RESUMO

The subunits KCNQ1 and KCNE1 generate the slowly activating, delayed rectifier potassium current, IKs, that responds to sympathetic stimulation and is critical for human cardiac repolarization. The A-kinase anchoring protein Yotiao facilitates macromolecular complex formation between IKs and protein kinase A (PKA) to regulate phosphorylation of KCNQ1 and IKs currents following beta-adrenergic stimulation. We have previously shown that adenylyl cyclase Type 9 (AC9) is associated with a KCNQ1-Yotiao-PKA complex and facilitates isoproterenol-stimulated phosphorylation of KCNQ1 in an immortalized cell line. However, requirement for AC9 in sympathetic control of IKs in the heart was unknown. Using a transgenic mouse strain expressing the KCNQ1-KCNE1 subunits of IKs, we show that AC9 is the only adenylyl cyclase (AC) isoform associated with the KCNQ1-KCNE1-Yotiao complex in the heart. Deletion of AC9 resulted in the loss of isoproterenol-stimulated KCNQ1 phosphorylation in vivo, even though AC9 represents less than 3% of total cardiac AC activity. Importantly, a significant reduction of isoproterenol-stimulated IKs currents was also observed in adult cardiomyocytes from IKs-expressing AC9KO mice. AC9 and Yotiao co-localize with N-cadherin, a marker of intercalated disks and cell-cell junctions, in neonatal and adult cardiomyocytes, respectively. In conclusion, AC9 is necessary for sympathetic regulation of PKA phosphorylation of KCNQ1 in vivo and for functional regulation of IKs in adult cardiomyocytes.

10.
Sci China Life Sci ; 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31463739

RESUMO

Mouth ulcer is associated with inflammation and high risk of bacterial infection, which aggravates the patient's condition. Currently, there is no effective treatment for mouth ulcer. Herein, we report that vitamin-modified iron oxide nanoparticles improve the healing of mouth ulcer through anti-inflammation and antibacterial activities. We discovered that vitamin B2 (VB2) modified iron oxide nanoparticles performed enhanced peroxidase-like, catalase-like, and superoxide dismutase (SOD)-like activities, acting as typical iron oxide nanozymes (IONzymes) with triad activities. In particular, VB2 modification significantly improved the SOD-like activity, thus providing a reactive oxygen species (ROS)-scavenging ability. Cellular antioxidant experiments showed that vitamin B2 modified IONzymes (VB2-IONzymes) protect human oral keratinocytes (HOK) and BALB/3T3 cells from hydrogen peroxide (H2O2), and these cells have high biocompatibility to eukaryotic cells. In addition, VB2-IONzymes exerted an antibacterial activity against Streptococcus mutans, Staphylococcus aureus, and Escherichia coli. Importantly, VB2-IONzymes accelerated the recovery of mouth ulcer and reduced the local secretion of inflammatory factors in mouse ulcer model via ROS scavenging and antibacterial activity. Taken together, our work demonstrates that vitamin B2 modification endows iron oxide nanoparticles with enhanced enzyme-like activities and VB2-IONzymes may be a promising reagent in the treatment of mouth ulcer because of their intrinsic anti-inflammation and antibacterial capabilities.

11.
Curr Genet ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31463774

RESUMO

Enoyl-CoA hydratase (Ech) is an important and well-recognized enzyme that functions in the degradation of fatty acids by ß-oxidation. However, its functions in plant pathogenic fungi are not well known. We characterized an Ech1 orthologue, FgEch1, in Fusarium graminearum. The FgEch1 deletion mutant was defective in the utilization of short-chain fatty acids and conidiation, but not in hyphal growth on glucose-rich media or in perithecium formation. The FgEch1 deletion mutant showed reduced deoxynivalenol (DON) production and virulence in plants. Deletion of FgEch1 also led to increased production of lipid droplets and autophagy. FgEch1, which was localized in the mitochondrion, required the MTS domain for mitochondrial localization and function in F. graminearum. Taken together, these data indicate that mitochondrial FgEch1 is important for conidiation, DON production, and plant infection.

12.
Adv Healthc Mater ; : e1900831, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31464099

RESUMO

Tendon to bone (enthesis) rupture, which may cause disability and persistent pain, shows high rate of re-rupture after surgical repair. Tendon or enthesis scaffolds have been widely studied, but few of these materials can recapitulate the tissue continuity. Thus, this study is conducted to prepare a triphasic decellularized bone-fibrocartilage-tendon (D-BFT) composite scaffold. The D-BFT scaffold is developed using a combination of physical, chemical, and enzymatic treatments using liquid nitrogen, Triton-X 100, sodium-dodecyl sulfate, and DNase I, which effectively removes the cell components while preserving the biological composite and microstructure. Moreover, the mechanical properties of D-BFT are highly preserved and similar to those of the human Achilles tendon. Additionally, in vitro, mesenchymal stem cells (MSCs) adhered, proliferated, and infiltrated into the D-BFT scaffold, and MSC differentiation is confirmed by up-regulation of osteogenic-related and tenogenic-related genes. The repair outcomes are explored by applying the D-BFT scaffold in the model of femur-tibia defects in vivo, which shows good repair results. Thus, the D-BFT scaffold developed in this study is a promising graft for enthesis regeneration.

13.
Medicine (Baltimore) ; 98(35): e17008, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464958

RESUMO

Urinary kallidinogenase may assist recovery acute ischemic stroke. This study evaluated the effect of urinary kallidinogenase on National Institute of Health Stroke Scale (NIHSS) score, modified Rankin scale (mRS) score, and fasting glucose levels in patients with acute ischemic stroke (AIS) combined with diabetes mellitus and impaired fasting glucose.Patients with AIS and abnormal glucose metabolism were enrolled in this prospective cohort study and divided into 2 groups. The human urinary kallidinogenase (HUK) group were treated with urinary kallidinogenase and standard treatment; the control group received standard treatment. NIHSS scores, mRS scores, and fasting blood glucose were evaluated and compared.A total of 113 patients were included: 58 in the HUK group and 55 in the control group. NIHSS scores decreased with treatment in both groups (time effect P < .05), but were lower in the HUK group (main effect P = .026). The mRS score decreased in both groups from 10 until 90 days after treatment (time effect P < .05); the 2 groups were similar (main effect, P = .130). Blood glucose levels decreased in both groups 10 days after treatment (time effect, P < .05), but there was no significant treatment effect (main effect, P = .635). Multivariate analysis showed blood uric acid >420 µmol/L (odds ratio [OR]: 0.053, 95% confidence interval [CI]: 0.008-0.350; P = .002) and application of HUK (OR: 0.217, 95% CI: 0.049-0.954; P = .043) were associated with 90% NIHSS recovery. Baseline NIHSS score was independently associated with poor curative effect.Urinary kallidinogenase with conventional therapy significantly improved NIHSS scores in patients with AIS. Urinary kallidinogenase also showed a trend toward lower fasting blood glucose levels, although the level did not reach significance.

14.
Mar Drugs ; 17(9)2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443597

RESUMO

Cancer remains one of the most lethal diseases worldwide. There is an urgent need for new drugs with novel modes of action and thus considerable research has been conducted for new anticancer drugs from natural sources, especially plants, microbes and marine organisms. Marine populations represent reservoirs of novel bioactive metabolites with diverse groups of chemical structures. This review highlights the impact of marine organisms, with particular emphasis on marine plants, algae, bacteria, actinomycetes, fungi, sponges and soft corals. Anti-cancer effects of marine natural products in in vitro and in vivo studies were first introduced; their activity in the prevention of tumor formation and the related compound-induced apoptosis and cytotoxicities were tackled. The possible molecular mechanisms behind the biological effects are also presented. The review highlights the diversity of marine organisms, novel chemical structures, and chemical property space. Finally, therapeutic strategies and the present use of marine-derived components, its future direction and limitations are discussed.

15.
Australas J Ageing ; 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31400038

RESUMO

OBJECTIVE: To develop anthropometric prediction equations for estimating appendicular skeletal muscle (ASM) in Chinese knee osteoarthritis patients. METHODS: Subjects were divided into the model development group (MD group: 104 cases, 47 men and 57 women) and cross-validation group (CV group: 69 cases, 38 men and 31 women). Stepwise multiple linear regression analyses were undertaken in the MD group to identify the best equations. Agreement between the estimated ASM and ASM measured by dual-energy X-ray absorptiometry (DXA) was tested in the CV group. RESULTS: Two models were developed in the MD group. Validation in the CV group showed that our models (R2  = 0.83 and R2  = 0.90) had a high coefficient of determination. The mean bias of ASM estimated by the two models from the ASM measured by DXA in the CV group showed no significant difference (P > 0.05). CONCLUSION: These models could be useful for older Chinese patients with knee osteoarthritis to estimate ASM.

16.
Biomed Res Int ; 2019: 4963289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396531

RESUMO

Protein-protein interaction (PPI) plays an extremely remarkable role in the growth, reproduction, and metabolism of all lives. A thorough investigation of PPI can uncover the mechanism of how proteins express their functions. In this study, we used gene ontology (GO) terms and biological pathways to study an extended version of PPI (protein-protein functional associations) and subsequently identify some essential GO terms and pathways that can indicate the difference between two proteins with and without functional associations. The protein-protein functional associations validated by experiments were retrieved from STRING, a well-known database on collected associations between proteins from multiple sources, and they were termed as positive samples. The negative samples were constructed by randomly pairing two proteins. Each sample was represented by several features based on GO and KEGG pathway information of two proteins. Then, the mutual information was adopted to evaluate the importance of all features and some important ones could be accessed, from which a number of essential GO terms or KEGG pathways were identified. The final analysis of some important GO terms and one KEGG pathway can partly uncover the difference between proteins with and without functional associations.

17.
World Neurosurg ; 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31421302

RESUMO

Endoscopic endonasal transsphenoidal (EET) approach for skull base tumors has become increasingly popular. We know that bone defects in the skull base can cause cerebrospinal fluid rhinorrhea, but for patients who need to be intubated through the nose, the tube can enter the brain through skull base bone defect. Nasogastric tube feeding into the brain is a rare occurrence, and this situation can occur only in the case of skull base defect. We present a rare case of a patient with an unusual complication after EET approach for pituitary adenoma resection. This particular case suggest that bone defects after EET surgery can not only cause cerebrospinal fluid rhinorrhea but also cause the entry of the nasogastric tube into the brain. For patients with a history of EET surgery, endoscopy-assisted gastric tube implantation can be performed if necessary.

18.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 33(8): 940-946, 2019 Aug 15.
Artigo em Chinês | MEDLINE | ID: mdl-31407550

RESUMO

Objective: To explore the effectiveness of Ilizarov external fixation without bone graft in the treatment of atrophic femoral shaft nonunion. Methods: The clinical data of 12 patients with atrophic femoral shaft nonunion admitted between October 2010 and January 2017 were retrospectively analyzed. There were 8 males and 4 females, aged from 24 to 61 years, with an average age of 41.7 years. The nonunion sites located in the middle and upper femur in 7 cases and in the distal femur or supracondylar in 5 cases. The disease duration ranged from 1 to 9 years, with an average of 3.7 years. Previous operations ranged from 1 to 9 times, with an average of 2.8 times. The original fixator was removed, the fracture end of nonunion was debrided, and Ilizarov external fixator was installed. In patients with the length of bone defect less than 4 cm, direct compression fixation was performed during operation; in patients with limb shortening more than 2.5 cm, proximal femoral osteotomy and bone lengthening components were required to prepare limb lengthening after operation; all patients did not receive bone graft. The wearing time of external fixator, clinical bone healing time of nonunion fracture end, and complications were recorded. The effectiveness was evaluated by Paley's nonunion evaluation criteria. Results: All patients were followed up 24-50 months, with an average of 30 months. Bony union was achieved in all 12 cases with a healing time of 6.0-23.5 months (mean, 11.5 months). The wearing time of external fixator ranged from 7 to 25 months, with an average of 13.5 months. At last follow-up, according to Paley's nonunion evaluation criteria, the results were excellent in 6 cases, good in 4 cases, and fair in 2 cases, with an excellent and good rate of 83.3%. Sagittal angulation deformity of femur more than 7° occurred in 4 cases, with no significant effect on knee extension function, and no special treatment such as osteotomy was performed. Two patients had shorter limbs (>2.5 cm) after operation and were replaced by high shoes; 4 patients with trans-knee fixation lost knee joint mobility of 10-30° after operation; 10 cases of needle tract infection occurred, of which 4 cases with infection and loosening of fixed needle were replaced and re-fixed after needle extraction, the remaining 6 cases of infection without loosening of fixed needle were controlled by local dressing change, needle nursing, and oral cephalosporin anti-inflammatory drugs. No complications such as deep infection and vascular nerve injury occurred. Conclusion: Ilizarov external fixation has a high healing rate for atrophic femoral shaft nonunion, which is relatively minimally invasive and can avoid bone grafting. Its preliminary effectiveness is exact, and it is also effective for patients who have experienced multiple failed operations. It is necessary to pay attention to the nursing and rehabilitation training after external fixation.

19.
Cancer Immunol Res ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387897

RESUMO

Immunosuppression is common in head and neck squamous cell carcinoma (HNSCC). In previous studies, the TIGIT/CD155 pathway was identified as an immune checkpoint signaling pathway that contributes to the "exhaustion" state of infiltrating T cells. Here, we sought to explore the clinical significance of TIGIT/CD155 signaling in HNSCC and identify the therapeutic effect of TIGIT/CD155 pathway in transgenic mouse model. TIGIT was overexpressed on tumor-infiltrating CD8+ and CD4+ T cells in both HNSCC patients and mouse models, and was correlated with immune checkpoint molecules (PD-1, TIM-3, LAG-3). TIGIT was also expressed on murine regulatory T cells (Tregs) and correlated with immune suppression. Using a human HNSCC tissue microarray, we found that CD155 was expressed in tumor and tumor-infiltrating stromal cells, and also indicated poor overall survival. Multispectral immunohistochemistry indicated that CD155 was coexpressed with CD11b or CD11c in tumor-infiltrating stromal cells. Anti-TIGIT treatment significantly delayed tumor growth in transgenic HNSCC mouse models and enhanced antitumor immune responses by activating CD8+ T-cell effector function and reducing the population of Tregs. In vitro coculture studies showed that anti-TIGIT treatment significantly abrogated the immunosuppressive capacity of MDSCs, by decreasing Arg1 transcripts, and Tregs, by reducing TGFß1 secretion. In vivo depletion studies showed that the therapeutic efficacy by anti-TIGIT mainly relies on CD8+ T cells and Tregs. Blocking PD-1/PD-L1 signaling increased the expression of TIGIT on Tregs. These results present a translatable method to improve antitumor immune responses by targeting TIGIT/CD155 signaling in HNSCC.

20.
ACS Chem Neurosci ; 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369236

RESUMO

Lanosterol, an amphipathic molecule, was discovered only very recently to effectively hinder the aggregation of lens proteins and dissolve the extremely stable fibrillar aggregates in cataracts. Here, we combined computational and experimental approaches to study how lanosterol disrupts the aggregation of another important peptide, amyloid-ß (Aß) peptide, associated with the Alzheimer's Disease (AD). Molecular dynamics simulations using the core amyloidogenic segment (KLVFFA) of Aß peptide revealed that lanosterol exhibits at least two types of inhibition mechanism on the self-assembly of Aß peptides. First, lanosterol entangles with peptides and forms a hydrophobic core with residues Phe-19 and Phe-20 in particular. Second, it interferes with the steric zipper interaction at the ß-sheet-ß-sheet interface. These simulation data suggest that lanosterol induces the unfolding of the Aß peptide and the separation of the ß-sheet layers. This predicted inhibition effect of lanosterol was then confirmed by an in vitro ThT fluorescence assay and AFM imaging. The cell toxicity assay also showed that the treatment of lanosterol indeed mitigates the cytotoxicity of the Aß peptide in PC-12 cells. Moreover, lanosterol shows a stronger suppression effect on Aß peptides' aggregation than cholesterol because of its higher hydrophobicity. This result establishes a foundation for the development of lanosterol-based potential therapies for AD and other protein conformational diseases.

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