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1.
BMC Neurol ; 22(1): 27, 2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35031011

RESUMO

BACKGROUND: Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis who also present with status epilepticus (SE) often have a poor prognosis. The aim of this study is to explore simple and effective predictors for anti-NMDAR encephalitis accompanied with SE. METHODS: We retrospectively analyzed 65 anti-NMDAR encephalitis patients from January 2015 to December 2018 who admitted to the Third Affiliated Hospital of Sun Yat-sen University. Patients were divided into SE group and non-SE groups. Their pre-treatment data and 3-month follow-up data were retrospectively analyzed. RESULTS: The results showed that compared with the non-SE group, the levels of serum uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) in anti-NMDAR encephalitis patients with SE decreased significantly before treatment. Additionally, the levels of serum UA and HDL-C increased while the level of C-reactive protein (CRP) decreased 3 months after treatment in the SE group. Compared with the non-SE group, the SE patients had higher modified Rankin scale (mRS) scores before (mRS1) and after treatment (mRS2). Serum UA concentrations before treatment showed significantly negative correlations with mRS1 (r = - 0.407, p < 0.01) and mRS2 (r = - 0.458, p < 0.001), while the level of serum CRP before treatment had strong positive correlations with mRS1 (r = 0.304, p < 0.05) and mRS2 (r = 0.301, p < 0.05) in anti-NMDAR encephalitis patients. The receiver operating characteristic curve demonstrated that the combined detection of UA, HDL-C and CRP before treatment had a significantly higher value (the area under the curve = 0.848; 95% confidence interval [CI], 0.74-0.957; p < 0.001) to predict anti-NMDAR encephalitis accompanied with SE than that of single detection. CONCLUSIONS: Hence, the combined detection of serum UA, HDL-C and CRP before treatment may be simple and effective indicators for predicting SE in anti-NMDAR encephalitis, which may be helpful in early stages to remind clinicians to be alert to the emergence of SE.

2.
Cell Mol Neurobiol ; 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34988760

RESUMO

Cerebral ischemic stroke is one of the leading causes of morbidity and mortality worldwide, and rapidly increasing annually with no more effective therapeutic measures. Thus, the novel diagnostic and prognostic biomarkers are urgent to be identified for prevention and therapy of ischemic stroke. Recently, long noncoding RNAs (lncRNAs), a major family of noncoding RNAs with more than 200 nucleotides, have been considered as new targets for modulating pathological process of ischemic stroke. In this review, we summarized that the lncRNA-maternally expressed gene 3 (MEG3) played a critical role in promotion of neuronal cell death and inhibition of angiogenesis in response to hypoxia or ischemia condition, and further described the challenge of overcrossing blood-brain barrier (BBB) and determination of optimal carrier for delivering lncRNA' drugs into the specific brain regions. In brief, MEG3 will be a potential diagnostic biomarker and drug target in treatment and therapy of ischemic stroke in the future.

3.
Cell Death Differ ; 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34974534

RESUMO

MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme involved in DNA damage response and gene transcription, and its dysregulation has been linked with Charcot-Marie-Tooth disease, neurodevelopmental disorder, and cancer. Despite its functional importance, how MORC2 is regulated remains enigmatic. Here, we report that MORC2 is O-GlcNAcylated by O-GlcNAc transferase (OGT) at threonine 556. Mutation of this site or pharmacological inhibition of OGT impairs MORC2-mediated breast cancer cell migration and invasion in vitro and lung colonization in vivo. Moreover, transforming growth factor-ß1 (TGF-ß1) induces MORC2 O-GlcNAcylation through enhancing the stability of glutamine-fructose-6-phosphate aminotransferase (GFAT), the rate-limiting enzyme for producing the sugar donor for OGT. O-GlcNAcylated MORC2 is required for transcriptional activation of TGF-ß1 target genes connective tissue growth factor (CTGF) and snail family transcriptional repressor 1 (SNAIL). In support of these observations, knockdown of GFAT, SNAIL or CTGF compromises TGF-ß1-induced, MORC2 O-GlcNAcylation-mediated breast cancer cell migration and invasion. Clinically, high expression of OGT, MORC2, SNAIL, and CTGF in breast tumors is associated with poor patient prognosis. Collectively, these findings uncover a previously unrecognized mechanistic role for MORC2 O-GlcNAcylation in breast cancer progression and provide evidence for targeting MORC2-dependent breast cancer through blocking its O-GlcNAcylation.

4.
Chemosphere ; 286(Pt 1): 131555, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34303048

RESUMO

Coal combustion can release large amounts of polycyclic aromatic hydrocarbons (PAHs), which persist in various environment matrices (e.g., road dust) and hence cause the carcinogenic risk to human health. In this study, an exhaustive characterization of road dust samples coupling their physicochemical characteristics and stable isotope compositions (δ13C and δ15N) was conducted to evaluate the source, level, spatial distribution, and carcinogenic risk of PAHs in a typical coal-utilization city. Concentrations of Σ16 PAHs ranged from 605.5 to 25,374.3 ng/g with a mean concentration of 4083.0 ng/g. Pollution levels of sites around the coal-fired power plant (Zone 1) were significantly higher than those in other zones (p < 0.05). PAH concentration showed significant correlations with both C and N fractions (p < 0.01). Compositions of δ13C and δ15N in road dust coupled to principal component analysis and the partitions and diagnostic ratios of PAHs contributed to associating road dust to several local sources of contamination. Coal combustion and vehicular exhaust were major sources of PAHs around the power plant and urban area. Results of incremental lifetime cancer risk showed 81.5% of all sampling sites suffered potential risk (>10-6) for both adults and children, while children around the power plant suffered the highest risk. Despite the estimation of only potential risk being posed by PAHs in road dust, human exposure to the various environmental matrices, scientific and systematic assessment of carcinogenic risks by PAHs in the total environment warrants further investigations.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Adulto , Criança , China , Cidades , Carvão Mineral/análise , Poeira/análise , Monitoramento Ambiental , Humanos , Hidrocarbonetos Policíclicos Aromáticos/análise , Medição de Risco
5.
J Hazard Mater ; 421: 126700, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34332487

RESUMO

Microplastics (MPs) are emerging contaminants in terrestrial systems that cause diverse impacts on plants. However, little is known about whether MPs especially micro-sized MPs can be accumulated and translocated in plants particularly food crops. Hereby, a hydroponic experiment was conducted to verify whether nano-sized (80 nm) and micro-sized (1 µm) fluorescently labeled polystyrene (PS) microspheres can enter rice roots and translocate to aerial parts. Plant samples were taken for detection of PS after 14 days and 40 days exposure, respectively. Both nano- and micro-sized PS microspheres were detected in roots, stems, and leaves of rice seedlings by using confocal laser scanning microscopy. Both 80 nm and 1 µm PS microspheres accumulated in the vascular systems of plant tissues, especially root stele, stem vascular bundles and leaf veins, and mostly aggregated on cell walls and in the intercellular regions. These findings imply that both nano- and micro-sized MPs could be absorbed by rice roots and subsequently translocated to aerial parts, and apoplastic transport may be the main pathway. In conclusion, rice seedlings can accumulate nano/microplastics in their roots and translocate them to aboveground tissues, thereby possibly transferring the accumulated nano/microplastics to higher trophic levels through the food chain.


Assuntos
Microplásticos , Oryza , Hidroponia , Plásticos , Poliestirenos , Plântula
6.
Talanta ; 238(Pt 1): 123005, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34857336

RESUMO

Salmonella, Escherichia coli O157:H7 (E. coli O157:H7) and Shigella flexneri (S. flexneri) might contaminate similar types of meat products and cause deadly diseases in humans. In reality, ground beef samples may carry more than one pathogen and a rapid and accurate detection method for the simultaneous identification of multiple specific pathogenic strains in ground beef is crucial. In this study, a sample pretreatment protocol and a flow cytometry method were developed for rapid and multiplexed quantification of the three pathogens without cultural enrichment in ground beef. The whole process of sample pretreatment, staining, and instrument analysis can be accomplished within 1 h. The three bacteria upon sample pretreatment were demonstrated good recoveries (93.8%-101.2%). The quantitative detection range of the mothed was 103 to 108 cells/g for all three pathogens, and the detection limit for Salmonella, E. coli O157:H7 and S. flexneri in ground beef were 3.1 × 103 cells/g, 2.1 × 103 cells/g and 2.3 × 103 cells/g, respectively. Therefore, the as-developed approach is a rapid and quantitative method for multiplexed detection of Salmonella, E. coli O157:H7, and S. flexneri in ground beef.


Assuntos
Escherichia coli O157 , Produtos da Carne , Animais , Bovinos , Contagem de Colônia Microbiana , Citometria de Fluxo , Microbiologia de Alimentos , Humanos , Salmonella , Shigella flexneri
7.
Chemosphere ; 287(Pt 1): 131968, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34438214

RESUMO

The effective interception of membrane leads to the accumulation of microplastics (MPs) in membrane bioreactor (MBR) process for long-term operation. However, the influence of MPs accumulation on the performance of MBR hasn't been well understood. In this study, the accumulation of polypropylene microplastics (PP-MPs) in two MBRs run for 3 yr with or without discharging sludge was simulated by operating the lab-scale MBRs for 84 days. The variations of pollutant removal, membrane fouling, composition of soluble microbial product (SMP) and extracellular polymeric substance (EPS), and microbial community of MBRs were systematically investigated. The results show that the removal efficiency of COD and NH4+-N was not depressed by PP-MPs accumulation. However, the presence of PP-MPs in the range of 0.14-0.30 g/L could inhibit the growth of microorganisms, enhance the secretion of SMP and EPS, and reduce the microbial richness and diversity. In the contrary, the high concentration of PP-MPs (2.34-5.00 g/L) exhibited the opposite effects and mitigated membrane fouling, suggesting the important role of MPs concentration. It was also found that the exposure to high concentration of PP-MPs enhanced relative abundance of Clostridia, and inhibited the growth of Proteobacteria. The findings of this study provide a foresight to understand the effects of MPs accumulation on the performance of MBRs.


Assuntos
Microplásticos , Purificação da Água , Reatores Biológicos , Matriz Extracelular de Substâncias Poliméricas , Membranas Artificiais , Plásticos , Esgotos
8.
Sci Total Environ ; 806(Pt 4): 150879, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34627893

RESUMO

Anaerobic ammonium-oxidizing (anammox) bacteria are iron abundant and depend heavily on iron-binding proteins. The iron demand of anammox bacteria is relatively large. However, it still remains some doubts where these large quantities of available iron come from and how they are regulated in anammox bacteria. Herein, iron-rich nanoparticles in anammoxosomes were detected by synchrotron soft X-ray tomography coupled with scanning transmission X-ray microscopy (STXM). The iron-rich nanoparticles were identified as ferric oxide (α-Fe2O3) mineral cores, and the local atomic structure of iron-rich nanoparticles was obtained by X-ray absorption fine-structure (XAFS) spectra. The bacterioferritin of Q1Q315 and Q1Q5F8 were detected by proteomics analysis. On this basis, the metabolic pathway centered on iron-rich nanoparticles was proposed.


Assuntos
Compostos de Amônio , Nanopartículas , Bactérias , Ferro , Oxirredução
10.
G3 (Bethesda) ; 11(8)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34849817

RESUMO

We applied miRNA expression profiling method to Populus trichocarpa stems of the three developmental stages, primary stem (PS), transitional stem (TS), and secondary stem (SS), to investigate miRNA species and their regulation on lignocellulosic synthesis and related processes. We obtained 892, 872, and 882 known miRNAs and 1727, 1723, and 1597 novel miRNAs, from PS, TS, and SS, respectively. Comparisons of these miRNA species among different developmental stages led to the identification of 114, 306, and 152 differentially expressed miRNAs (DE-miRNAs), which had 921, 2639, and 2042 candidate target genes (CTGs) in the three respective stages of the same order. Correlation analysis revealed 47, 439, and 71 DE-miRNA-CTG pairs of high negative correlation in PS, TS, and SS, respectively. Through biological process analysis, we finally identified 34, 6, and 76 miRNA-CTG pairs from PS, TS, and SS, respectively, and the miRNA target genes in these pairs regulate or participate lignocellulosic biosynthesis-related biological processes: cell division and differentiation, cell wall modification, secondary cell wall biosynthesis, lignification, and programmed cell death processes. This is the first report on an integrated analysis of genome-wide mRNA and miRNA profilings during multiple phases of poplar stem development. Our analysis results imply that individual miRNAs modulate secondary growth and lignocellulosic biosynthesis through regulating transcription factors and lignocellulosic biosynthetic pathway genes, resulting in more dynamic promotion, suppression, or regulatory circuits. This study advanced our understanding of many individual miRNAs and their essential, diversified roles in the dynamic regulation of secondary growth in woody tree species.

11.
J Hazard Mater ; : 127803, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34862104

RESUMO

The advanced oxidation process of peroxymonosulfate activated by solid catalyst is one of the main technologies to solve the pollution of antibiotics in water environment.In this work, a series of composites (MCW) containing Mn, Co, and W were synthesized using green ball milling, which does not produce the three wastes (waste gas, waste water and industrial residue). It shows a unique and high catalytic activity for peroxymonosulfate-based degradation of doxycycline (DC) under the pH condition between 4 and 9, and it can be reused five times. MCW composites remove DC using singlet oxygen and superoxide free radicals, as well as a large number of oxygen vacancies for electron storage. The formation rate of free radicals is determined by the conversion rates of Mn3+/Mn2+ and Co3+/Co2+. In addition, there are three ways to degrade DC to form 18 kinds of intermediates, and the toxicity of all the intermediates were predicted by ECOSAR program. The highly active catalysts obtained using a green synthetic route for the activation of peroxymonosulfate show a great potential for decontamination of antibiotics wastewater.

12.
Front Neurol ; 12: 774247, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956055

RESUMO

Objectives: To assess the hemispheric differences in characteristics, stroke-related complications, and outcomes of patients with large hemisphere infarctions (LHI). Methods: We enrolled consecutive patients admitted within 24 h after the diagnosis of LHI (defined as an ischemic stroke involving more than 50% of the territory of the middle cerebral artery in computed tomography and/or magnetic resonance imaging). Univariate and multivariate analysis were performed to explore the association between lateralization and stroke-related complications and clinical outcomes. Results: A total of 314 patients with LHI were enrolled, with 171 (54.5%) having right hemispheric involvement. Right-sided patients with LHI had lower baseline National Institutes of Health Stroke Scale (NIHSS) score (18 vs. 22, p < 0.001), higher frequency of atrial fibrillation (69.0 vs. 52.4%, p = 0.003), and higher proportion of cardio-embolism (73.1 vs. 56.6%, p = 0.013) than the left. Right-sided LHI had higher incidence rates of malignant brain edema (MBE) (48.5 vs. 30.8%, p = 0.001) and a composite of cardiovascular events (29.8 vs. 17.5%, p = 0.011) during hospitalization. The incidence rate of 1-month mortality (34.5 vs. 23.8%, p = 0.036) was higher in right-sided patients with LHI, but there were no hemispheric differences in the incidence rates of 3-month mortality and unfavorable outcome (both p > 0.05). Multivariate analyses suggested right hemisphere involvement was independently associated with increased risk of MBE (adjusted OR 2.37, 95% CI 1.26-4.43, p = 0.007) and composite of cardiovascular events (adjusted OR 2.04, 95% CI 1.12-3.72, p = 0.020). However, it was not independently associated with 1-month death, 3-month mortality, and 3-month unfavorable outcome (all p > 0.05). Conclusions: Right-sided patients with LHI had higher frequency of atrial fibrillation and cardio-embolism than the left-sided patients. Right hemisphere involvement was independently associated with increased risk of MBE and composite of cardiovascular events during hospitalization, whereas stroke lateralization was not an independent predictor of mortality and unfavorable outcome in patients with LHI.

13.
Small Methods ; 5(2): e2000701, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34927891

RESUMO

Electrocatalytic hydrogen production for industrial level requires highly active and cost-effective catalysts at large current densities. Herein A-site Ba-deficient double perovskite PrBa0.94 Co2 O5+ δ (PB0.94 C) is used as a precursor for fabricating PB0.94 C-based double/simple perovskite heterostructure (PB0.94 C-DSPH). PB0.94 C-DSPH with enhanced electrochemical surface area, more hydrophilic surface, and high conductivity ensures abundant active sites, rapid release of gas, and efficient charge transfer at high current densities. The resultant PB0.94 C-DSPH delivers the overpotential of 364 mV at a current density of 500 mA cm-2 for hydrogen evolution reaction in 1.0 m KOH solution, along with excellent long-term durability. Promisingly, the electrolyzer with PB0.94 C-DSPH cathode and NiFe-layered double hydroxide anode demonstrates high performance for overall water splitting by yielding high current density of 500 mA cm-2 at 1.93 V. Density functional theory calculations indicate that the double/simple perovskite heterostructure promotes the water adsorption, the dissociation of molecular H2 O, and the OH* desorption considerably, which controls the whole hydrogen evolution process. The proposed PB0.94 C-DSPH solves the problem of low hydrogen-evolution efficiency at high current density faced by noble metal-based catalysts in basic environment. This study may provide a route to explore high-demand elements in the earth for addressing the critical catalysts in clean-energy utilizations.

14.
Medicine (Baltimore) ; 100(51): e27112, 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34941025

RESUMO

BACKGROUND: The traditional Chinese medicine prescription Suhexiang Pill (SHXP), a classic prescription for the treatment of plague, has been recommended in the 2019 Guideline for coronavirus disease 2019 (COVID-19) diagnosis and treatment of a severe type of COVID-19. However, the bioactive compounds and underlying mechanisms of SHXP for COVID-19 prevention and treatment have not yet been elucidated. This study investigates the mechanisms of SHXP in the treatment of COVID-19 based on network pharmacology and molecular docking. METHODS: First, the bioactive ingredients and corresponding target genes of the SHXP were screened from the traditional Chinese medicine systems pharmacology database and analysis platform database. Then, we compiled COVID-19 disease targets from the GeneCards gene database and literature search. Subsequently, we constructed the core compound-target network, the protein-protein interaction network of the intersection of compound targets and disease targets, the drug-core compound-hub gene-pathway network, module analysis, and hub gene search by the Cytoscape software. The Metascape database and R language software were applied to analyze gene ontology biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Finally, AutoDock software was used for molecular docking of hub genes and core compounds. RESULTS: A total of 326 compounds, 2450 target genes of SHXP, and 251 genes related to COVID-19 were collected, among which there were 6 hub genes of SHXP associated with the treatment of COVID-19, namely interleukin 6, interleukin 10, vascular endothelial growth factor A, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor (TNF), and epidermal growth factor. Functional enrichment analysis suggested that the effect of SHXP against COVID-19 is mediated by synergistic regulation of several biological signaling pathways, including Janus kinase/ STAT3, phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt), T cell receptor, TNF, Nuclear factor kappa-B, Toll-like receptor, interleukin 17, Chemokine, and hypoxia-inducible factor 1 signaling pathways. SHXP may play a vital role in the treatment of COVID-19 by suppressing the inflammatory storm, regulating immune function, and resisting viral invasion. Furthermore, the molecular docking results showed an excellent binding affinity between the core compounds and the hub genes. CONCLUSION: This study preliminarily predicted the potential therapeutic targets, signaling pathways, and molecular mechanisms of SHXP in the treatment of severe COVID-19, which include the moderate immune system, relieves the "cytokine storm," and anti-viral entry into cells.

15.
Medicine (Baltimore) ; 100(51): e28157, 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34941066

RESUMO

ABSTRACT: To compare the efficacy and safety of calcineurin inhibitor (CNI) and Tripterygium wilfordii polyglycoside tablets (TWPs) in treating idiopathic membranous nephropathy (IMN) with CNI and glucocorticoids (GCs).Data of patients with IMN who were treated with CNI+TWPs (TWP group) or CNI+GCs (GC group) and followed up for more than 12 months at the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from 2017 to 2020 were retrospectively analyzed. The 24-h urine protein (24hUP), serum albumin (ALB), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), serum creatinine, alanine aminotransferase, and aspartate transaminase levels on the third, sixth, ninth, and twelfth months of treatment and phospholipase A2 receptor (PLA2R) level before and after treatment were compared in both groups.We recruited 64 patients who were assigned to either the GC group (n = 31) or TWP group (n = 33). No difference in baseline indicators between the two groups were observed (P > .05). After 12 months, the 24hUP levels of both groups significantly decreased compared with that at baseline (P < .01). At the end of the sixth month, 24hUP of the TWP group were less and reduced more quickly than those in the GC group (P < .05), but there is no difference at the other time point (P > .05). After treatment, the number of patients who up to the standard of TG and the ALB levels in both groups increased (P < .05), the LDL-C levels and the number of patients positive for PLA2R in both groups were reduced (P < .05), and no significant difference was observed in the overall changes of 24hUP, ALB and LDL-C levels, TG compliance rate, and PLA2R positive rate between both groups (P > .05). During treatment, no patient in either group had hepatorenal dysfunction, one case in the TWP group and two cases in the GC group experienced side effects, but no apparent difference in the side effects were observed between both groups (P > .05).Two therapeutic schemes have the advantage of reducing urinary protein excretion in patients with IMN. Compared with CNI+GCs, CNI+TWPs have high efficiency and is widely applied, which might be considered as an optimum therapy in the future.

16.
Int J Pharm ; : 121299, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34929311

RESUMO

Traditional encapsulated microbubbles are recently used as delivery carriers for drugs and genes, but they have low efficiency. If the local microbubble concentration could be increased, this might be able to improve the therapeutic efficacy of diseases. In this study, we developed novel cationic magnetic microbubbles (MBM), which could simultaneously realize targeted aggregation under a magnetic field as well as ultrasonographic real-time visualization. Their physicochemical properties, biocompatibility, ultrasonography, magnetic response characteristics, and biodistribution were systematically evaluated. Here, the MBM were 2.55±0.14µm in size with a positive zeta potential, and had a good biocompatibility. They were able to enhance ultrasonographic contrast both in vitro and in vivo. MBM could be attracted by an external magnet for directional movement and aggregation in vitro. We confirmed that MBM also had a great magnetic response in vivo, by means of fluorescence imaging and contrast-enhanced ultrasound imaging. Following intravenous injection into tumor-bearing mice, MBM showed excellent stability in the internal circulation, and could accumulate in the tumor vasculature through magnetic targeting. With the excellent combination of magnetic response and acoustic properties, cationic magnetic microbubbles (MBM) have promising potential for use as a new kind of drug/gene carrier for theranostics in the future.

17.
Cells ; 10(11)2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34831112

RESUMO

Pulmonary premature ageing and fibrogenesis as in idiopathic pulmonary fibrosis (IPF) occur with the DNA damage response in lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that naturally occurring ageing is associated with the DNA damage response (DDR) and activation of the p53 signalling pathway. Telomerase deficiency induced by telomerase RNA component (TERC) knockout (KO) accelerates not only replicative senescence but also altered differentiation and apoptosis of the pulmonary alveolar stem cells (AEC2) in association with increased innate immune natural killer (NK) cells in TERC KO mice. TERC KO results in increased senescence-associated heterochromatin foci (SAHF) marker HP1γ, p21, p16, and apoptosis-associated cleaved caspase-3 in AEC2. However, additional deficiency of the tumour suppressor p53 in the Trp53-/- allele of the late generation of TERC KO mice attenuates the increased senescent and apoptotic markers significantly. Moreover, p53 deficiency has no significant effect on the increased gene expression of T1α (a marker of terminal differentiated AEC1) in AEC2 of the late generation of TERC KO mice. These findings demonstrate that, in natural ageing or premature ageing accelerated by telomere shortening, pulmonary senescence and IPF develop with alveolar stem cell p53-dependent premature replicative senescence, apoptosis, and p53-independent differentiation, resulting in pulmonary senescence-associated low-grade inflammation (SALI). Our studies indicate a natural ageing-associated molecular mechanism of telomerase deficiency-induced telomere DDR and SALI in pulmonary ageing and IPF.

18.
J Ethnopharmacol ; 285: 114852, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34838619

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pancreatic cancer is a common malignancy worldwide due to its poor prognosis and high mortality rate. It is clinically proven that the combination of chemotherapeutic drugs and Traditional Chinese Medicine injections (TCMIs) significantly improves the therapeutic effect. AIM OF THE STUDY: To evaluate the efficacy and clinical benefits of TCMIs in combination with chemotherapy in the treatment of pancreatic cancer and to explore the mechanism of clinical advantage of Aidi injection. METHODS: Randomized controlled trials (RCTs) were searched in databases by NMA before December 29, 2020. WinBUGS 1.4, Stata 14.0, and R 4.0.4 software were used for calculations. All results were expressed as odds ratios and 95% credible intervals. Through the network pharmacology method, the chemical components and their targets, as well as the disease targets were further analyzed. And then, biological experiments were integrated to verify the results of network pharmacology analysis. (PROSPERO ID: CRD42021283559). RESULTS: A total of 33 RCTs with 8 TCMIs and 2011 patients were included. The results of NMA showed that Aidi injection can significantly improve the clinical efficacy (OR = 0.34, 95%CI: 0.16-0.74), and the clinical advantage was that it can significantly alleviate the leukopenia and thrombocytopenia caused by chemotherapy (OR = 5.65, 95%CI: 1.18-28.13). A total of 23 chemical compounds and 280 potential targets for Aidi injection were obtained from the online databases. Among them, there were 22 compounds, 50 targets and 211 signaling pathways closely related to leukopenia. Five genes were predicted to be core targets of ADI in alleviating leukopenia, and 2 of them (TP53 and VEGFA) were confirmed by biological experiments as regulatory targets of ADI in the treatment of PC. CONCLUSIONS: In conclusion, TCMIs in combination with chemotherapy, can improve clinical efficacy and safety in the treatment of pancreatic cancer. However, the overall evidence base is low, and large samples with multi-center RCTs are still needed to support further research findings. Aidi injection can alleviate leukopenia mainly by intervening in oxidative stress, regulating cell proliferation and apoptosis, and regulating the inflammatory response. The combined application of NMA, network pharmacology, and biological experiments provides a reference for clinical evaluation and mechanism of action exploration of other drugs.

19.
Front Immunol ; 12: 670338, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745083

RESUMO

Proteins controlling mitochondrial fission have been recognized as essential regulators of mitochondrial functions, mitochondrial quality control and cell apoptosis. In the present study, we identified the critical B cell survival regulator TRAF3 as a novel binding partner of the key mitochondrial fission factor, MFF, in B lymphocytes. Elicited by our unexpected finding that the majority of cytoplasmic TRAF3 proteins were localized at the mitochondria in resting splenic B cells after ex vivo culture for 2 days, we found that TRAF3 specifically interacted with MFF as demonstrated by co-immunoprecipitation and GST pull-down assays. We further found that in the absence of stimulation, increased protein levels of mitochondrial TRAF3 were associated with altered mitochondrial morphology, decreased mitochondrial respiration, increased mitochondrial ROS production and membrane permeabilization, which eventually culminated in mitochondria-dependent apoptosis in resting B cells. Loss of TRAF3 had the opposite effects on the morphology and function of mitochondria as well as mitochondria-dependent apoptosis in resting B cells. Interestingly, co-expression of TRAF3 and MFF resulted in decreased phosphorylation and ubiquitination of MFF as well as decreased ubiquitination of TRAF3. Moreover, lentivirus-mediated overexpression of MFF restored mitochondria-dependent apoptosis in TRAF3-deficient malignant B cells. Taken together, our findings provide novel insights into the apoptosis-inducing mechanisms of TRAF3 in B cells: as a result of survival factor deprivation or under other types of stress, TRAF3 is mobilized to the mitochondria through its interaction with MFF, where it triggers mitochondria-dependent apoptosis. This new role of TRAF3 in controlling mitochondrial homeostasis might have key implications in TRAF3-mediated regulation of B cell transformation in different cellular contexts. Our findings also suggest that mitochondrial fission is an actionable therapeutic target in human B cell malignancies, including those with TRAF3 deletion or relevant mutations.

20.
Oxid Med Cell Longev ; 2021: 3960773, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804365

RESUMO

Maintenance of normal function of mitochondria is vital to the fate and health of cardiomyocytes. Mitochondrial quality control (MQC) mechanisms are essential in governing mitochondrial integrity and function. The ubiquitin-proteasome system (UPS), mitochondrial dynamics, and mitophagy are three major components of MQC. With the progress of research, our understanding of MQC mechanisms continues to deepen. Gradually, we realize that the three MQC mechanisms are not independent of each other. To the contrary, there are crosstalk among the mechanisms, which can make them interact with each other and cooperate well, forming a triangle interplay. Briefly, the UPS system can regulate the level of mitochondrial dynamic proteins and mitophagy receptors. In the process of Parkin-dependent mitophagy, the UPS is also widely activated, performing critical roles. Mitochondrial dynamics have a profound influence on mitophagy. In this review, we provide new processes of the three major MQC mechanisms in the background of cardiomyocytes and delve into the relationship between them.

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