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1.
Leukemia ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414485

RESUMO

U2AF1 is involved in the recognition of the 3' splice site during pre-mRNA splicing. Mutations in U2AF1 are frequently observed in myelodysplastic syndromes. However, the role of wild-type U2AF1 in normal hematopoiesis has remained elusive. Using a novel conditional U2af1 knockout allele, we have found that deletion of U2af1 results in profound defects in hematopoiesis characterized by pancytopenia, ablation of hematopoietic stem/progenitor cells (HSPC) leading to bone marrow failure and early lethality in mice. U2af1 deletion impairs HSPC function and repopulation capacity. U2af1 deletion also causes increased DNA damage and reduced survival in hematopoietic progenitors. RNA sequencing analysis reveals significant alterations in the expression of genes related to HSC maintenance, cell proliferation, and DNA damage response-related pathways in U2af1-deficient HSPC. U2af1 deficiency also induces splicing alterations in genes important for HSPC function. This includes altered splicing and perturbed expression of Nfya and Pbx1 transcription factors in U2af1-deficient HSPC. Collectively, these results suggest an important role for U2af1 in the maintenance and function of HSPC in normal hematopoiesis. A better understanding of the normal function of U2AF1 in hematopoiesis is important for development of appropriate therapeutic approaches for U2AF1 mutant induced hematologic malignancies.

2.
ACS Nano ; 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33448788

RESUMO

Compressible and superelastic 3D printed monoliths have shown great promise in various applications including energy storage, soft electronics, and sensors. Although such elastic monoliths have been constructed using some limited materials, most notably graphene, it has not yet been achieved in nature's most abundant material, cellulose, partly due to the strong hydrogen-bonding network within cellulose. Here, we report a 3D-printed cellulose nanofibril monolith that demonstrates superb elasticity (over 91% strain recovery after 500 cycles of compressive test), compressibility (up to 90% compressive strain), and pressure sensitivity (0.337 kPa-1) at 43% relative humidity. Such a high-performance CNF monolith is achieved through both hierarchical architecture design by 3D printing and freeze-drying and incorporation of hygroscopic salt for water absorption. The facile and efficient design strategy for a highly flexible CNF monolith is expected to expand to materials beyond cellulose and can realize much broader applications in flexible sensors, thermal insulation, and many other fields.

3.
Sci Rep ; 11(1): 40, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420124

RESUMO

Glypican-3 (GPC3) is a cell surface heparan sulfate proteoglycan that is being evaluated as an emerging therapeutic target in hepatocellular carcinoma (HCC). GPC3 has been shown to interact with several extracellular signaling molecules, including Wnt, HGF, and Hedgehog. Here, we reported a cell surface transmembrane protein (FAT1) as a new GPC3 interacting protein. The GPC3 binding region on FAT1 was initially mapped to the C-terminal region (Q14517, residues 3662-4181), which covered a putative receptor tyrosine phosphatase (RTP)-like domain, a Laminin G-like domain, and five EGF-like domains. Fine mapping by ELISA and flow cytometry showed that the last four EGF-like domains (residues 4013-4181) contained a specific GPC3 binding site, whereas the RTP domain (residues 3662-3788) and the downstream Laminin G-2nd EGF-like region (residues 3829-4050) had non-specific GPC3 binding. In support of their interaction, GPC3 and FAT1 behaved concomitantly or at a similar pattern, e.g. having elevated expression in HCC cells, being up-regulated under hypoxia conditions, and being able to regulate the expression of EMT-related genes Snail, Vimentin, and E-Cadherin and promoting HCC cell migration. Taken together, our study provides the initial evidence for the novel mechanism of GPC3 and FAT1 in promoting HCC cell migration.

4.
Clin Ther ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33454124

RESUMO

BACKGROUND: Henagliflozin, a novel selective inhibitor of sodium-glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus. PURPOSE: To evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers. METHODS: Two clinical studies were conducted. One was a single ascending dose (SAD) study (2.5-200 mg) involving 80 healthy subjects, and the other was a multiple ascending dose (MAD) study (1.25-100 mg for 10 days) involving 48 healthy subjects. The tolerability, PK profiles of henagliflozin and its main metabolites, and the urinary glucose excretion over 24 h were characterized in these 2 studies. FINDINGS: No serious adverse events were observed in the healthy subjects after single- and multiple-dose oral administration of henagliflozin, suggesting that this drug was well tolerated. Henagliflozin was rapidly absorbed, with a Tmax of 1.5-3 h, and then eliminated from plasma with a half-life of 11-15 h. It was not accumulated following once-daily oral administration. Plasma exposure of henagliflozin exhibited dose-proportional PK properties over the dose ranges of 2.5-200 mg (SAD) and 1.25-100 mg (MAD). The excretion of henagliflozin in urine was found to be very low, with 3.00%-5.13% of the dose. The glucuronide metabolites M5-1, M5-2 and M5-3 were the main metabolites detected in plasma samples, which accounted for up to 54.3%, 19.8%, and 27.5%, respectively, of the parent drug at steady state. Both the SAD and MAD studies demonstrated that the urinary glucose excretion over 24 h was dose-dependently increased and displayed saturation kinetics at >25 mg. No significant changes in the levels of serum glucose and urine electrolytes were found following a single or multiple doses of henagliflozin administration. IMPLICATIONS: Henagliflozin was well tolerated and showed predictable PK/PD profiles in these healthy subjects. Henagliflozin did not affect blood glucose level or urinary electrolyte excretion. It is best characterized for once-daily administration with a maximum dose of 25 mg. ChinaDrugTrials.org.cn identifiers: CTR20131986 and CTR20140132.

5.
J Med Chem ; 64(1): 677-694, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33370104

RESUMO

A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.

6.
Nanotechnology ; 32(6): 065502, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33086215

RESUMO

Catalytic and electrocatalytic applications of supported metal nanoparticles are hindered due to an aggregation of metal nanoparticles and catalytic leaching under harsh operations. Hence, stable and leaching free catalysts with high surface area are extremely desirable but also challenging. Here we report a gold nanoparticles-hosted mesoporous nitrogen doped carbon matrix, which is prepared using bovine serum albumin (BSA) through calcination. BSA plays three roles in this process as a reducing agent, capping agent and carbon precursor, hence the protocol exhibits economic and sustainable. Gold nanoparticles at N-doped BSA carbon (AuNPs@NBSAC)-modified three-electrode strip-based flexible sensor system has been developed, which displayed effective, sensitive and selective for simultaneous detection of uric acid (UA) and dopamine (DA). The AuNPs@NBSAC-modified sensor showed an excellent response toward DA with a linear response throughout the concentration range from 1 to 50 µM and a detection limit of 0.05 µM. It also exhibited an excellent response toward UA, with a wide detection range from 5 to 200 µM as well as a detection limit of 0.1 µM. The findings suggest that the AuNPs@NBSAC nanohybrid reveals promising applications and can be considered as potential electrode materials for development of electrochemical biosensors.

7.
Biomaterials ; 267: 120454, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33160122

RESUMO

The development of tumor acidic microenvironment-responsive theranostic agents is a research hotspot. Herein, we developed highly photostable amphiphilic croconium dye-anchored red blood cell membrane vesicle (denoted as LET-5) for tumor pH-responsive near-infrared fluorescence (NIRF) and photoacoustic (PA) duplex imaging-guided photothermal therapy. In tumor acidic microenvironment, both NIRF and PA signals of LET-5 were significantly enhanced and the photothermal effect of LET-5 was activated. Notably, cell membrane-based vesicle with enhanced stability and long blood circulation significantly improved the tumor accumulation of croconium dye, thus achieving better therapeutic effect than free croconium dye. These findings provide a promising approach to construct amphiphilic dye-anchored cell membrane vesicle for cancer theranostics.

8.
IEEE Trans Image Process ; 30: 617-627, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33232230

RESUMO

Cross-modal retrieval aims to identify relevant data across different modalities. In this work, we are dedicated to cross-modal retrieval between images and text sentences, which is formulated into similarity measurement for each image-text pair. To this end, we propose a Cross-modal Relation Guided Network (CRGN) to embed image and text into a latent feature space. The CRGN model uses GRU to extract text feature and ResNet model to learn the globally guided image feature. Based on the global feature guiding and sentence generation learning, the relation between image regions can be modeled. The final image embedding is generated by a relation embedding module with an attention mechanism. With the image embeddings and text embeddings, we conduct cross-modal retrieval based on the cosine similarity. The learned embedding space well captures the inherent relevance between image and text. We evaluate our approach with extensive experiments on two public benchmark datasets, i.e., MS-COCO and Flickr30K. Experimental results demonstrate that our approach achieves better or comparable performance with the state-of-the-art methods with notable efficiency.

9.
Tree Physiol ; 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33367887

RESUMO

Fruit semi-russeting is an undesirable quality trait that occurs in fruit production. It is reported that preharvest fruit bagging could effectively alleviate fruit exocarp semi-russeting, but the physiological and molecular mechanisms remain unclear. In the present study, we performed an in-depth investigation into pear fruit semi-russeting from morphologic, metabolic and transcriptomic perspectives by comparing control (semi-russeted) and bagged (non-russeted) 'Cuiguan' pear fruits. The results showed that significant changes in cutin and suberin resulted in pear fruit semi-russeting. Compared with the skin of bagged fruits, the skin of the control fruits presented reduced cutin contents accompanied by an accumulation of suberin, which resulted in fruit semi-russeting; α, ω-dicarboxylic acids accounted for the largest proportion of typical suberin monomers. Moreover, combined transcriptomic and metabolic analysis revealed a series of genes involved in cutin and suberin biosynthesis, transport and polymerization differentially expressed between the two groups. Furthermore, the expression levels of genes involved in the stress response and in hormone biosynthesis and signaling were significantly altered in fruits with contrasting phenotypes. Finally, a number of transcription factors, including those of the MYB, NAC, bHLH and bZIP families, were differentially expressed. Taken together, the results suggest that the multilayered mechanism through which bagging alleviates pear fruit semi-russeting is complex, and the large number of candidate genes identified provides a good foundation for future functional studies.

10.
Front Cell Infect Microbiol ; 10: 535940, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363046

RESUMO

Objective: The gut microbiota is associated with nonalcoholic fatty liver disease (NAFLD). We isolated the Escherichia coli strain NF73-1 from the intestines of a NASH patient and then investigated its effect and underlying mechanism. Methods: 16S ribosomal RNA (16S rRNA) amplicon sequencing was used to detect bacterial profiles in healthy controls, NAFLD patients and NASH patients. Highly enriched E. coli strains were cultured and isolated from NASH patients. Whole-genome sequencing and comparative genomics were performed to investigate gene expression. Depending on the diet, male C57BL/6J mice were further grouped in normal diet (ND) and high-fat diet (HFD) groups. To avoid disturbing the bacterial microbiota, some of the ND and HFD mice were grouped as "bacteria-depleted" mice and treated with a cocktail of broad-spectrum antibiotic complex (ABX) from the 8th to 10th week. Then, E. coli NF73-1, the bacterial strain isolated from NASH patients, was administered transgastrically for 6 weeks to investigate its effect and mechanism in the pathogenic progression of NAFLD. Results: The relative abundance of Escherichia increased significantly in the mucosa of NAFLD patients, especially NASH patients. The results from whole-genome sequencing and comparative genomics showed a specific gene expression profile in E. coli strain NF73-1, which was isolated from the intestinal mucosa of NASH patients. E. coli NF73-1 accelerates NAFLD independently. Only in the HFD-NF73-1 and HFD-ABX-NF73-1 groups were EGFP-labeled E. coli NF73-1 detected in the liver and intestine. Subsequently, translocation of E. coli NF73-1 into the liver led to an increase in hepatic M1 macrophages via the TLR2/NLRP3 pathway. Hepatic M1 macrophages induced by E. coli NF73-1 activated mTOR-S6K1-SREBP-1/PPAR-α signaling, causing a metabolic switch from triglyceride oxidation toward triglyceride synthesis in NAFLD mice. Conclusions: E. coli NF73-1 is a critical trigger in the progression of NAFLD. E. coli NF73-1 might be a specific strain for NAFLD patients.

11.
Physiol Behav ; : 113284, 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33309703

RESUMO

The aims of the study were (1) to compare oral physiology, anatomy and food oral processing behavior of consumers by age (Chinese young adults vs Chinese older adults) and by ethnicity (Chinese (Asian) vs. Dutch (Caucasian)) and (2) to explore relationships between oral physiology, anatomy and food oral processing behavior of Chinese consumers. Oral physiology (mastication performance, saliva flow rate and dental status) and anatomy (volume of oral cavity, tongue dimensions, facial anthropometry, height and weight) were determined in Chinese (Asian) young adults (n=32; 18-30 yrs) and Chinese (Asian) older adults (n=32; 60-85 yrs) and compared to previously determined oral physiology and anatomy of Dutch (Caucasian) young adults (n=32; 18-30 yrs) and Dutch (Caucasian) older adults (n=32; 65-85 yrs). Oral processing behavior (consumption time, chews per bite, bite size, eating rate) of solid foods (cooked carrot, sausage and tofu-gan) was quantified using video recordings. Regarding the effect of age on physiology, anatomy and food oral processing behavior, Chinese (Asian) older adults consumed all foods with lower eating rates compared to Chinese (Asian) young adults probably due to changes in oral physiology and anatomy. Regarding the effect of ethnicity on oral physiology, anatomy and food oral processing behavior, Chinese (Asians) had lower percentages of normal occlusion, slightly wider and shorter tongues, lower head height:width ratio and lower BMI compared to Dutch (Caucasians). Overall, Chinese adults displayed similar food oral processing behavior compared to Dutch adults. Consumption time, chews per bite and bite size did not differ between Chinese and Dutch adults. Only a small difference in eating rate were observed between these groups. Body weight and number of teeth were the physiological and anatomical parameters that related the strongest with oral processing behavior of solid foods. We conclude that age and ethnicity impact oral physiology, anatomy and oral processing behavior of solid foods. Oral physiology and anatomy only partially explain the variation in oral processing behavior of solid foods in consumer groups differing in ethnicity and age. Other factors such as culture and consumption habits are suggested to have a stronger influence on oral processing behavior.

12.
J Hazard Mater ; 405: 124689, 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33278724

RESUMO

Bauxite residue discharged to disposal areas, which could generate environmental pollution issues. Long-term natural restoration may improve the physicochemical properties of the residues, in turn supporting vegetation establishment, and effectively managing pollution. Nevertheless, the effects of short-term human intervention on soil formation in the weathered disposal areas are still relatively unknown. Thus, residue samples with different depths from different regions including no vegetation, sparse vegetation, complete vegetation coverage, and complete vegetation coverage following sewage sludge treatment were selected to analyze microbial community using Illumina high-throughput sequencing technology and evaluate soil formation process. Long-term weathering changed pH, the fraction of water-stable aggregates and nutrient concentrations, whilst promoting Proteobacteria, Chloroflexi, Acidobacteria and Planctomycete populations. Sewage sludge addition enhanced aggregate stability and significantly changed microbial community diversity. Sewage sludge application enriched the relative abundances of Proteobacteria and Bacteroidetes, whilst decreasing the relative abundance of Acidobacteria, which may be due to variation in environmental factors. Canonical correspondence analysis revealed that pH and EC were the main factors affecting microbial structure, followed by organic carbon content and aggregate stability. The results enhance the understanding of soil formation in bauxite residue and reveal the potential benefit of human intervention in ecological reconstruction at disposal areas.

13.
Molecules ; 25(23)2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33256251

RESUMO

Astragali Radix total flavonoids (ARTF) is one of the main bioactive components of Astragali Radix (AR), and has many pharmacological effects. However, its metabolism and effective forms remains unclear. The HPLC-DAD-ESI-IT-TOF-MSn technique was used to screen and tentatively identify the in vivo original constituents and metabolites of ARTF and to clarify their distribution in rats after oral administration. In addition, modern chromatographic methods were used to isolate the main metabolites from rat urine and NMR spectroscopy was used to elucidate their structures. As a result, 170 compounds (23 original constituents and 147 metabolites) were tentatively identified as forms existing in vivo, 13 of which have the same pharmacological effect with ARTF. Among 170 compounds, three were newly detected original constituents in vivo and 89 were new metabolites of ARTF, from which 12 metabolites were regarded as new compounds. Nineteen original constituents and 65 metabolites were detected in 10 organs. Four metabolites were isolated and identified from rat urine, including a new compound (calycoisn-3'-O-glucuronide methyl ester), a firstly-isolated metabolite (astraisoflavan-7-O-glucoside-2'-O-glucuronide), and two known metabolites (daidzein-7-O-sulfate and calycosin-3'-O-glucuronide). The original constituents and metabolites existing in vivo may be material basis for ARTF efficacy, and these findings are helpful for further clarifying the effective forms of ARTF.

14.
J Affect Disord ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33257043

RESUMO

BACKGROUND: Growing evidence supports a clear association between COVID-19 pandemic and mental health. However, little is known about the longitudinal course of psychopathology in young adults at different stages of the pandemic. METHODS: This large-scale, longitudinal, population-based survey was conducted among college students in China. The rates of three mental health problems (acute stress, anxiety, and depressive symptoms), and their change patterns at two phases of the pandemic (early vs under-control) were measured. Predictors of changes in mental health symptoms were examined utilizing multivariate regression. RESULTS: Among the 164,101 college students who participated in the first wave survey (T1=during onset of outbreak), 68,685 (41.9%) completed a follow-up survey (T2=during remission). In the follow-up survey, the prevalence of probable acute stress (T1: 34.6%; T2: 16.4%) decreased, while the rates of depressive (T1: 21.6%; T2: 26.3%) and anxiety symptoms (T1: 11.4%; T2: 14.7%) increased. Senior students, with suspected or conformed cases in their community and COVID-19 related worries (all AORs > 1.20, ps < 0.001) were found to have a higher risk of developing mental health problems in at least one wave. Less physical exercise, low perceived social support, and a dysfunctional family were found to negatively impact psychological symptoms. CONCLUSIONS: Acute stress, anxiety, and depressive symptoms have been prevalent among college students during the COVID-19 epidemic, and showed a significant increase after the initial stage of the outbreak. Some college students, especially those with the risk factors noted above, exhibited persistent or delayed symptoms.

15.
BMC Genomics ; 21(Suppl 6): 500, 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33349238

RESUMO

BACKGROUND: Next-generation sequencing (NGS) enables unbiased detection of pathogens by mapping the sequencing reads of a patient sample to the known reference sequence of bacteria and viruses. However, for a new pathogen without a reference sequence of a close relative, or with a high load of mutations compared to its predecessors, read mapping fails due to a low similarity between the pathogen and reference sequence, which in turn leads to insensitive and inaccurate pathogen detection outcomes. RESULTS: We developed MegaPath, which runs fast and provides high sensitivity in detecting new pathogens. In MegaPath, we have implemented and tested a combination of polishing techniques to remove non-informative human reads and spurious alignments. MegaPath applies a global optimization to the read alignments and reassigns the reads incorrectly aligned to multiple species to a unique species. The reassignment not only significantly increased the number of reads aligned to distant pathogens, but also significantly reduced incorrect alignments. MegaPath implements an enhanced maximum-exact-match prefix seeding strategy and a SIMD-accelerated Smith-Waterman algorithm to run fast. CONCLUSIONS: In our benchmarks, MegaPath demonstrated superior sensitivity by detecting eight times more reads from a low-similarity pathogen than other tools. Meanwhile, MegaPath ran much faster than the other state-of-the-art alignment-based pathogen detection tools (and compariable with the less sensitivity profile-based pathogen detection tools). The running time of MegaPath is about 20 min on a typical 1 Gb dataset.

16.
Am J Nucl Med Mol Imaging ; 10(5): 212-225, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224617

RESUMO

High liver uptake presents a problem for 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) as a radiotracer for imaging cellular proliferation in the liver with positron emission tomography (PET). This investigation re-visited some issues related to the high liver background uptake of [18F]FLT with an animal model of woodchucks. Several enzymes involved in the hepatic catabolism of FLT, thymidine phosphorylase (TP, TYMP), uridine 5'-diphospho-glucuronosyl-transferases (UDP-GTs, short for UGTs), and ß-glucuronidase (GUSB), their homology as well as hepatic expression between the human and the woodchuck was examined. Inhibitors of these enzymes, TP inhibitor (TPI) tipiracil hydrochloride, UGT inhibitor probenecid, ß-glucuronidase inhibitor L-aspartate, were administered to the animals at human equivalent doses either intravenously (i.v.) and orally before the injection of tracer-dose [18F]FLT for PET imaging to examine any changes in liver uptake. Liver tissue samples were harvested from the animals after PET imaging and used to perform polymerase chain reaction (PCR) for TP expression or assays for enzymatic activities of TP and ß-glucuronidase. Non-radiolabeled (cold) FLT was also applied for enzyme saturation. Animals administered with TPI displayed lower radioactivity in the liver in comparison with the baseline scan. The application of probenecid did not change [18F]FLT liver uptake even though it reduced renal uptake. L-aspartate reduced the liver background uptake of [18F]FLT slightly. The application of cold FLT reduced overall uptake of [18F]FLT including the liver background. Therefore, the combined application of cold FLT and [18F]FLT merits further clinical investigation for reducing liver background uptake of [18F]FLT.

17.
Front Pharmacol ; 11: 590929, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192531

RESUMO

Amygdalin, the main component of Prunus persica (L.) Stokes, has been used to treat atherosclerosis in mouse model due to its anti-inflammatory role. However, the underlying mechanism remains poorly understood. This study aimed to evidence the influence of amygdalin on high-fat diet-induced atherosclerosis in ApoE knock-out (ApoE-/-) mice, and unravel its anti-inflammatory mechanism. ApoE-/- mice fed with high-fat diet for eight weeks were randomly divided into four groups and injected with amygdalin at the concentration of 0.08 or 0.04 mg/kg for 12 weeks. Additionally, bone marrow-derived macrophages were intervened with oxidized low-density lipoprotein (oxLDL) or lipopolysaccharide plus various concentrations of amygdalin for further exploration. Body weight, serum lipid profiles and inflammatory cytokines were detected by ELISA, gene expression by RT-PCR, plaque sizes by Oil Red O, lymphatic vessels of heart atrium and Tnfα production by immunofluorescence staining. MAPKs, AP-1 and NF-κB p65 pathways were also explored. Amygdalin decreased body weight, serum lipids, plaque size, lymphatic vessels and inflammatory cytokines (Il-6, Tnfα), Nos1 and Nos2, and increased Il-10 expression in ApoE-/- mice. In oxLDL-induced bone marrow-derived macrophages, amygdalin reduced inflammatory cytokines (Il-6, Tnfα), Nos1 and Nos2, and increased Il-10 production. These effects were associated with the decreased phosphorylation of Mapk1, Mapk8, Mapk14, Fos and Jun, and the translocation of NF-κB p65 from nucleus to cytoplasm. The results suggested that amygdalin could attenuate atherosclerosis and play an anti-inflammatory role via MAPKs, AP-1 and NF-κB p65 signaling pathways in ApoE-/- mice and oxLDL-treated bone marrow-derived macrophages.

18.
Front Bioeng Biotechnol ; 8: 594491, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33195164

RESUMO

Photodynamic therapy (PDT) is already (Food and Drug Administration) FDA approved and used in the clinic for oncological treatment of pancreatic, lung, esophagus, bile duct, and of course several cancers of skin. It is an important tool in the oncological array of treatments, but for it exist several shortcomings, the most prominent of which is the shallow depth penetration of light within tissues. One-way researchers have attempted to circumvent this is through the creation of self-exciting "auto-PDT" nanoplatforms, which do not require the presence of an external light source to drive the PDT process. Instead, these platforms are driven either through oxidative chemical excitation in the form of chemiluminescence or radiological excitation from beta-emitting isotopes in the form of Cherenkov luminescence. In both, electronic excitations are generated and then transferred to the photosensitizer (PS) via Resonance Energy Transfer (RET) or Cherenkov Radiation Energy Transfer (CRET). Self-driven PDT has many components, so in this review, using contemporary examples from literature, we will breakdown the important concepts, strategies, and rationale behind the design of these self-propagating PDT nanoplatforms and critically review the aspects which make them successful and different from conventional PDT. Particular focus is given to the mechanisms of excitation and the different methods of transfer of excited electronic energy to the photosensitizer as well as the resulting therapeutic effect. The papers reviewed herein will be critiqued for their apparent therapeutic efficiency, and a basic rationale will be developed for what qualities are necessary to constitute an "effective" auto-PDT platform. This review will take a biomaterial engineering approach to the review of the auto-PDT platforms and the intended audience includes researchers in the field looking for a new perspective on PDT nanoplatforms as well as other material scientists and engineers looking to understand the mechanisms and relations between different parts of the complex "auto-PDT" system.

19.
Cell Biol Toxicol ; 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33130971

RESUMO

Inflammatory bowel disease (IBD) is a chronic idiopathic disorder causing inflammation in the gastro-intestinal tract, which is lack of effective drug targets and medications. To identify novel therapeutic agents against consistent targets, we exploited a systems pharmacology-driven framework that incorporates drug-target networks of natural product and IBD disease genes. Our in silico approach found that Ligustilide (LIG), one of the major active components of Angelica acutiloba and Cnidium Officinale, potently attenuated IBD. The following in vivo and in vitro results demonstrated that LIG prevented experimental mice colitis induced by dextran sulfate sodium (DSS) via suppressing inflammatory cell infiltration, the activity of MPO and iNOS, and the expression and production of IL-1ß, IL-6, and TNF-α. Subsequently, the network analysis helped to validate that LIG alleviated colitis by inhibiting NF-κB and MAPK/AP-1 pathway through activating PPARγ, which were further confirmed in RAW 264.7 cells and bone marrow-derived macrophages in vitro. In summary, this study reveals that LIG activated PPARγ to inhibit the activation of NF-κB and AP-1 signaling thus eventually alleviated DSS-induced colitis, which has promising activities and may serve as a candidate for the treatment of IBD.Graphical abstract This study suggested novel computational and experimental pharmacology approaches to identify potential IBD therapeutic agents by exploiting polypharmacology of natural products. We demonstrated that LIG could attenuate inflammation in IBD by inhibiting NF-κB and AP-1 pathways via PPARγ activation to reduce the expression of pro-inflammatory cytokines in macrophages. These findings offer comprehensive pre-clinical evidence that LIG may serve as a promising candidate for IBD therapy in the future. Graphical headlights: 1. Systems pharmacology uncovered Ligustilide attenuates experimental colitis in mice. 2. Network-based analysis predicted the mechanism of Ligustilide against IBD, which was validated by inhibiting PPARγ-mediated inflammation pathways. 3. Ligustilide activated PPARγ to inhibit NF-κB and AP-1 activation thus eventually alleviated DSS-induced colitis.4. Ligustilide has promising activities and may serve as a candidate for the treatment of IBD.

20.
FASEB J ; 2020 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-33161580

RESUMO

Exosomes are important transporters of miRNAs, which play varying roles in the healing of the bone fracture. Angiogenesis is one of such critical events in bone healing, and we previously reported the stimulatory effect of mechanical loading in vessel remodeling. Focusing on type H vessels and exosomal miR-214-3p, this study examined the mechanism of loading-driven angiogenesis. MiRNA sequencing and qRT-PCR revealed that miR-214-3p was increased in the exosomes of the bone-losing ovariectomized (OVX) mice, while it was significantly decreased by knee loading. Furthermore, compared to the OVX group, exosomes, derived from the loading group, promoted the angiogenesis of endothelial cells. In contrast, exosomes, which were transfected with miR-214-3p, decreased the angiogenic potential. Notably, knee loading significantly improved the microvascular volume, type H vessel formation, and bone mineral density and contents, as well as BV/TV, Tb.Th, Tb.N, and Tb.Sp. In cell cultures, the overexpression of miR-214-3p in endothelial cells reduced the tube formation and cell migration. Collectively, this study demonstrates that knee loading promotes angiogenesis by enhancing the formation of type H vessels and downregulating exosomal miR-214-3p.

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