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1.
Methods Mol Biol ; 2366: 3-17, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34236629

RESUMO

Posttranslational modifications of NF-κB, including phosphorylation, acetylation, and methylation, have emerged as important regulatory mechanisms to control the transcriptional outcomes of this important transcription factor. These modifications work independently, sequentially or in combination to modulate the diverse biological functions of NF-κB in cancer and inflammatory response. Here, we describe some experimental methods to detect the in vitro and in vivo phosphorylation and acetylation of NF-κB, specifically focusing on the RelA subunit of NF-κB. These methods include labeling the phospho- or acetyl- groups with radioisotopes in vitro and immunoblotting with site-specific anti-phospho-serine or acetyl-lysine antibodies in culture cells and tissue samples.

2.
J Med Chem ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34236840

RESUMO

Triple-negative breast cancer (TNBC) is a lethal malignancy without safe and effective therapeutic drugs. In this study, the anti-TNBC bioassay-guided isolation of the medicinal plant Croton kongensis followed by the structural modification led to the construction of a small ent-kaurane diterpenoid library (1-25). With subsequent biological screening, 20 highly potent compounds (IC50s < 3 µM) were identified. Among them, 8,9-seco-ent-kaurane 6 displayed comparable activity (IC50s ∼ 80 nM) to doxorubicin but with better selectivity. The analysis of structure-activity relationships suggested that the cleavage of the C8-C9 bond and the presence of α,ß-unsaturated ketone moiety were essential for the activity. The mechanistic study revealed that 6 induced apoptosis, autophagy, and metastasis suppression in TNBC cells via inhibition of Akt. In vivo, 6 significantly suppressed the TNBC tumor growth without causing side effects. All these results suggested that 6 may serve as a promising lead for the development of novel anti-TNBC agents in the future.

3.
Nat Prod Res ; : 1-6, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34241556

RESUMO

A new C19-diterpenoid alkaloid named gyalanutine A (1) and fourteen known compounds 2-15 were isolated from the plant of Delphinium gyalanum C. Marquand & Airy Shaw. Compound 1 displayed an unusual lycoctonine-type C19-diterpenoid alkaloid skeleton with the cleavage of N-C19 and C7-C17 bonds, and the construction of the N-C7 bond. Structures were identified by multiple spectroscopic analyses including 1 D, 2 D NMR, IR and HR-ESI-MS. Compounds were tested for acetylcholinesterase inhibitory and anti-inflammatory activity.

4.
Sci China Life Sci ; 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34258712

RESUMO

While precision medicine driven by genome sequencing has revolutionized cancer care, such as lung cancer, its impact on gastric cancer (GC) has been minimal. GC patients are routinely treated with chemotherapy, but only a fraction of them receive the clinical benefit. There is an urgent need to develop biomarkers or algorithms to select chemo-sensitive patients or apply targeted therapy. Here, we carried out retrospective analyses of 1,020 formalin-fixed, paraffin-embedded GC surgical resection samples from 5 hospitals and developed a mass spectrometry-based workflow for proteomic subtyping of GC. We identified two proteomic subtypes: the chemo-sensitive group (CSG) and the chemo-insensitive group (CIG) in the discovery set. The 5-year overall survival of CSG was significantly improved in patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (64.2% vs. 49.6%; Cox P-value=0.002), whereas no such improvement was observed in CIG (50.0% vs. 58.6%; Cox P-value=0.495). We validated these results in an independent validation set. Further, differential proteome analysis uncovered 9 FDA-approved drugs that may be applicable for targeted therapy of GC. A prospective study is warranted to test these findings for future GC patient care.

5.
PLoS Pathog ; 17(7): e1009769, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34265026

RESUMO

The virulence evolution of multiple infections of parasites from the same species has been modeled widely in evolution theory. However, experimental studies on this topic remain scarce, particularly regarding multiple infections by different parasite species. Here, we characterized the virulence and community dynamics of fungal pathogens on the invasive plant Ageratina adenophora to verify the predictions made by the model. We observed that A. adenophora was highly susceptible to diverse foliar pathogens with mixed vertical and horizontal transmission within leaf spots. The transmission mode mainly determined the pathogen community structure at the leaf spot level. Over time, the pathogen community within a leaf spot showed decreased Shannon diversity; moreover, the vertically transmitted pathogens exhibited decreased virulence to the host A. adenophora, but the horizontally transmitted pathogens exhibited increased virulence to the host. Our results demonstrate that the predictions of classical models for the virulence evolution of multiple infections are still valid in a complex realistic environment and highlight the impact of transmission mode on disease epidemics of foliar fungal pathogens. We also propose that seedborne fungi play an important role in structuring the foliar pathogen community from multiple infections within a leaf spot.

6.
Lancet Oncol ; 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34252374

RESUMO

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

7.
Cell Death Dis ; 12(7): 665, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215721

RESUMO

It has been reported that growth differentiation factor 11 (GDF11) protects against myocardial ischemia/reperfusion (IR) injury, but the underlying mechanisms have not been fully clarified. Considering that GDF11 plays a role in the aging/rejuvenation process and that aging is associated with telomere shortening and cardiac dysfunction, we hypothesized that GDF11 might protect against IR injury by activating telomerase. Human plasma GDF11 levels were significantly lower in acute coronary syndrome patients than in chronic coronary syndrome patients. IR mice with myocardial overexpression GDF11 (oe-GDF11) exhibited a significantly smaller myocardial infarct size, less cardiac remodeling and dysfunction, fewer apoptotic cardiomyocytes, higher telomerase activity, longer telomeres, and higher ATP generation than IR mice treated with an adenovirus carrying a negative control plasmid. Furthermore, mitochondrial biogenesis-related proteins and some antiapoptotic proteins were significantly upregulated by oe-GDF11. These cardioprotective effects of oe-GDF11 were significantly antagonized by BIBR1532, a specific telomerase inhibitor. Similar effects of oe-GDF11 on apoptosis and mitochondrial energy biogenesis were observed in cultured neonatal rat cardiomyocytes, whereas GDF11 silencing elicited the opposite effects to oe-GDF11 in mice. We concluded that telomerase activation by GDF11 contributes to the alleviation of myocardial IR injury through enhancing mitochondrial biogenesis and suppressing cardiomyocyte apoptosis.

8.
Electrophoresis ; 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34278592

RESUMO

Biological cells in vivo typically reside in a dynamic flowing microenvironment with extensive biomechanical and biochemical cues varying in time and space. These dynamic biomechanical and biochemical signals together act to regulate cellular behaviors and functions. Microfluidic technology is an important experimental platform for mimicking extracellular flowing microenvironment in vitro. However, most existing microfluidic chips for generating dynamic shear stress and biochemical signals require expensive, large peripheral pumps and external control systems, unsuitable for being placed inside cell incubators to conduct cell biology experiments. This study has developed a microfluidic generator of dynamic shear stress and biochemical signals based on autonomously oscillatory flow. Further, based on the lumped-parameter and distributed-parameter models of multiscale fluid dynamics, the oscillatory flow field and the concentration field of biochemical factors has been simulated at the cell culture region within the designed microfluidic chip. Using the constructed experimental system, the feasibility of the designed microfluidic chip has been validated by simulating biochemical factors with red dye. The simulation results demonstrate that dynamic shear stress and biochemical signals with adjustable period and amplitude can be generated at the cell culture chamber within the microfluidic chip. The amplitudes of dynamic shear stress and biochemical signals is proportional to the pressure difference and inversely proportional to the flow resistance, while their periods are correlated positively with the flow capacity and the flow resistance. The experimental results reveal the feasibility of the designed microfluidic chip. Conclusively, the proposed microfluidic generator based on autonomously oscillatory flow can generate dynamic shear stress and biochemical signals without peripheral pumps and external control systems. In addition to reducing the experimental cost, due to the tiny volume, it is beneficial to be integrated into cell incubators for cell biology experiments. Thus, the proposed microfluidic chip provide a novel experimental platform for cell biology investigations. This article is protected by copyright. All rights reserved.

9.
Kaohsiung J Med Sci ; 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34288387

RESUMO

Liver transplantation (LT) candidates often present with poor oral hygiene, which could potentially lead to systemic infections and sepsis owing to their cirrhotic state. In this study, we investigated the oral health status of LT candidates and propose guidance for the detection and treatment of encountered oral lesions among these patients. The decayed, missing, and filled teeth (DMFT) index was determined through oral examination. The presence of dental calculus was detected using panoramic radiography and defined by the radiopaque dental calculus (RDC). From January 2011 to August 2018, 56 LT candidates were enrolled with a median follow-up of 39 months. The overall mean numbers of decayed, missing, and filled teeth among these patients were 2.7 ± 2.8, 10.9 ± 8.3, and 5.4 ± 4.5, respectively. Eighteen patients (32.1%) had RDC. The 5-year survival rates of all 56 patients was 57.7%, while that of those who either received LT (23 patients) or not were 82.1% and 39.8%, respectively. A Cox regression model revealed better overall survival of patients after LT (adjusted hazard ratio [aHR] = 0.067, p = 0.001), worse survival among patients with RDC (aHR = 3.468, p = 0.010), at Child-Pugh stages B and C (aHR for stage B = 11.889, p = 0.028; aHR for stage C = 19.257, p = 0.013) compared to patients at Child-Pugh stage A, and those with a model for end-stage liver disease (MELD) score ≥25 (aHR = 13.721, p = 0.018). This study demonstrates that RDC was associated with worse prognosis in LT candidates. We therefore recommend that interprofessional collaboration should be a routine preoperative procedure for the evaluation of oral hygiene among LT candidates.

10.
Redox Biol ; 45: 102058, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34218200

RESUMO

Tripartite motif (TRIM) 31 has been implicated in diverse biological and pathological conditions. However, whether TRIM31 plays a role in ischemic stroke progression is not clarified. Here we demonstrated that TRIM31 was significantly downregulated in the ischemic brain and the deficiency of TRIM31 alleviated brain injury induced by middle cerebral artery occlusion by reducing reactive oxygen species production and maintaining mitochondrial homeostasis. Mechanistically, we found that TRIM31 is an E3 ubiquitin ligase for TP53-induced glycolysis and apoptosis regulator (TIGAR), which confers protection against brain ischemia by increasing the pentose phosphate pathway flux and preserving mitochondria function. TRIM31 interacted with TIGAR and promoted the polyubiquitination of TIGAR, consequently facilitated its degradation in a proteasome-dependent pathway. Furthermore, TIGAR knockdown effectively abolished the protective effect of TRIM31 deficiency after cerebral ischemia. In conclusion, we identified that TRIM31 was a novel E3 ubiquitin ligase for TIGAR, played a critical role in regulating its protein level, and subsequently involved in the ischemic brain injury, suggesting TRIM31 as a potential therapeutic target for ischemic stroke.

11.
J Sep Sci ; 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34240804

RESUMO

Semen of Cuscuta chinensis has been reported to have an anti-osteoporosis effect, however, the components which account for the anti-osteoporosis effect have not been clarified. In this work we propose a biochemometrics strategy that integrates quantitation, anti-osteoporosis evaluation in zebrafish, and grey relationship analysis for the identification of anti-osteoporosis components from the semen of Cuscuta chinensis. In the beginning, a precise and accurate liquid chromatography-tandem mass spectrometry method was established for simultaneous quantitation of seven major components in crude and salt-processed Cuscuta chinensis. The mode of multiple reaction monitoring was used. Chloramphenicol was selected as the internal standard. The method showed good linearity and repeatability. The recovery rates of each component ranged from 95.4 to 103.9%. The precisions of intra-day and inter-day were all within 5.0%. The method was then applied for quantitation of the seven major components in 11 batches of crude and salt-processed Cuscuta chinensis. Subsequently, the anti-osteoporosis effects of crude and salt-processed Cuscuta chinensis were evaluated in zebrafish. Principle component analysis, grey relationship analysis, and partial least squares regression were applied for deciphering the relationship between the contents of seven major components and the anti-osteoporosis effects. Hyperin, p-hydroxycinnamic acid, and astragalin were found to be the major anti-osteoporosis components.

12.
Shock ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34265832

RESUMO

OBJECTIVES: Mechanical stretch induced alveolar epithelial cell (AEC) apoptosis participates in the onset of ventilator induced lung injury (VILI). In this study, we explored whether death associated protein kinase 1 (DAPK1) mediated cyclic stretch (CS) induced AEC apoptosis and VILI though P53 pathway. MATERIALS AND METHODS: AEC apoptosis was induced by CS using the FX-5000T Flexercell Tension Plus system. C57BL/6 mouse received high tidal volume ventilation to build VILI model. DAPK1 inhibitor, P53 inhibitor or DAPK1 plasmid was used to regulate the expression of DAPK1 and P53, respectively. Flow cytometery was performed to assay cell apoptosis and the changes of mitochondrial membrane potential (MMP); Immunoblotting was adopted to analyse related protein expression; The binding of related proteins was detected by coimmunoprecipitation; AEC apoptosis in vivo was determined by immunohistochemistry assay. RESULTS: CS promoted AEC apoptosis, increased DAPK1 and P53 expression and induced the binding of DAPK1 and P53; inhibition of DAPK1 or P53 reduced CS induced AEC apoptosis, suppressed the expression of Bax, increased Bcl-2 level and stabilized MMP; AEC apoptosis and the level of P53 were both increased after overexpressing of DAPK1. Moreover, DAPK1 plasmid transfection also promoted the expression of Bax and the change of MMP, but decreased the level of Bcl-2. Inhibition of DAPK1 or P53 in vivo alleviated high tidal volume ventilation induced AEC apoptosis and lung injury. CONCLUSIONS: DAPK1 contributes to AEC apoptosis and the onset of VILI though P53 and its intrinsic pro-apoptotic pathway. Inhibition of DAPK1 or P53 alleviates high tidal volume ventilation induced lung injury and AEC apoptosis.

13.
J Phys Chem Lett ; : 6794-6803, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34270259

RESUMO

Intricate potential energy surfaces (PESs) of some transition metal complexes (TMCs) pose challenges in mapping out initial excited-state pathways that could influence photochemical outcomes. Ultrafast intersystem crossing (ISC) dynamics of four structurally related platinum(II) dimer complexes were examined by detecting their coherent vibrational wavepacket (CVWP) motions of Pt-Pt stretching mode in the metal-metal-to-ligand-charge-transfer excited states. Structurally dependent CVWP behaviors (frequency, dephasing time, and oscillation amplitudes) were captured by femtosecond transient absorption spectroscopy, analyzed by short-time Fourier transformation, and rationalized by quantum mechanical calculations, revealing dual ISC pathways. The results suggest that the ligands could fine-tune the PESs to influence the proximity of the conical intersections of the excited states with the Franck-Condon state and thus to control the branching ratio of the dual ISC pathways. This comparative study presents future opportunities in control excited-state trajectories of TMCs via ligand structures.

14.
Artigo em Inglês | MEDLINE | ID: mdl-34271193

RESUMO

Fish skeletal muscles are composed of spatially well-separated fiber types, namely, red and white muscles with different physiological functions and metabolism. To compare the DNA methylation profiles of the two types of muscle tissues and identify potential candidate genes for the muscle growth and development under epigenetic regulation, genome-wide DNA methylation of the red and white muscle in Chinese perch Siniperca chuatsi were comparatively analyzed using bisulfate sequencing methods. An average of 0.9 billion 150-bp paired-end reads were obtained, of which 86% were uniquely mapped to the genome. Methylation mostly occurred at CG sites at a ratio of 94.43% in the red muscle and 93.16% in the white muscle. The mean methylation levels at C-sites were 5.95% in red muscle and 5.83% in white muscle, whereas the mean methylation levels of CG, CHG, and CHH were 73.23%, 0.62%, and 0.67% in red muscle, and 71.01%, 0.62%, and 0.67% in white muscle, respectively. A total of 4192 differentially methylated genes (DMGs) were identified significantly enriched in cell signaling pathways related to skeletal muscle differentiation and growth. Various muscle-related genes, including myosin gene isoforms and regulatory factors, are differentially methylated in the promoter region between the red and white muscles. Further analysis of the transcriptional expression of these genes showed that the muscle regulatory factors (myf5, myog, pax3, pax7, and twitst2) and myosin genes (myh10, myh16, myo18a, myo7a, myo9a, and myl3) were differentially expressed between the two kinds of muscles, consistent with the DNA methylation analysis results. ELISA assays confirmed that the level of 5mC in red muscle was significantly higher than in white muscle (P < 0.05). The RT-qPCR assays revealed that the expression levels of the three DNA methylation transferase (dnmt) subtypes, dnmt1, dnmt3ab, and dnmt3bb1, were significantly higher in red muscle than in white muscle. The higher DNA methylation levels in the red muscle may result from higher DNA methylation transferase expression in the red muscles. Thus, this study might provide a theoretical foundation to better understand epigenetic regulation in the growth and development of red and white muscles in animals, at least in Chinese perch fish.

15.
Adv Healthc Mater ; : e2100046, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34263551

RESUMO

Monitoring the concentration of useful biomarkers via electronic skins (e-skins) is highly important for the development of wearable health management systems. While some biosensor e-skins with high flexibility, sensitivity, and stability have been developed, little attention has been paid to their long-term comfortability and optical transparency. Here, a conformable, gas permeable, and transparent skin-like Cu2 O@Ni micromesh structural glucose monitoring patch is reported. With its self-supporting micromesh structure, the skin-like glucose monitoring patch exhibits excellent shape conformability, high gas permeability, and high optical transmittance. The skin-like glucose biosensor achieves real-time monitoring of glucose concentrations with high sensitivity (15 420 µA cm- 2 mM- 1 ), low detection limit (50 nM), fast response time (<2 s), high selectivity, and long-term stability. These desirable performance properties arise from the synergistic effects of the self-supporting micromesh configuration, high conductivity of the metallic Ni micromesh, and high electrocatalytic activities of the Cu2 O toward glucose. This work presents a versatile and efficient strategy for constructing conformable, gas permeable, and transparent biosensor e-skins with excellent practicability towards wearable electronics.

16.
Int J Cardiol ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34246724

RESUMO

AIMS: To determine the prevalence and incidence of AF among HF subtypes in a biracial community-based cohort. METHODS: We studied 6496 participants in the Atherosclerosis Risk in Community study (mean age, 75.8 ± 5.3, 59% women, 23% black) who attended the 2011-2013 visit. HF was identified from physician adjudicated diagnosis, hospital discharges, and self-report. HF subtypes were based on echocardiography. A left ventricular ejection fraction <40% represents HF with reduced ejection fraction (HFrEF), 40%-49% for HF with midrange ejection fraction (HFmEF), and ≥ 50% for HF with preserved ejection fraction (HFpEF). AF was ascertained through 2017 from study electrocardiograms, hospital discharges, and death certificates. Confounder-adjusted logistic regression and Cox models were used to estimate associations of HF subtype with prevalent and incident AF. RESULTS: Among eligible participants, 393 had HF (HFpEF = 232, HFmEF = 41, HFrEF = 35 and unclassified HF = 85) and 735 had AF. Compared to those without HF, all HF subtypes were more likely to have prevalent AF [odds ratio (95% confidence interval (CI)) 7.4 (5.6-9.9) for HFpEF, 8.1 (4.3-15.3) for HFmEF, 10.0 (5.0-20.2) for HFrEF, 8.8 (5.6-14.0) for unclassified HF]. Among participants without AF at baseline (n = 5761), 610 of them developed AF. Prevalent HF was associated with increased risk of AF [hazard ratio (95%CI) 2.3 (1.6-3.2) for HFpEF, 5.0 (2.7-9.3) for HFmEF, 3.5 (1.7-7.6) for HFrEF, 1.9 (0.9-3.7) for unclassified HF]. CONCLUSION: AF and HF frequently co-occur, with small differences by HF subtype, underscoring the importance of understanding the interplay of these two epidemics and evaluating shared preventive and therapeutic strategies.

17.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(8): 728-735, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34236033

RESUMO

Objective To investigate the role of the exosomes (EX) derived from polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) preconditioned by hypoxia in the treatment of the collagen-induced arthritis (CIA) mouse model. Methods CIA mouse model was induced by bovine type II collagen(Col2) and Freund's adjuvant. PMN-MDSCs were isolated from CIA mouse spleen by magnetic beads. PMN-MDSC-derived exosomes (PMN-MDSC-EXs) were extracted from the supernatant of PMN-MDSCs under normal (210 mL/L O2) and hypoxia (10 mL/L O2) conditions. PMN-MDSC-EXs were identified by transmission electron microscopy and flow cytometry. The surface-specific markers of PMN-MDSC-EXs were detected by Western blotting, including CD9, CD63, heat shock protein 70 (HSP70), and calnexin. PMN-MDSC-EXs were added to the CD4+ T cell proliferation system in vitro to detect immunosuppressive ability. PMN-MDSC-EXs were injected into the CIA mouse model through the tail vein. The clinic scores of joints were recorded every three days, and the joint structures were observed by HE staining. The levels of total IgG, Col2 antibody, interferon γ (IFN-γ), interleukin 17 (IL-17) in the serum were detected by ELISA. The content of miR-29a-3p and miR-93-5p in PMN-MDSC-EXs under normal and hypoxia conditions was detected by real-time quantitative PCR. Results PMN-MDSCs were successfully isolated from the spleens of CIA mice and PMN-MDSC-EXs was prepared under normal and hypoxia conditions. Compared with normal PMN-MDSC-EXs, hypoxia-treated PMN-MDSC-EXs could inhibit the proliferation of CD4+ T cells more effectively. The swelling degree of toes, clinical scores, and joint damage in the group of hypoxia-treated PMN-MDSC-EXs were significantly reduced. The levels of total IgG, Col2 antibody, IFN-γ and IL-17 in the serum decreased after the treatment with hypoxia-treated PMN-MDSC-EXs. The content of miR-29a-3p and miR-93-5p in hypoxia-treated PMN-MDSC-EXs was much higher than that in normal PMN-MDSC-EXs. Conclusion Under hypoxia condition, the immunosuppressive ability of PMN-MDSC-EXs is stronger, which can alleviate the arthropathy of CIA mice more effectively.


Assuntos
Artrite Experimental , Exossomos , Células Supressoras Mieloides , Animais , Bovinos , Proliferação de Células , Hipóxia , Camundongos
18.
Nat Commun ; 12(1): 4218, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244515

RESUMO

Iron alloying of oxidic cobaltate catalysts results in catalytic activity for oxygen evolution on par with Ni-Fe oxides in base but at much higher alloying compositions. Zero-field 57Fe Mössbauer spectroscopy and X-ray absorption spectroscopy (XAS) are able to clearly identify Fe4+ in mixed-metal Co-Fe oxides. The highest Fe4+ population is obtained in the 40-60% Fe alloying range, and XAS identifies the ion residing in an octahedral oxide ligand field. The oxygen evolution reaction (OER) activity, as reflected in Tafel analysis of CoFeOx films in 1 M KOH, tracks the absolute concentration of Fe4+. The results reported herein suggest an important role for the formation of the Fe4+ redox state in activating cobaltate OER catalysts at high iron loadings.

19.
Artigo em Inglês | MEDLINE | ID: mdl-34281011

RESUMO

Gait disorders are a relevant factor for falls and possible to measure with wearable devices. If a wearable sensor can detect differences in gait parameters between fallers and non-fallers has not yet been studied. The aim of this study was to measure and compare gait parameters, vestibular function, and balance performance between fallers and non-fallers among a group of older persons. Participants were senior members (n = 101) of a Swedish non-profit gymnastic association. Gait parameters were obtained using an inertial measurement unit (IMU) that the participants wore on the leg while walking an obstacle course and on an even surface. Vestibular function was assessed by the Head-shake test, the Head impulse test, and the Dix-Hallpike maneuver. Balance was assessed by the Timed Up and Go, the Timed Up and Go manual, and the Timed Up and Go cognitive tests. Falls during the 12-month follow-up period were monitored using fall diaries. Forty-two persons (41%) had fallen during the 12-month follow-up. Fallers had more limited ability to vary their gait (gait flexibility) than non-fallers (p < 0.001). No other differences between fallers and non-fallers were found. The use of gait flexibility, captured by an IMU, seems better for identifying future fallers among healthy older persons than Timed Up and Go or Timed Up and Go combined with a cognitive or manual task.

20.
Phytochemistry ; 190: 112866, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34271299

RESUMO

Seven previously undescribed diterpenoid alkaloids, eight reaction products and thirteen known compounds were isolated from the whole plant of Delphinium grandiflorum L. (Ranunculaceae). Grandiflonines A and B have an unprecedented C20-diterpenoid alkaloid skeleton, which features inversion of the configuration of C-18. Their structures were determined by comprehensive analyses of spectroscopic data, X-ray diffraction and Mosher's method. The probable biosynthetic pathway of grandiflonine A was discussed. Additionally, the analgesic activity and anti-inflammatory activity by inhibition of NO production were evaluated. Among them, deoxylappaconitine (ED50 = 0.35 mg/kg, TI = 46.22) showed significant analgesic activity that was superior to the reference drug lappaconitine (ED50 = 3.5 mg/kg, TI = 3.34).

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