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1.
J Am Chem Soc ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34665964

RESUMO

Grain boundary management is critical to the performance and stability of polycrystalline perovskite solar cells (PSCs), especially large-area devices. However, typical passivators are insulating in nature and limit carrier transport. Here, we design a supramolecular binder for grain boundaries to simultaneously passivate defects and promote hole transport across perovskite grain boundaries. By doping the monoamine porphyrins (MPs, M = Co, Ni, Cu, Zn, or H) into perovskite films, MPs self-assemble into supramolecules at grain boundaries. Organic cations in perovskites protonate MPs in supramolecules to form ammonium porphyrins bound on the perovskite grain surface, to passivate defects and extract holes from the perovskite lattice. Periodic polarons in supramolecules (especially NiP-supramolecule) promote the transport of extracted holes across boundaries, reducing nonradiative carrier recombination. The NiP-doped PSCs reveal a certified efficiency of 22.1% for an active area of 1.0 cm2 with the remarkably improved open-circuit voltage and fill factor. The unencapsulated device retained over 80% initial performance under AM 1.5G solar light continuous illumination or heating at 85 °C over 3000 h.

2.
Sheng Wu Gong Cheng Xue Bao ; 37(8): 2719-2736, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472291

RESUMO

Primary liver cancer (PLC) is an aggressive tumor and prone to metastasize and recur. According to pathological features, PLC are mainly categorized into hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed hepatocellular cholangiocarcinoma, and fibrolamelic hepatocellular carcinoma, etc. At present, surgical resection, radiotherapy and chemotherapy are still the main treatments for PLC, but the specificities are poor and the clinical effects are limited with a 5-year overall survival rate of 18%. Liver cancer stem cells (LCSCs) are a specific cell subset existing in liver cancer tissues. They harbor the capabilities of self-renewal and strong tumorigenicity, driving tumor initiation, metastasis, drug resistance and recurrence of PLC. Therefore, the identification of molecular markers and the illustration of mechanisms for stemness maintenance of LCSCs can not only reveal the molecular mechanisms of PLC tumorigenesis, but also lay a theoretical foundation for the molecular classification, prognosis evaluation and targeted therapy of PLC. The latest research showed that the combination of 5-fluorouracil and CD13 inhibitors could inhibit the proliferation of CD13+ LCSCs, thereby reducing overall tumor burden. Taken together, LCSCs could be the promising therapeutic targets of PLC in the future. This review summarizes the latest progress in molecular markers, mechanisms for stemness maintenance and targeted therapies of LCSCs.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/genética , Células-Tronco Neoplásicas , Prognóstico
3.
ChemMedChem ; 2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34569159

RESUMO

In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized. In screening their in vitro activity, we found all the tested compounds were more potent against the highly aggressive triple-negative breast cancer cell line MDA-MB-231. Cellular functional assays showed that representative compounds could induce G1-phase arrest and trigger apoptosis, evidenced by the alteration of Bax, Bcl-2, caspase-3 and PARP levels. Furthermore, these compounds significantly enhanced the autophagic flux with increased expression of LC3-II and Beclin-1, as well as decreased level of p62, which may attribute to simultaneously inhibition of the phosphorylation of p70S6K, 4E-BP1 and AKT, the key substrates of the mTOR signaling pathway. In vivo, two compounds revealed potent antitumor activity in mice bearing MDA-MB-231. Altogether, our work describes novel leads to yield more potent chemotherapeutics against triple-negative breast cancers, possibly mesenchymal stem-like subtype.

4.
Small ; 17(41): e2103986, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34510759

RESUMO

Injecting micro/nanorobots into the body to kill tumors is one of the ultimate ambitions for medical nanotechnology. However, injecting current micro/nanorobots based on 3D-printed biocompatible materials directly into blood vessels for targeted therapy is often difficult, and mistakes in targeting can cause serious side effects, such as blood clots, oxidative stress, or inflammation. The natural affinity of macrophages to tumors, and their natural phagocytosis and ability to invade tumors, make them outstanding drug delivery vehicles for targeted tumor therapy. Hence, a magnetically controlled cell robot (MCR) based on a macrophage drug carrier is proposed. Here, living macrophages are converted into MCRs through endocytosis of specially-designed magnetic nanoparticles loaded with doxorubicin and indocyanine green. Following this, the MCRs can be transported to tumors through the blood vessels using external magnetic fields, and penetrate the blood vessels into the interior of the tumor due to their deformability. With the MCR's cascaded drug release, targeted killing of tumors in mice is demonstrated, with minimal effects on the normal surrounding tissue. The ability to impart precise drug doses onto natural cells, such as macrophages, and load various functional components into the MCRs, offers an efficient method for precise targeted therapy.

5.
J Control Release ; 337: 557-570, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371056

RESUMO

Current clinical agents for autoimmunity disorders treatment often cause substantial adverse effects and safety concerns, owing to non-specific immune modulation. Due to the prominent contribution of effector T cells in pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and preferential location of co-stimulatory receptor-ligand pair OX40-OX40L at the inflamed sites, selectively targeting autoaggressive T cells by blockade OX40-OX40L, might represent an alternative strategy. Herein, we developed a new strategy to antagonize OX40-OX40L interaction by engineering a cell membrane derived nanovesicles (NVs) expressing OX40 receptors (OX40 NVs), and explored their potential for autoimmune disorders therapy. OX40 NVs showed specific binding capability to inflamed HUVECs in vitro, it also possessed distinct arthritic-targeting capacity in RA inflamed joints, and preferential accumulation in IBD inflamed colon. OX40 NVs efficiently suppressed the progression of both RA and IBD diseases through reducing CD4+OX40+ T cells population, and proinflammatory cytokines (i.e., TNF-α and IL-1ß), while reinforcing Tregs immune-suppressive effect, with superior therapeutic efficacy than anti-OX40L. Additionally, dexamethasone (DEX) loading can further enhance the potential of OX40 NVs for RA treatment. Owing to their preferential localization to inflamed sites, and potent immune-suppression ability, targeting OX40-OX40L blockade by OX40 NVs for autoimmune therapy is highly promising.

6.
Hum Brain Mapp ; 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34390079

RESUMO

With the development of electrical stimulation technology, especially the emergence of temporally interfering (TI) stimulation, it is necessary to discuss the influence of current frequency on stimulation intensity. Accurate skull modeling is important for transcranial current stimulation (tCS) simulation prediction because of its large role in dispersing current. In this study, we simulated different frequencies of transcranial alternating current stimulation (tACS) and TI stimulation in single-layer and layered skull model, compared the electric field via error parameters such as the relative difference measure and relative magnification factor. Pearson correlation analysis and t-test were used to measure the differences in envelope amplitude. The results showed that the intensity of electric field in the brain generated by per unit of stimulation current will increase with current frequency, and the layered skull model had a better response to frequency. An obvious pattern difference was found between the electric fields of the layered and single-layer skull individualized models. For TI stimulation, the Pearson correlation coefficient between the envelope distribution of the layered skull model and the single-layer skull was only 0.746 in the individualized model, which is clearly lower than the correlation coefficient of 0.999 determined from the spherical model. Higher carrier frequencies seemed to be easier to generate a large enough brain electric field envelope in TI stimulation. In conclusion, we recommend using layered skull models instead of single-layer skull models in tCS (particularly TI stimulation) simulation studies in order to improve the accuracy of the prediction of stimulus intensity and stimulus target.

7.
J Hazard Mater ; 421: 126746, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34388923

RESUMO

Deep convolutional neural network (DCNN) has proved to be a promising tool for identifying organic chemicals of environmental concern. However, the uncertainty associated with DCNN predictions remains to be quantified. The training process contains many random configurations, including dataset segmentation, input sequences, and initial weight, etc. Moreover, the DCNN working mechanism is non-linear and opaque. To increase confidence to use this novel approach, persistent, bioaccumulative, and toxic substances (PBTs) were utilized as representative chemicals of environmental concern to estimate the prediction uncertainty under five distinguished datasets and ten different molecular descriptor (MD) arrangements with 111,852 chemicals and 2424 available MDs. An internal correlation coefficient test indicated that the prediction confidence reached 0.98 when a mean of 50 DCNNs' predictions was used instead of a sing DCNN prediction. A threshold for PBT categorization was determined by considering costs between false-negative and false-positive predictions. As revealed by the guided backpropagation-class activation mapping (GBP-CAM) saliency images, only 12% of all selected MDs were activated by DCNN and influenced decision-making process. However, the activated MDs not only varied among chemical classes but also shifted with different DCNNs. Principal component analysis indicated that 2424 MDs could transform into 370 orthogonal variables. Both results suggest that redundancy exists among selected MDs. Yet, DCNN was found to adapt to redundant data by focusing on the most important information for better prediction performance.

8.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 39(4): 425-433, 2021 Aug 01.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34409798

RESUMO

OBJECTIVES: To investigate the effects of circ_0005379 on the proliferation, apoptosis, migration, and invasion of oral squamous cell carcinoma (OSCC) cells and its mechanism. METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression levels of circ_0005379 and miR-17-5p in OSCC tissues and SCC15 cell lines. Western blot was used to detect the expression levels of acyl-CoA oxidase 1 (ACOX1). The circ_0005379 overexpression vector was transfected into SCC15 cells. Methyl thiazolyl tetrazolium blue staining, flow cytometry, Transwell, and Western blot were used to detect the effects of circ_0005379 overexpression on the proliferation, apoptosis, migration, and invasion of SCC15 cells and the expression of E-cadherin, ß-catenin, and Snail proteins. Dual luciferase reporter assay and RNA immunoprecipitation were used to examine the regulation of circ_0005379, miR-17-5p, miR-17-5p, and ACOX1 in SCC15 cells. A nude mouse xenograft model of SCC15 cells stably overexpressing circ_0005379 was established, and the effect of circ_0005379 overexpression on the growth of xenografts in nude mice was observed. RESULTS: Compared with adjacent cancer tissues, the expression levels of circ_0005379 and ACOX1 proteins in OSCC tissues were decreased (P<0.05), and the expression level of miR-17-5p was increased (P<0.05). Compared with HOK-16A cells, the expression levels of circ_0005379 and ACOX1 proteins in SCC15 cell lines were decreased (P<0.05), and the expression level of miR-17-5p was increased (P<0.05). After overexpressing circ_0005379, the activity and number of migrating and invading SCC15 cells and the expression levels of ß-catenin and Snail proteins were decreased (P<0.05); however, the apoptosis rate and expression level of E-cadherin protein were increased (P<0.05). In SCC15 cells, circ_0005379 targeted the negative regulation of miR-17-5p expression, and miR-17-5p targeted the negative regulation of ACOX1 expression. Overexpressing miR-17-5p or silencing ACOX1 could reverse the effects of circ_0005379 overexpression on the proliferation, apoptosis, migration, and invasion of OSCC cell lines. The tumor volume and weight of nude mice overexpressing circ_0005379 were decreased (P<0.05), the expression levels of circ_0005379 and ACOX1 protein in tumor tissues were increased (P<0.05), and the expression level of miR-17-5p was decreased (P<0.05). CONCLUSIONS: circ_0005379 may inhibit the proliferation, migration, and invasion of OSCC cells by downregulating the expression of miR-17-5p and upregulating ACOX1, which promote apoptosis and inhibit tumor growth in vivo. circ_0005379 may be a potential target for OSCC treatment.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , MicroRNAs , Neoplasias Bucais , Acil-CoA Oxidase , Animais , Carcinoma de Células Escamosas/genética , Proliferação de Células , Humanos , Camundongos , Camundongos Nus , Neoplasias Bucais/genética , RNA Circular , Carcinoma de Células Escamosas de Cabeça e Pescoço
9.
Bioengineered ; 12(1): 5173-5183, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34405758

RESUMO

The gut microbiota is widely considered to be involved in several diseases, including atherosclerosis, obesity, chronic obstructive pulmonary disease (COPD) and pulmonary arterial hypertension (PAH). This study aimed to determine if changes in the gut microbiome and metabolome play a major role in the early pathogenesis of PAH. Male Wistar rats were injected with monocrotaline (MCT) (55 mg/kg) at day 1 and injected with calcium-sensing receptor (CaSR) antagonist NPS2143 (4.5 mg/kg/d) from days 1 to 21. Fecal samples were obtained. The gut microbiota and metabolome were analyzed by 16S rRNA gene sequencing and mass spectrometry-based analysis to investigate the effect of PAH in this rat model. MCT injection had a marked effect on the composition of the gut microbiota. This finding was further confirmed by metabolomic analysis with identification of several metabolites relevant to the gut microflora. However, NPS2143 partially abrogated this intestinal flora disorder and reversed fecal metabolite abnormalities. In conclusion, our study shows correlations between changes in the gut microbiome and the metabolome in PAH, which are affected by NPS2143.

10.
J Food Sci ; 86(10): 4594-4610, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34392537

RESUMO

Intelligent pH-indicator films based on soy protein isolate (SPI) were prepared using pH-sensitive dyes (bromothymol blue and methyl red). The addition of mixed indicators imparts pH-indicator films with an appreciable microstructure, acceptable water resistance, and favorable optical properties. The incorporation of the mixed indicators did not lead to significant improvement in the mechanical properties of films due to weak ionic cross-linking by hydrogen bonding between the SPI macromolecules and low-molecular-weight indicators. Fourier-transform infrared spectroscopy indicated hydrogen bond-mediated intermolecular interactions, and scanning electron microscopy showed that BB/MR were well dispersed in the SPI film. The indicator addition hindered the sorption and passage of water molecules. The water vapor permeability, moisture sorption, moisture content, and total soluble matter were 4.32 to 6.12 ×10-12  g·cm/cm2 ·s·Pa, 36.70% to 73.33%, 25.28% to 44.11%, and 8.21% to 25.56%, respectively. Also, the addition of indicators reduced UV light transmittance with minimal effect on the transparency of the film. The presence of indicators enhanced the pH sensitivity, seen as a visible color reaction at different pHs (total color difference, ΔE > 5). When the pH-indicator film containing 8 ml/100 ml final film emulsions was used to monitor the fresh-cut apple freshness, a green color for fresh status was observed, which turned blue after 60 h. Collectively, our findings suggested that indicator-containing SPI films have the potential for monitoring the freshness of fruits. PRACTICAL APPLICATION: pH-indicator films can help consumers to identify the freshness of packaged food by a change in the color of the packaging material, which is easily visible to the unaided eye without the need for opening the packaging. This protects consumers' interests.


Assuntos
Compostos Azo , Azul de Bromotimol , Embalagem de Alimentos , Frutas , Proteínas de Soja , Embalagem de Alimentos/métodos , Frutas/normas , Concentração de Íons de Hidrogênio , Malus , Proteínas de Soja/química
11.
Toxicol In Vitro ; 76: 105220, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34271082

RESUMO

Recently, more and more attention has been focused on silica nanoparticles (SiNPs) as they are increasingly used in various fields. Yet, their biological effects, especially on human beings, largely remain unknown. This study was implanted to assess the biological responses in vitro elicited by human macrophages exposed to the SiNPs and to explore its toxicity and fibrosis biomarker. We found that SiNPs suppressed the viability of THP-1 cells in a dose-dependent manner while they triggered apoptosis and promoted the secretion of inflammatory factors. Next, SiNPs-induced macrophage supernatant was used to act on fibroblast (MRC-5), indicating that the expression of hydroxyproline (Hyp), α-SMA, and collagonIin MRC-5 increased after SiNPs treatment. To further explore the biomarker of fibrosis, Liquid-mass spectrometry facilitated quantitative proteomics, identified 3247 proteins, of which 791 proteins were expressed differentially in human embryonic lung fibroblasts after treated with SiNPs. In conclusion, our observations suggest that SiNPs induced THP-1-derived macrophage damage and apoptosis. Moreover, SiNPs induced macrophages to secrete cytokines that promote fibroblasts' proliferation and differentiation and changed protein expression in MRC-5 cells, regulating biological processes such as apoptosis, protein synthesis, and cell growth. Among these results, our findings could provide a basis for determining fibrosis biomarkers of silica nanoparticle exposure.

12.
Plant Mol Biol ; 106(6): 521-531, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34224063

RESUMO

KEY MESSAGE: We characterize a functional lincRNA, XH123 in cotton seedling in defense of cold stress. The silencing of XH123 leads to increased sensitivity to cold stress and the decay of chloroplast. Cotton, which originated from the arid mid-American region, is one of the most important cash crops worldwide. Cultivated cotton is now widely spread throughout high-altitude regions such as those in the far northwest of Asia. In such areas, spring temperatures below 12 ℃ impose cold stress on cotton seedlings, with concomitant threat of lost yield and productivity. It is documented that cold stress can induce differential expression of long noncoding RNAs (lncRNAs) in cotton; however, it is not yet clear if these cold-responsive lncRNAs are actively involved with tolerance of cold stress at the molecular level. Here, we select ten long intergenic non-coding RNAs as candidate genes and use virus-induced gene silencing and additional cold treatments to examine their roles in the response to cold stress during the cotton seedling stage. One such gene, XH123, was revealed to be involved in tolerance of cold stress. Specifically, XH123-silenced plants demonstrated sensitivity to cold stress, exhibiting chloroplast damage and increased endogenous levels of reactive oxygen species. The transcriptome profile of XH123-silenced seedlings was similar to that of cold-stressed seedlings having the known cold stress gene PIF3 silenced. These results imply that the lincRNA XH123 is actively involved with cold stress regulation in cotton during the seedling stage.


Assuntos
Resposta ao Choque Frio/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica de Plantas , Gossypium/genética , RNA Longo não Codificante/genética , RNA de Plantas/genética , Adaptação Fisiológica/genética , Cloroplastos/genética , Cloroplastos/metabolismo , Cloroplastos/ultraestrutura , Temperatura Baixa , Inativação Gênica , Gossypium/crescimento & desenvolvimento , Microscopia Eletrônica de Transmissão , Folhas de Planta/genética , Folhas de Planta/metabolismo , Folhas de Planta/ultraestrutura , RNA-Seq/métodos , Plântula/genética , Plântula/crescimento & desenvolvimento
13.
Molecules ; 26(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205408

RESUMO

As one of the nanostructures with enzyme-like activity, nanozymes have recently attracted extensive attention for their biomedical applications, especially for bacterial disinfection treatment. Nanozymes with high peroxidase activity are considered to be excellent candidates for building bacterial disinfection systems (nanozyme-H2O2), in which the nanozyme will promote the generation of ROS to kill bacteria based on the decomposition of H2O2. According to this criterion, a cerium oxide nanoparticle (Nanoceria, CeO2, a classical nanozyme with high peroxidase activity)-based nanozyme-H2O2 system would be very efficient for bacterial disinfection. However, CeO2 is a nanozyme with multiple enzyme-like activities. In addition to high peroxidase activity, CeO2 nanozymes also possess high superoxide dismutase activity and antioxidant activity, which can act as a ROS scavenger. Considering the fact that CeO2 nanozymes have both the activity to promote ROS production and the opposite activity for ROS scavenging, it is worth exploring which activity will play the dominating role in the CeO2-H2O2 system, as well as whether it will protect bacteria or produce an antibacterial effect. In this work, we focused on this discussion to unveil the role of CeO2 in the CeO2-H2O2 system, so that it can provide valuable knowledge for the design of a nanozyme-H2O2-based antibacterial system.


Assuntos
Bactérias/efeitos dos fármacos , Cério/farmacologia , Peróxido de Hidrogênio/farmacologia , Nanopartículas/química , Nanoestruturas/química , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Bactérias/metabolismo , Oxirredução/efeitos dos fármacos , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo
14.
Hum Brain Mapp ; 42(15): 5051-5062, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34291850

RESUMO

The discovery of preclinical Alzheimer's disease (preAD) provides a wide time window for the early intervention of AD. The coupling relationships between glucose and oxygen metabolisms from hybrid PET/MRI can provide complementary information on the brain's physiological state for preAD. In this study, we purpose to explore the change of coupling relationship among 27 normal controls (NCs), 20 preADs, and 15 cognitive impairments (CIs). For each subject, we calculated the Spearman partial correlation between the fractional amplitude of low-frequency fluctuations (fALFF) and the regional homogeneity (ReHo) from functional image (fMRI), and the standard uptake value ratio (SUVR) from [18F] fluorodeoxyglucose positron emission tomography (18 F-FDG PET), in the whole-brain and default mode network (DMN) as a novel potential biomarker. The diagnostic performance of this biomarker was evaluated by the receiver operating characteristic analysis. Significant Spearman correlations between the FDG SUVR and the fALFF/ReHo were found in 98% of subjects. For the DMN-based biomarker, there was a significant decreasing trend for the preAD and CI groups compared to the NC group, whereas no significant difference in preAD based on whole-brain. The correlation ρ value for the FDG SUVR/ReHo showed the highest area under curve of the preAD classification (0.787). The results imply the coupling relationship changed during the preAD stage in the DMN area.

15.
High Alt Med Biol ; 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34324381

RESUMO

Wang, Luyao, Bo Zhou, Chenghui Yang, Shuya Pan, Yulan Huang, and Jinyu Wang. The effect of ultrahigh altitude on the mental health of civil servants in western China based on propensity score matching. High Alt Med Biol. 00:000-000, 2021. Objective: This study aims to analyze the net effect of ultrahigh altitude on the mental health of civil servants in western China after adjusting for sociodemographic factors. Methods: A cross-sectional study was performed to survey the mental health of 2,939 civil servants working at an altitude of more than 1,500 m in 13 areas of the Tibetan Qiang Autonomous Prefecture of Ngawa using the Insomnia Severity Index Questionnaire, 7-item Generalized Anxiety Disorder Scale, and Patient Health Questionnaire-9. Ultrahigh altitude refers to an area above 3,500 m above sea level, which may have an impact on the sleep and mood of residents. Therefore, our research was divided into two groups based on altitude (ultrahigh altitude >3,500 m; high altitude = 1,500-3,400 m). Propensity score matching (PSM) was used to control for sociodemographic factors and compare the differences in mental health between the two groups. Results: After kernel matching, the mean bias of the covariates was reduced from 21.6 to 1.8. The severity of insomnia, depression, and anxiety in civil servants at ultrahigh altitudes was still significantly greater than that in civil servants at high altitudes after controlling for sociodemographic factors, and the average treatment effects on the treated were 1.39, 1.35, and 0.80, respectively; the results were significant (α < 0.01). PSM regression analysis further showed that for every 100 m increase in altitude, the severity of anxiety, depression, and insomnia increased by 0.042 points (p < 0.001), 0.063 points (p < 0.001), and 0.070 points (p < 0.001), respectively, all of which were higher than those obtained with ordinary least squares regression. Conclusion: Ultrahigh altitude significantly increases the severity of insomnia, depression, and anxiety after adjusting for sociodemographic factors.

16.
Mol Pharm ; 18(7): 2634-2646, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34134485

RESUMO

Breast cancer was the leading cause of newly diagnosed cases of tumors in 2020, ranking as the second highest cause of female death. Chemotherapy remains the conventional treatment of choice for breast tumors in most clinical cases. However, it is often accompanied by a poor prognosis and severe side effects, resulting from an insufficient accumulation of the drug at tumor sites and an unsystematic distribution of the drug across the body. Inspired by the fact that breast tumor cells overexpress integrin α2ß1 on the surface, we designed and constructed an integrin α2ß1 targeting DGEA-modified liposomal doxorubicin (DGEA-Lipo-DOX) platform for application in breast cancer therapy. The DGEA-Lipo-DOX was stable with a uniform particle size of 121.1 ± 3.8 nm and satisfactory drug encapsulation. Demonstrated in vitro and in vivo, the constructed platform exhibited improved antitumor ability. The DGEA-Lipo-DOX showed 4-fold enhanced blood circulation and 6-fold increased accumulation of DOX at the tumor sites compared to those of free DOX, resulting in a significantly enhanced antitumor efficacy in tumor-bearing mice. A preliminary safety evaluation suggested that the systemic toxicity of DOX was relieved by DGEA-Lipo delivery. Collectively, binding integrin α2ß1 by DGEA may represent an alternative therapeutic strategy for potentially safer breast cancer treatment.

17.
Front Immunol ; 12: 658097, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093545

RESUMO

Clinical studies in a range of cancers have detected elevated levels of the Wnt antagonist Dickkopf-1 (DKK1) in the serum or tumors of patients, and this was frequently associated with a poor prognosis. Our analysis of DKK1 gene profile using data from TCGA also proves the high expression of DKK1 in 14 types of cancers. Numerous preclinical studies have demonstrated the cancer-promoting effects of DKK1 in both in vitro cell models and in vivo animal models. Furthermore, DKK1 showed the ability to modulate immune cell activities as well as the immunosuppressive cancer microenvironment. Expression level of DKK1 is positively correlated with infiltrating levels of myeloid-derived suppressor cells (MDSCs) in 20 types of cancers, while negatively associated with CD8+ T cells in 4 of these 20 cancer types. Emerging experimental evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. This review introduces the rapidly growing body of literature revealing the cancer-promoting and immune regulatory activities of DKK1. In addition, this review also predicts that by understanding the interaction between different domains of DKK1 through computational modeling and functional studies, the underlying functional mechanism of DKK1 could be further elucidated, thus facilitating the development of anti-DKK1 drugs with more promising efficacy in cancer immunotherapy.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Animais , Biomarcadores Tumorais , Gerenciamento Clínico , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunomodulação , Peptídeos e Proteínas de Sinalização Intercelular/química , Terapia de Alvo Molecular , Neoplasias/terapia , Prognóstico , Transdução de Sinais , Relação Estrutura-Atividade , Resultado do Tratamento , Via de Sinalização Wnt , beta Catenina/metabolismo
18.
J Agric Food Chem ; 69(23): 6665-6675, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34074097

RESUMO

Gut bacteria-derived enzymes play important roles in the metabolism of dietary fiber through enabling the hydrolysis of polysaccharides. In this study, we identified and characterized a 29 kDa novel acetyl xylan esterase, BTAxe1, from Bacteroides thetaiotaomicron VPI5482. Then, we solved the structure of BTAxe1 and performed the rational design. Mutants N65S and N65A increased the activities toward short-chain (pNPA, pNPB) to near four-fold, and gained the activities toward longer-chain substrate (pNPO). Molecular docking analysis showed that the mutant N65S had a larger substrate binding pocket than the wild type. Hydrolysis studies using natural substrates showed that either N65S or N65A showed higher activity of that of wild-type, yielding 131.31 and 136.09 mM of acetic acid from xylan. This is the first study on the rational design of gut bacteria-derived Axes with broadened substrate specificity and enhanced activity, which can be referenced by other acetyl esterases or gut-derived enzymes.


Assuntos
Bacteroides thetaiotaomicron , Acetilesterase/genética , Acetilesterase/metabolismo , Bacteroides thetaiotaomicron/genética , Simulação de Acoplamento Molecular , Especificidade por Substrato
19.
BMC Genomics ; 22(1): 443, 2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34120591

RESUMO

BACKGROUND: An evolutionary model using diploid and allotetraploid cotton species identified 80 % of non-coding transcripts in allotetraploid cotton as being uniquely activated in comparison with its diploid ancestors. The function of the lncRNAs activated in allotetraploid cotton remain largely unknown. RESULTS: We employed transcriptome analysis to examine the relationship between the lncRNAs and mRNAs of protein coding genes (PCGs) in cotton leaf tissue under abiotic stresses. LncRNA expression was preferentially associated with that of the flanking PCGs. Selected highly-expressed lncRNA candidates (n = 111) were subjected to a functional screening pilot test in which virus-induced gene silencing was integrated with abiotic stress treatment. From this low-throughput screen, we obtained candidate lncRNAs relating to plant height and tolerance to drought and other abiotic stresses. CONCLUSIONS: Low-throughput screen is an effective method to find functional lncRNA for further study. LncRNAs were more active in abiotic stresses than PCG expression, especially temperature stress. LncRNA XLOC107738 may take a cis-regulatory role in response to environmental stimuli. The degree to which lncRNAs are constitutively expressed may impact expression patterns and functions on the individual gene level rather than in genome-wide aggregate.


Assuntos
Gossypium , RNA Longo não Codificante , Secas , Regulação da Expressão Gênica de Plantas , Gossypium/genética , Filogenia , Proteínas de Plantas/genética , RNA Longo não Codificante/genética , Estresse Fisiológico/genética
20.
Cereb Cortex ; 31(10): 4427-4438, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-33973012

RESUMO

Somatotopy is an important guiding principle for sensory fiber organization in the primary somatosensory cortex (S1), which reflects tactile information processing and is associated with disease-related reorganization. However, it is difficult to measure the neuronal encoding scheme in S1 in vivo in normal participants. Here, we investigated the somatotopic map of the undominant hand using a Bayesian population receptive field (pRF) model. The model was established in hand space with between- and within-digit dimensions. In the between-digit dimension, orderly representation was found, which had low variability across participants. The pRF shape tended to be elliptical for digits with high spatial acuity, for which the long axis was along the within-digit dimension. In addition, the pRF width showed different change trends in the 2 dimensions across digits. These results provide new insights into the neural mechanisms in S1, allowing for in-depth investigation of somatosensory information processing and disease-related reorganization.

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