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1.
World J Clin Cases ; 9(26): 7682-7692, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34621819

RESUMO

BACKGROUND: There are no studies on the use of roxadustat in patients on regular peritoneal dialysis in China. AIM: To observe the efficacy and safety of roxadustat in treating renal anaemia in peritoneal dialysis patients. METHODS: Patients with renal anaemia who were regularly followed at the Peritoneal Dialysis Center of the First Affiliated Hospital of China Medical University from November 1, 2019 to June 30, 2020 were selected. A before-and-after self-control design was performed to retrospectively analyse the treatment effects on anaemia in patients treated with recombinant human erythropoietin (EPO) and roxadustat. RESULTS: A total of 31 patients with renal anaemia on long-term peritoneal dialysis treated with roxadustat were included. Haemoglobin (Hb) levels were maintained or increased in all patients (100%), and no patients had a decrease in Hb compared with the previous phase. Patients had a mean Hb of 86.2 ± 14.8 g/L with Hb compliance (Hb ≥ 110 g/L) of 16.1% during the EPO phase and a mean Hb of 112.4 ± 18.5 g/L with Hb compliance of 67.7% during the roxadustat phase. No major adverse cardiovascular events occurred in any patient. CONCLUSION: The application of roxadustat in peritoneal dialysis patients with renal anaemia can effectively improve the Hb compliance rate.

2.
Injury ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34625240

RESUMO

BACKGROUND: Chest trauma was the third most common cause of death in polytrauma patients, accounting for 25% of all deaths from traumatic injury. Chest trauma involves in injury to the bony thorax, intrathoracic organs and thoracic medulla. This study aimed to investigate the incidence, clinical characteristics, and outcome of polytrauma patients with pulmonary contusion, flail chest and upper thoracic spinal injury. METHODS: Patients who met inclusion criteria were divided into groups: Pulmonary contusion group (PC); Pulmonary contusion and flail chest group (PC + FC); Pulmonary contusion and upper thoracic spinal cord injury group (PC + UTSCI); Thoracic trauma triad group (TTT): included patients with flail chest, pulmonary contusion and the upper thoracic spinal cord injury coexisted. Outcomes were determined, including 30-day mortality and 6-month mortality. RESULTS: A total 84 patients (2.0%) with TTT out of 4176 polytrauma patients presented to Tongji trauma center. There was no difference in mean ISS among PC + FC group, PC + UTSCI group and TTT group. Patients with TTT had a longer ICU stay (21.4 days vs. 7.5 and 6.2; p<0.01), relatively higher 30-day mortality (40.5% vs. 6.0% and 4.3%; p<0.01), and especially higher 6-month mortality (71.4% vs. 6.5%, 13.0%; p<0.01), compared to patients with PC + FC or with PC + UTSCI. The leading causes of death for patients with TTT were ARDS (44.1%) and pulmonary infection (26.5%) during first 30 days after admission. For those patients who died later than 30 days during the 6 months, the predominant underlying cause of death was MOF (53.8%). CONCLUSIONS: Lethal triad of thoracic trauma (LTTT) were described in this study, which consisting of pulmonary contusion,flail chest and the upper thoracic spine cord injury. Like the classic "lethal triad", there was a synergy between the factors when they coexist, resulting in especially high mortality rates. Polytrauma patients with LTTT were presented relatively high 30-day mortality and 6 months mortality. We should pay much more attention to the patients with LTTT for further minimizing complications and mortality.

3.
Appl Opt ; 60(27): 8480-8484, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34612949

RESUMO

An all-fiber mode power splitter (MPS) for mode-division multiplexing (MDM) transmission is proposed and numerically investigated. The MPS is based on the configuration of the symmetric few-mode fiber (FMF) coupler, with the operation of four modes (LP01, LP11, LP21, and LP02). By comprehensively optimizing the FMF coupling parameters, including both the coupling area distance D and the coupling length L, MPSs with various power splitting ratios from 90%:10% to 50%:50% under the condition of different single guided mode injection are obtained. Then, the MPS with a 90%:10% power splitting ratio under the simultaneous injection of LP01, LP11, LP21, and LP02 modes is reported, which can be used as the mode tap for the optical performance monitoring. Moreover, based on the proposed MPS structure, selective mode power strippers with more than 25 dB mode extinction ratio for LP01, LP11, LP21, and LP02 modes are numerically verified. The arbitrary single guided mode arising in the FMF can be selectively coupled into another FMF, together with an insertion loss of less than 1 dB. Owing to the flexible setting of the mode power splitting ratio, the proposed MPS may become a potential solution to realizing system performance monitoring and mode power routing in MDM systems.

4.
Orthop Surg ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596359

RESUMO

OBJECTIVE: To design a novel blocking screws (BSs) geometry and insertion method to treat distal tibia fracture with nailing and comparison of mechanical properties of novel and traditional screws. METHODS: Twenty-one synthetic left tibiae were sectioned to obtain 21 distal segments measuring 55 mm. Intramedullary (IM) 9-mm tibial nails were advanced to 6 mm from the ankle joint. Two transverse and one anterior-posterior (AP) locking screws were inserted. Both medial-lateral (ML) BSs were placed 10 mm from the topmost interlocking screw. A custom-made jig assisted in placing the novel and traditional BSs. The time spent in placing each BS was recorded. All the samples were repaired with an IM nail and without BSs, with two traditional BSs, and with two novel BSs. An initial loading from -150 to +150 N was applied to specimens in the ML direction at 185 mm from the nail end, followed by cyclic loading of the same for 10,000 cycles with failure-to-test loading of 350 N in the ML direction. The maximum displacement was measured at 80 mm from the nail end and recorded under initial loading. The damage of two kinds of BSs to the nail was recorded. RESULTS: Compared with average 5.21 min of the time of placing a traditional BS, the time spent in positioning a novel BS on the fracture model was 2.53 min. In the distal bone-implant constructs (BICs), the addition of traditional BSs decreased the maximum displacement of the BICs by 26.2%. The addition of the novel BSs decreased the displacement by 28.9%. All constructs survived 10,000 cycles without hardware deformation. The failure rate of the control group was significantly greater than that of the traditional group; however, the novel group was similar to the traditional group. The damage of the traditional BS to the nail was greater than that of the novel one. CONCLUSIONS: The novel and traditional BSs are comparably effective for increasing the primary mechanical stability of distal metaphyseal fractures after nailin. However, compared to the placement of a traditional BS, implanting a novel BS took more less time and caused less damage to the nail. Additionally, the most obvious advantage of the novel BS design and insertion technology was that the pressure and distance between it and the IM nail could be controlled by rotating the screw. These advantages of the novel BS will be beneficial for clinical application.

5.
Materials (Basel) ; 14(19)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34639992

RESUMO

Basalt fiber has been widely used in asphalt mixture due to its excellent mechanical properties and good combination with asphalt. In order to systematically evaluate the enhancement effect of basalt fiber on the fatigue performance of the mixtures, gradations of Stone Mastic Asphalt and Superpave with different nominal maximum aggregate sizes, namely SMA-13, SUP-20 and SUP-25, were prepared, and a four-point bending beam fatigue test was adopted under the strain control mode. The fatigue damage mode was assessed based on the phenomenology theory, energy dissipation theory and change rate of dissipated energy. The results showed that basalt fiber could well increase the fatigue life of the mixtures. Basalt fiber could also increase the cumulative dissipated energy of the mixtures, and it was linearly correlated with the fatigue life in double logarithmic coordinates. In the meantime, adding basalt fiber could increase the change rate of dissipated energy of the mixtures. Furthermore, it is not appropriate to take the stiffness modulus declined to 50% of the original as the fatigue failure criterion of the mixture; this paper suggested that it is reasonable when the stiffness modulus was 15-25% that of the initial. These findings provide a theoretical basis for exploring the fatigue failure of asphalt pavements.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34643766

RESUMO

BACKGROUND: In the past few years, immunotherapy has changed the way we treat solid tumors. People pay more and more attention to the immune microenvironment of laryngeal squamous cell carcinoma (LSCC). In this study, our immunotherapy research took advantage of the clinical database and focused our in-depth analysis on the tumor microenvironment (TME). METHODS: This study evaluated the relationship between the clinical outcome and the local tissue and overall immune status in 412 patients with primary LSCC. We constructed and validated a risk model that could predict prognosis, assess immune status, identify high-risk patients, and develop personalized treatment plans through bioinformatics. In addition, through immunohistochemical analysis, we verified the differential expression of CTSL and KDM5D genes with the largest weight coefficients in the model in LSCC tissues and their influence on the prognosis and tumor-infiltrating lymphocytes (TILs). RESULTS: We found that interstitial tumor-infiltrating lymphocytes, tumor parenchymal-infiltrating lymphocyte volume, tumor infiltrates lymphocytes of frontier invasion, and the platelet-to-lymphocyte ratio (PLR) were independent factors affecting the prognosis of patients with LSCC. A novel risk model can guide clinicians to accurately predict prognosis, identify high-risk patients, and formulate personalized treatment plans. The differential expression of genes such as CTSL and KDM5D has a significant correlation with the TILs of LSCC and the prognosis of patients. CONCLUSION: Local and systemic inflammatory markers in patients with laryngeal squamous cell carcinoma are reliable prognostic factors. The risk model and CTSL, KDM5D gene have important potential research value.

7.
J Pharm Biomed Anal ; 206: 114389, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34601206

RESUMO

HKUST-1, a kind of metal-organic framework (MOF) composed by Cu2+ and trimesic acid, loaded on reduced graphene oxide and multi-walled carbon nanotubes nanocomposite [HKUST-1 @ (RGO-MWCNT)] was successfully synthesized by a facile and simple route. Then, a highly sensitive non-enzymatic salvianic acid A (SAA) electrochemical sensor was fabricated by modifying HKUST-1 @ (RGO-MWCNT) on a glassy carbon electrode, taking full advantage of the synergistic effect between the redox catalytic capacity of Cu2+ and the electrical conductivity of carbon materials. The sensor showed a low limit of detection of 0.081 µM, limit of quantitation of 0.27 µM, high sensitivity of 509.6 µA/mM and a good relationship between reduction peak current and concentration of SAA from 2 to 4600 µM. Meanwhile, the sensor had the advantages of repeatability and stability. Finally, it was used to detect SAA in real samples with noteworthy electroanalytical performance. In short, the sensor has considerable potential for the electroanalysis of SAA. Moreover, the study provides a promising composite of MOF and carbon materials with potential application in the analysis of effective components of herbaceous medicinal plants.


Assuntos
Grafite , Estruturas Metalorgânicas , Nanotubos de Carbono , Preparações Farmacêuticas , Técnicas Eletroquímicas
8.
Cancer Lett ; 524: 109-120, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34673127

RESUMO

Prostate cancer (PCa), especially castration-resistant PCa, is a common and fatal disease. circRNAs had been confirmed to affect the proliferation of a variety of malignant tumors. Exploring the role of circRNAs in PCa progression and discovering new therapeutic targets are of great importance for the treatment of PCa. In the present study, we found that the expression of circPFKP was significantly increased in PCa tissues compared with adjacent noncancerous prostate tissues, and was correlated with the D'Amico risk classification, N stage, and prognostic stage group of PCa. CircPFKP promotes the proliferation of PCa cells in vitro and in vivo. Suppressing circPFKP induced the G1/S arrest of PCa cells. Mechanistically, circPFKP interacted with IMPDH2, promoted the biogenesis of guanine nucleotides. Moreover, the replenishment of intracellular guanine nucleotides pool reverses the inhibitory effect of knocking-down circPFKP on PCa cell proliferation. hnRNPF might promote circPFKP generation by binding to flanking Alu elements. Our results identify a novel functional interaction of circPFKP with IMPDH2, which promotes the proliferation of PCa cells.

9.
Int J Hypertens ; 2021: 3275081, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646579

RESUMO

Objective: Preeclampsia (PE) is a severe complication in pregnancy and a leading cause of maternal and infant mortality. However, the exact underlying etiology of PE remains unknown. Emerging evidence indicates that the cause of PE is associated with genetic factors. Therefore, the aim of this study is to identify susceptibility genes to PE. Materials and Methods: Human Exome BeadChip assays were conducted using 370 cases and 482 controls and 21 loci were discovered. A further independent set of 958 cases and 1007 controls were recruited for genotyping to determine whether the genes of interest ROS1 and PTPRK are associated with PE. Immunohistochemistry was used for localization. Both qPCR and Western blotting were utilized to investigate the levels of PTPRK in placentas of 20 PE and 20 normal pregnancies. Results: The allele frequency of PTPRK rs3190930 differed significantly between PE and controls and was particularly significant in severe PE subgroup and early-onset PE subgroup. PTPRK is primarily localized in placental trophoblast cells. The mRNA and protein levels of PTPRK in PE were significantly higher than those in controls. Conclusion: These results suggest that PTPRK appears to be a previously unrecognized susceptibility gene for PE in Han Chinese women, and its expression is also associated with PE, while ROS1 rs9489124 has no apparent correlation with PE risk.

10.
Endocr Connect ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34678757

RESUMO

As a member of the seven-transmembrane rhodopsin-like G protein-coupled receptor superfamily, the melanocortin-3 receptor is vital for the regulation of energy homeostasis and rhythms synchronizing in mammals and its pharmacological effect could be directly influenced by the presence of melanocortin accessory proteins, MRAP1 and MRAP2. The tetrapod amphibian Xenopus laevis (xl) retains higher duplicated genome than extant teleosts and serves as an ideal model system for embryonic development and physiological studies. However, the melanocortin system of the Xenopus laevis has not been thoroughly evaluated yet. In this work, we performed sequence alignment, phylogenetic and synteny analysis of two xlMC3Rs. Co-immunoprecipitation and immunofluorescence assay further confirmed the co-localization and in vitro interaction of xlMC3Rs with xlMRAPs on the plasma membrane. Our results demonstrated that xlMRAP2.L/S could improve α-MSH stimulated xlMC3Rs signaling and suppress their surface expression. Moreover, xlMC3R.L showed a similar profile on the ligands and surface expression in the presence of xlMRAP1.L. Overall, the distinct pharmacological modulation of xlMC3R.L and xlMC3R.S by dual MRAP2 proteins elucidated the functional consistency of melanocortin system during genomic duplication of tetrapod vertebrates.

11.
Cancer Manag Res ; 13: 7263-7276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34584453

RESUMO

Introduction: The incidence of prostate cancer remains high worldwide, while exploring new therapeutic targets for prostate cancer is essential. Heterogeneous nuclear ribonucleoproteins have been proved to regulate tumorigeneses in various cancers. This study aimed to explore the role of HNRNPC in prostate cancer progression. Methods: HNRNPC expression and its correlation with clinical features and immune infiltration were analyzed by bioinformatics analysis. The effects of HNRNPC on prostate cell proliferation, migration, and invasion were accessed by EdU, colony formation, transwell, and wound-healing assays. Results: The expression level of HNRNPC was significantly increased in prostate cancer tissues and was correlated with the T stage, N stage, Gleason score, PSA level, residual tumors, overall survival, disease-specific survival, and progression-free interval of prostate cancer patients. Silencing HNRNPC inhibited the proliferation and metastasis of prostate cancer cells. The expression of HNRNPC was negatively correlated with the infiltration level of most immune cells in prostate cancer. Mechanistically, HNRNPC may function through regulating gene expression at the posttranscriptional level. Conclusion: HNRNPC could be a potential marker for the treatment and prognosis prediction of prostate cancer.

12.
J Gastrointest Oncol ; 12(4): 1601-1612, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34532114

RESUMO

Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide and has a high mortality rate. With the development of tumor molecular biology, more and more attention is being paid to the mechanisms of cell pathways in colorectal carcinogenesis, such as the Hippo/Yes-associated protein 1 (YAP1) and Wnt/ß-catenin signaling pathways. The abnormal expression of YAP1 and ß-catenin have been reported in CRC, and can lead to excessive cell proliferation, and eventually, tumor formation. Secreted frizzled-related protein 2 (SFRP2) levels have been found to be decreased in a variety of cancers, and SFRP2 is an antagonist that binds directly to Wnt signal. At present, the molecular basis of colorectal tumors is still not fully understood. In the present study, we sought to identify the molecular mechanisms underlying YAP1 and SFRP2 in the development of CRC. Methods: We constructed CRC cell lines that stably overexpressed YAP1 and SFRP2 using lentivirus packaging and cell infection. The levels of expression of the proteins were evaluated by western blot and immunofluorescence assays. Protein complex immunoprecipitation (Co-IP) was used to detect the interaction between YAP1, SFRP2, and ß-catenin. The functional roles of YAP1 and SFRP2 in CRC was determined by a Cell Counting Kit-8 (CCK8) proliferation assay and flow cytometric apoptosis assay. Results: The data of the present study showed that the overexpression of SFRP2 promoted the expression of YAP1 and ß-catenin protein, and the overexpression of YAP1 promoted the expression of ß-catenin protein. YAP1 overexpression promoted cell proliferation, while SFRP2 overexpression inhibited cell proliferation and promoted cell apoptosis. Conclusions: Our findings showed that the expression of YAP1, SFRP2, and ß-catenin is correlated in CRC cells. The Hippo pathway and Wnt pathway interact with each other in the pathogenesis of CRC, and YAP1 and SFRP2 are involved in the formation and development of CRC.

13.
Am J Physiol Renal Physiol ; 321(5): F617-F628, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34569253

RESUMO

The ligand-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating renal function. Activation of FXR by its specific agonists exerts renoprotective action in animals with acute kidney injury (AKI). In the present study, we aimed to identify naturally occurring agonists of FXR with potential as therapeutic agents in renal ischemia-reperfusion injury. In vitro and in vivo FXR activation was determined by a dual-luciferase assay, docking analysis, site-directed mutagenesis, and whole kidney transcriptome analysis. Wild-type (WT) and FXR knockout (FXR-/-) mice were used to determine the effect of potential FXR agonist on renal ischemia-reperfusion injury (IRI). We found that alisol B 23-acetate (ABA), a major active triterpenoid extracted from Alismatis rhizoma, a well-known traditional Chinese medicine, can activate renal FXR and induce FXR downstream gene expression in mouse kidney. ABA treatment significantly attenuated renal ischemia-reperfusion-induced AKI in WT mice but not in FXR-/- mice. Our results demonstrate that ABA can activate renal FXR to exert renoprotection against ischemia-reperfusion injury-induced AKI. Therefore, ABA may represent a potential therapeutic agent in the treatment of ischemic AKI.NEW & NOTEWORTHY In the present study, we found that alisol B 23-acetate (ABA), an identified natural farnesoid X receptor (FXR) agonist from the well-known traditional Chinese medicine Alismatis rhizoma, protects against ischemic acute kidney injury (AKI) in an FXR-dependent manner, as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative stress, and suppressed inflammatory factor expression. Therefore, ABA may have great potential as a novel therapeutic agent in the treatment of AKI in the future.

14.
Stem Cell Res ; 56: 102532, 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34509917

RESUMO

Akaluc, an enzyme engineered from luciferase, provides a potential powerful tool for tracing transplanted cells in vivo because of its near-infrared emission light. To enable evaluation of its potency, we inserted the Akaluc gene at AAVS1 locus using CRISPR/Cas9 technology and generated a clonal human embryonic stem stable cell line (Named H1-AAVS1-EF1α-Akaluc-KI or AkalucHES). AkalucHES could efficiently express Akaluc and were traced easily in vivo. We verified that AkalucHES expressed the pluripotency markers and showed normal stem cell morphology. Furthermore, AkalucHES maitains normal karyotype and is able to differentiate toward three germ-layer in vivo. So the Akaluc is effective for tracing transplanted cells in vivo.

15.
BMC Med ; 19(1): 190, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465315

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is a clinically aggressive disease with abundant variants that cause homologous recombination repair deficiency (HRD). Whether TNBC patients with HRD are sensitive to anthracycline, cyclophosphamide and taxane (ACT), and whether the combination of HRD and tumour immunity can improve the recognition of ACT responders are still unknown. METHODS: Data from 83 TNBC patients in The Cancer Genome Atlas (TCGA) was used as a discovery cohort to analyse the association between HRD and ACT chemotherapy benefits. The combined effects of HRD and immune activation on ACT chemotherapy were explored at both the genome and the transcriptome levels. Independent cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) were adopted to validate our findings. RESULTS: HRD was associated with a longer ACT chemotherapy failure-free interval (FFI) with a hazard ratio of 0.16 (P = 0.004) and improved patient prognosis (P = 0.0063). By analysing both HRD status and ACT response, we identified patients with a distinct TNBC subtype (ACT-S&HR-P) that showed higher tumour lymphocyte infiltration, IFN-γ activity and NK cell levels. Patients with ACT-S&HR-P had significantly elevated immune inhibitor levels and presented immune activation associated with the increased activities of both innate immune cells and adaptive immune cells, which suggested treatment with immune checkpoint blockade as an option for this subtype. Our analysis revealed that the combination of HRD and immune activation enhanced the efficiency of identifying responders to ACT chemotherapy (AUC = 0.91, P = 1.06e-04) and synergistically contributed to the clinical benefits of TNBC patients. A transcriptional HRD signature of ACT response-related prognostic factors was identified and independently validated to be significantly associated with improved survival in the GEO cohort (P = 0.0038) and the METABRIC dataset (P < 0.0001). CONCLUSIONS: These findings highlight that HR deficiency prolongs FFI and predicts intensified responses in TNBC patients by combining HRD and immune activation, which provides a molecular basis for identifying ACT responders.


Assuntos
Neoplasias de Mama Triplo Negativas , Antraciclinas , Ciclofosfamida , Humanos , Reparo de DNA por Recombinação , Taxoides , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética
16.
Cell Regen ; 10(1): 30, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34487238

RESUMO

Polycomb repressive complexes (PRCs) are essential in mouse gastrulation and specify neural ectoderm in human embryonic stem cells (hESCs), but the underlying molecular basis remains unclear. Here in this study, by employing an array of different approaches, such as gene knock-out, RNA-seq, ChIP-seq, et al., we uncover that EZH2, an important PRC factor, specifies the normal neural fate decision through repressing the competing meso/endoderm program. EZH2-/- hESCs show an aberrant re-activation of meso/endoderm genes during neural induction. At the molecular level, EZH2 represses meso/endoderm genes while SOX2 activates the neural genes to coordinately specify the normal neural fate. Moreover, EZH2 also supports the proliferation of human neural progenitor cells (NPCs) through repressing the aberrant expression of meso/endoderm program during culture. Together, our findings uncover the coordination of epigenetic regulators such as EZH2 and lineage factors like SOX2 in normal neural fate decision.

17.
J Chem Inf Model ; 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34494836

RESUMO

Toll-like receptor 3 (TLR3) is an endosomal receptor involved in initiating immune responses upon viral infection by directly recognizing double-stranded RNA (dsRNA). As one of the most heavily glycosylated TLR family members, the role of glycan at N413 of TLR3 in ligand recognition has been in debate for decades. Herein, to investigate the role of glycans in TLR3, specifically at amino acid residue N413, molecular dynamic simulations were performed. The loop region of LRR12 (residues 323-355), which protrudes from the dsRNA binding TLR3 lateral surface was found to be vital for interacting with dsRNA via the formation of hydrogen bonds. The glycan at N413 not only prevented dsRNA from being exposed to the bulk water during the binding process but further stabilized dsRNA in the TLR3 binding site. When N413 was in the glycosylated form, the binding free energy of TLR3 interacting with dsRNA was significantly lower than that of TLR3 in the N413 unglycosylated form. Additionally, as the glycan at N413 functioned to alter the dynamics of the dsRNA binding process, its flexibility was meanwhile influenced by dsRNA. In all, these results demonstrate that the size, length, and branch of glycan at N413 affect the thermodynamics and dynamics of TLR3 recognition with dsRNA. This study further extends our understanding of the biological role of glycans in the innate immune recognition of dsRNA by TLR3 and provides a new perspective for modulating TLR3 function.

18.
Am J Transl Res ; 13(8): 8575-8588, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539980

RESUMO

COVID-19 has swept quickly across the world with a worrisome death toll. SARS-CoV-2 infection induces cytokine storm, acute respiratory distress syndrome with progressive lung damage, multiple organ failure, and even death. In this review, we summarize the pathophysiologic mechanism of neutrophil extracellular traps (NETs) and hypoxia in three main phases, focused on lung inflammation and thrombosis. Furthermore, microparticle storm resulted from apoptotic blood cells are central contributors to the generation and propagation of thrombosis. We focus on microthrombi in the early stage and describe in detail combined antithrombotic with fibrinolytic therapies to suppress microthrombi evolving into clinical events of thrombosis. We further discuss pulmonary hypertension causing plasmin, fibrinogen and albumin, globulin extruding into alveolar lumens, which impedes gas exchange and induces severe hypoxia. Hypoxia in turn induces pulmonary hypertension, and amplifies ECs damage in this pathophysiologic process, which forms a positive feedback loop, aggravating disease progression. Understanding the mechanisms paves the way for current treatment of COVID-19 patients.

19.
Biochem Biophys Res Commun ; 578: 70-76, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34547626

RESUMO

Lung cancer is one of the most malignant and prevalent tumors and accounts for the vast majority of cancer death worldwide. However, the molecular mechanisms underlying lung cancer progression are poorly understood. Here, we reveal that both transcription and protein expression levels of Cox15 were increased in lung cancer. Nrf2 specifically binds to the Cox15 promoter and triggers Cox15 expression at the transcriptional level. Cox15 functions as a novel oncogene that facilitates lung cancer cell proliferation. Additionally, Aripiprazole, a potent inhibitor of Cox15, executives profoundly suppressive effects on lung cancers cells growth and tumor progression in vivo and in vitro through exerting therapeutic effects. Taken together, our results unravel that Cox15 holds great potential to act as a prognostic molecule for lung cancer patients' prognosis in the future.

20.
Org Biomol Chem ; 19(39): 8607-8612, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34569587

RESUMO

The chiral keto-substituted propargylamines are an essential class of multifunctional compounds in the field of organic and pharmaceutical synthesis and have attracted considerable attention, but the related synthetic approaches remain limited. Therefore, a concise and efficient method for the enantioselective synthesis of ß-keto propargylamines via chiral phosphoric acid-catalyzed asymmetric Mannich reaction between ß-keto acids and C-alkynyl N-Boc N,O-acetals as easily available C-alkynyl imine precursors has been demonstrated here, affording a broad scope of ß-keto N-Boc-propargylamines in high yields (up to 97%) with generally high enantioselectivities (up to 97 : 3 er).

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