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1.
Front Nutr ; 9: 847966, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35571952

RESUMO

Stress exposure is a potential threat to humans who live or work in extreme environments, often leading to oxidative stress, inflammatory response, intestinal dysbiosis, and metabolic disorders. Gallnut tannic acid (TA), a naturally occurring polyphenolic compound, has become a compelling source due to its favorable anti-diarrheal, anti-oxidative, anti-inflammatory, and anti-microbial activities. Thus, this study aimed to evaluate the anti-stress effects of gallnut TA on the stress-induced inflammatory response, dysbiotic gut microbiota, and alterations of serum metabolic profile using beagle models. A total of 13 beagle dogs were randomly divided into the stress (ST) and ST + TA groups. Dietary supplementation with TA at 2.5 g/kg was individually fed to each dog in the ST + TA group for 14 consecutive days. On day 7, all dogs were transported for 3 h from a stressful environment (days 1-7) to a livable site (days 8-14). In our results, TA relieved environmental stress-induced diarrheal symptoms in dogs and were shown to protect from myocardial injury and help improve immunity by serum biochemistry and hematology analysis. Also, TA inhibited the secretion of serum hormones [cortisol (COR), glucocorticoid (GC), and adrenocorticotropic hormone (ACTH)] and the expression of heat shock protein (HSP) 70 to protect dogs from stress-induced injury, thereby relieving oxidative stress and inflammatory response. Fecal 16S rRNA gene sequencing revealed that TA stimulated the growth of beneficial bacteria (Allobaculum, Dubosiella, Coriobacteriaceae_UCG-002, and Faecalibaculum) and suppressed the growth of pathogenic bacteria (Escherichia-Shigella and Streptococcus), thereby increasing fecal butyrate levels. Serum metabolomics further showed that phytosphingosine, indoleacetic acid, arachidonic acid, and biotin, related to the metabolism of sphingolipid, tryptophan, arachidonic acid, and biotin, respectively, could serve as potential biomarkers of stress exposure. Furthermore, Spearman's correlation analysis showed strong relationships between the four potential serum biomarkers and differential bacteria. Overall, gallnut TA may be a potential prebiotic for the prevention and treatment of stress-induced metabolic disorders by targeting intestinal microbiota.

3.
J Ethnopharmacol ; 293: 115270, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35405250

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitine, a C19-norditerpenoid alkaloid, derives from many medicinal plants such as Aconitum carmichaelii Debx. (Chinese:), Aconitum kusnezoffii Reichb (Chinese:), which were used to rheumatic fever, painful joints and some endocrinal disorders. AIMS OF THE REVIEW: The present paper reviews research progress relating to the pharmacokinetics, physiological and pathological processes of aconitine, while some promising research direction and the detoxification of aconitine are also discussed. MATERIALS AND METHODS: The accessible literature on aconitine, from 1990 to 2020, obtained from published materials of electronic databases, such as SCI finder, PubMed, Web of Science, Science Direct, Springer and Google Scholar was systematically analyzed. RESULTS: In this review, we address the pharmacokinetics of aconitine, as well as its pharmacological effects including anti-cancer, anti-inflammatory, anti-virus, immunoregulation, analgesic, insecticide and inhibition of androgen synthesis. Further, we summarize the toxicity of aconitine such as cardiotoxicity and neurotoxicity, on which we strikingly focus on the ways to reduce the toxicity of aconitine based. CONCLUSIONS: Aconitine plays an vital role in a wide range of physiological and pathological processes and we can reduce the toxicity of aconitine by compatibility and hydrolysis. Although some issues still exist, such as the correlative relationship between the dose and toxicity of aconitine not being clear, our review may provide new ideas for the application of aconitine in the treatment of related diseases.

4.
RSC Med Chem ; 13(3): 280-299, 2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35434624

RESUMO

Based on the structural modification of regorafenib, 28 pyrazinyl-aryl urea derivatives were synthesized and their in vitro antiproliferative activities were evaluated. Six compounds (5-16, 5-17, 5-18, 5-19, 5-22, and 5-23) exhibited favorable inhibitory activity against the human bladder cancer T24 cell line, and 5-23 demonstrated the strongest inhibitory activity (IC50 = 4.58 ± 0.24 µM) with high selectivity. Compound 5-23 induced apoptosis in the low concentration range (≤7.5 µM) combined with shorter incubation time (≤10 h) via the activation of caspases, while high concentrations and prolonged incubation times led to necroptotic cell death by activating the RIPK1/RIPK3/MLKL signaling pathway. Induced apoptosis and necroptosis were closely associated with intracellular reactive oxygen species generation and decreased mitochondrial membrane potential. Compared with regorafenib, 5-23 displayed improved pharmacokinetic profiles in an in vivo rat model. Molecular docking and structure-activity relationship analyses were in agreement with the biological data. Compound 5-23 may be a potent anti-bladder cancer agent and this small molecule can be considered as a promising structure for further optimization.

6.
Bioengineered ; 13(3): 6719-6728, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35245979

RESUMO

Bile acids, the main organic solutes in bile, have been established to play an important role at physiological concentrations in gastrointestinal metabolism. However, under pathological conditions, such as cholestatic disease, cholestasis can damage hepatocytes/biliary epithelial cells leading to apoptosis or necrosis. Clinically, pancreatic head cancer usually presents with obstructive jaundice and increased serum bile acid levels, suggesting that pancreatic cancer is intricately correlated with a high bile acid environment in the human body. An increasing body of evidence suggests that bile acids are toxic to normal human and colon cancer cells. Nonetheless, the effect of bile acids on the occurrence and development of pancreatic cancer remains a matter of debate. In the present study, to explore the direct effects of high serum concentrations of bile acids on pancreatic cancer and the possible related mechanisms, human pancreatic cancer (PANC-1) cells were subject to different concentrations of bile acid mixtures to assess cell viability and the migration and invasion ability. Besides, we found that a high bile acid environment could inhibit the proliferation and migration of pancreatic cancer cells through ROS(Reactive oxygen species) induction and the EMT(epithelial-mesenchymal transition) pathway, thereby promoting the apoptosis of pancreatic cancer cells.Abbreviations BAs: Bile Acids; EMT: epithelial-mesenchymal transition; FBS: fatal bovine serum;CCK-8: Cell-Counting-Kit-8; ROS: reactive oxygen species; CA: cholic acid; CDCA: chenodeoxycholic acid; GCDCA: Glycochenodeoxycholic acid; PVDF: Poly vinylidene fluoride.


Assuntos
Colestase , Neoplasias Pancreáticas , Apoptose , Ácidos e Sais Biliares/farmacologia , Ácido Quenodesoxicólico/farmacologia , Colestase/patologia , Humanos , Espécies Reativas de Oxigênio/metabolismo
7.
Anal Sci ; 38(5): 749-757, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35298794

RESUMO

Acibenzolar-S-methyl (ASM) is the most commercially successful biological antibacterial agent used for crop through systemic acquired resistance (SAR). In this study, a reproducible and accurate procedure, based on the spectrophotometric/microplate reader analysis, has been developed to detect ASM in tobacco leaves. This method involves oxidation of methyl mercaptan by the Ellman's reagent 5,5'-dithio-bis (2-nitrobenzoic acid) (DTNB) to form the yellow derivative 5'-thio-2-nitrobenzoic acid (TNB2-), measurable at 412 nm. Methyl mercaptan can be produced by either the ASM transesterification with methanol or the SA-binding protein 2 (SABP2)-catalyzed ASM hydrolysis. The proportions of methanol, reaction time, temperature, the concentrations of EDTA and DTNB were optimized in a 96-well plate. The calibration curve of ASM was linear over the range of 25.2-315 µg g-1. The results of the intra- and inter-day accuracy and precision data were within the FDA acceptance criteria. With ASM as substrate, the turnover number of SABP2 was determined, with the kcat value of 31.1 min-1 using the Michaelis-Menten equation. In tobacco plants treated with 100 µM ASM, it was decreased as time elapsed in treated tobacco, reaching negligible values 72 h after treatment. The optimized method was applied for the determination of ASM transesterification with methanol and the kinetic data determination of SABP2-catalyzed ASM hydrolysis.


Assuntos
Metanol , Tabaco , Proteínas de Transporte/metabolismo , Catálise , Ácido Ditionitrobenzoico/metabolismo , Hidrólise , Compostos de Sulfidrila/análise , Tiadiazóis
8.
Front Plant Sci ; 13: 817105, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35310644

RESUMO

Alteration of ploidy in one particular plant species often influences their environmental adaptation. Warm-season bermudagrass is widely used as forage, turfgrass, and ground-cover plant for ecological remediation, but exhibits low shade tolerance. Adaptive responses to shade stress between triploid hybrid bermudagrass cultivars ["Tifdwarf" (TD), "Tifsport" (TS), and "Tifway" (TW)] and tetraploid common bermudagrass cultivar "Chuanxi" (CX) were studied based on changes in phenotype, photosynthesis, and secondary metabolites in leaves and stems. Shade stress (250 luminance, 30 days) significantly decreased stem diameter and stem internode length, but did not affect the leaf width of four cultivars. Leaf length of CX, TD, or TW showed no change in response to shade stress, whereas shade stress significantly elongated the leaf length of TS. The CX and the TS exhibited significantly higher total chlorophyll (Chl), Chl a, carotenoid contents, photosynthetic parameters [PSII photochemical efficiency (Fv/Fm), transpiration rate, and stomatal conductance] in leaves than the TW and the TD under shade stress. The CX also showed a significantly higher performance index on absorption basis (PIABS) in leaf and net photosynthetic rate (Pn) in leaf and stem than the other three cultivars under shade stress. In addition, the TS maintained higher proantho cyanidims content than the TW and the TD after 30 days of shade stress. Current results showed that tetraploid CX exhibited significantly higher shade tolerance than triploid TD, TS, and TW mainly by maintaining higher effective photosynthetic leaf area, photosynthetic performance of PSI and PSII (Pn and Fv/Fm), and photosynthetic pigments as well as lower Chl a/b ratio for absorption, transformation, and efficient use of light energy under shade stress. For differential responses to shade stress among three triploid cultivars, an increase in leaf length and maintenance of higher Fv/Fm, gas exchange, water use efficiency, carotenoid, and proanthocyanidin contents in leaves could be better morphological and physiological adaptations of TS to shade than other hybrid cultivars (TD and TW).

9.
Nanomaterials (Basel) ; 12(4)2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35215038

RESUMO

Dimers made of plasmonic particles support strong field enhancements but suffer from large absorption losses, while low-loss dielectric dimers are limited by relatively weak optical confinement. Hybrid dimers could utilize the advantages of both worlds. Here, we propose a hybrid nanoantenna that contains a dimer of core-dual shell nanoparticles known as the metal-dielectric-metal (MDM) structure. We discovered that the hybrid dimer sustained unidirectional forward scattering, which resulted in a nearly ideal Kerker condition in the frequency close to the resonance peak of the dimer due to enhancing the amplitude of the induced high-order electric multiples in the gap and effectively superimposing them with magnetic ones, which respond to the excitation of the plane wave in the dielectric layer of the dimer. Furthermore, when an electric quantum emitter is coupled to the dimer, our study shows that the optimal hybrid dimer simultaneously possesses high radiation directivity and low-loss features, which illustrates a back-to-front ratio of radiation 53 times higher than that of the pure dielectric dimer and an average radiation efficiency 80% higher than that of the pure metallic dimer. In addition, the unique structures of the hybrid hexamer direct almost decrease 75% of the radiation beamwidth, hence heightening the directivity of the nanoantenna based on a hybrid dimer.

10.
Front Med (Lausanne) ; 9: 804847, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35186992

RESUMO

PURPOSE: XEN gel stents are used for the treatment of open-angle glaucoma (OAG), including primary and secondary glaucoma that are uncontrolled by previous medical therapy and cases with previous failed surgery. Our aim was to systematically review of the clinical data of currently published ab-interno XEN gel stents with an emphasis on intraocular pressure (IOP), antiglaucoma medication outcomes, and safety profiles. METHODS: We analyzed all of the publications (MEDLINE, EMBASE, Cochrane Library) on the ab-interno XEN gel stent to evaluate the reduction in IOP and antiglaucoma medications following the procedure. The primary outcomes measured for the meta-analysis were reduction in IOP and anti-glaucoma medications. The secondary outcome were adverse events. For each study, we used a random effects analysis model to calculate the mean difference and 95% confidence intervals for the continuous results (reduction in IOP and antiglaucoma medications) using the inverse variance statistical method. RESULTS: Five hundred twenty-seven articles were checked and 56 studies were found to be relevant with a total of 4,410 eyes. There was a significant reduction in IOP as well as in the number of medications required in patients treated with ab-interno XEN implant either alone or combined with cataract surgery. This new treatment for various types of glaucoma reduced the IOP by 35% to a final average close to 15 mmHg. This reduction was accompanied by a decrease in the number of antiglaucoma medications in all the studies, approximately 2 classes of medication at the price of more needlings. The overall complete success rate was 21.0-70.8% after 2 years using strict criteria originally designed to record success rate in filtration surgery. The incidence of complications vision-threatening was low at <1%. CONCLUSIONS: XEN gel stent was effective and safe for primary and secondary OAG. Further studies should be performed to investigate the impact of ethnicity on the success and failure rate after XEN implantation.

11.
Medicine (Baltimore) ; 101(6): e28780, 2022 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-35147106

RESUMO

BACKGROUND: Limb spasms are a common complication of stroke. It not only affects the quality of life of stroke survivors, but also brings an economic burden. Tuina combined with physical therapy is widely used in the rehabilitation of poststroke spasticity. However, there is no supporting evidence for its efficacy and safety. This study aimed to evaluate the effectiveness and safety of Tuinas combined with physical therapy in the treatment of spasticity after stroke. METHODS: Literature will be collected from the following databases: China Biology Medicine (CBM), Wanfang Database, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), PubMed, Embase, Cochrane Library, and Web of Science; We will include randomized controlled trials of Tuina combined with physical therapy for poststroke spasticity range from the establishment to May 1, 2021. There were no limitations to the publication time, and the language was limited to Chinese and English. The primary outcome was evaluated using the Modified Ashworth scale, and the secondary outcomes were the simplified Fugl-Meyer Assessment scale, Modified Barthel Index, Functional Independence Measurement (FIM), and Visual Analog Scale. RevMan V.5.4.1 software was used for the meta-analysis. The Cochrane Intervention System Evaluation Manual analyzes the risk of bias, and the recommended grading assessment, development and evaluation are used to assess the quality of evidence. ETHICS AND DISSEMINATION: This study will be based on published systematic review studies, no ethical approval is required and the results of the study will be published in a peer-reviewed scientific journal. SYSTEMATIC REVIEW REGISTRATION: INPLASY2021110064.


Assuntos
Espasticidade Muscular/terapia , Modalidades de Fisioterapia , Acidente Vascular Cerebral/complicações , Humanos , Metanálise como Assunto , Espasticidade Muscular/etiologia , Qualidade de Vida , Projetos de Pesquisa , Reabilitação do Acidente Vascular Cerebral , Revisões Sistemáticas como Assunto
12.
Genes (Basel) ; 13(2)2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-35205234

RESUMO

Functional and expressional research of heat shock protein A6 (HSPA6) suggests that the gene is of great value for neurodegenerative diseases, biosensors, cancer, etc. Based on the important value of pigs in agriculture and biomedicine and to advance knowledge of this little-studied HSPA member, the stress-sensitive sites in porcine HSPA6 (pHSPA6) were investigated following different stresses. Here, two heat shock elements (HSEs) and a conserved region (CR) were identified in the pHSPA6 promoter by a CRISPR/Cas9-mediated precise gene editing strategy. Gene expression data showed that sequence disruption of these regions could significantly reduce the expression of pHSPA6 under heat stress. Stimulation studies indicated that these regions responded not only to heat stress but also to copper sulfate, MG132, and curcumin. Further mechanism studies showed that downregulated pHSPA6 could significantly affect some important members of the HSP family that are involved in HSP40, HSP70, and HSP90. Overall, our results provide a new approach for investigating gene expression and regulation that may contribute to gene regulatory mechanisms, drug target selection, and breeding stock selection.


Assuntos
Proteínas de Choque Térmico HSP70 , Proteínas de Choque Térmico , Animais , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Resposta ao Choque Térmico/genética , Regiões Promotoras Genéticas , Sequências Reguladoras de Ácido Nucleico , Suínos
13.
JTO Clin Res Rep ; 3(1): 100257, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34977823

RESUMO

INTRODUCTION: The adjuvant treatment of patients with resected lung adenocarcinoma (LUAD) remains unstandardized. We analyzed the survival outcomes of these patients based on EGFR mutation status and adjuvant chemotherapy treatment. METHODS: This noninterventional real-world study (ICAN) enrolled Chinese patients with resected stages I to III LUAD from April 8, 2010, to December 31, 2010. Tumor EGFR mutation status and 3-year disease-free survival (DFS) were determined. The extension phase provided long-term follow-up with overall survival (OS) as the primary end point. Secondary end points included DFS and prognostic factors of survival. Survival outcomes based on adjuvant chemotherapy treatment, EGFR mutation status, and postoperative stage were analyzed post hoc. RESULTS: Among 568 patients in the ICAN cohort, 472 continued to the extension phase and remained eligible. The 3-year DFS rate was 58.8%. In the extension cohort, 260 patients (55.1%) had EGFR-mutant disease and 207 (43.9%) received adjuvant chemotherapy. At a median follow-up of 109.0 (95% confidence interval [CI]: 106.6-111.4) months, median OS and DFS were 103.3 (95% CI: 101.7-104.9) and 67.4 (95% CI: 49.7-85.2) months, respectively. The 5-year OS and DFS rates were 68.9% (95% CI: 64.3-73.6) and 52.9% (95% CI: 48.2-57.7), respectively. EGFR wild-type disease was a significant independent predictor of worse OS (HR = 1.24, 95% CI: 1.07-1.44, p= 0.004) based on the Cox regression analysis of common factors. Post hoc subgroup analysis revealed that survival outcomes were not significantly different with adjuvant chemotherapy regardless of EGFR mutation status across all postoperative stages. CONCLUSIONS: EGFR mutations are common in operable LUAD, and recurrence and mortality after resection were considerable. Adjuvant chemotherapy did not improve survival outcomes, regardless of EGFR mutation status and postoperative stage.

14.
J Phys Chem Lett ; 13(2): 479-485, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-34995449

RESUMO

Prussian blue analogues are promising cathode material candidates for aqueous rechargeable metal-ion batteries. Although great efforts have been made on developing materials, there are still rare reports on optimizing cell performance from mechanistic understanding and studies. Here we unveil the alkali-metal-ion intercalation mechanism in Berlin green with a home-built spectroelectrochemical cell for operando X-ray Diffraction (XRD) and Raman spectroscopies, which allows us to obtain the correlated local structure, crystal structure, redox activity, and potential profiles during the charging and discharging processes. We found that the intercalation of Na+ follows a solid solution mechanism leading to a high capacity, and the intercalation of K+ follows a two-phase transition mechanism showing a high voltage. With this understanding, we propose a new strategy using a Na+/K+ hybrid cation electrolyte to realize both high voltage and energy density. This study offers a unique insight for improving the cell performance from the understanding of the reaction mechanism.

15.
Eur J Med Chem ; 229: 114082, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34995925

RESUMO

Snail and histone deacetylases (HDACs) have an important impact on cancer treatment, especially for their synergy. Therefore, the development of inhibitors targeting both Snail and HDAC might be a promising strategy for the treatment of cancers. In this work, we synthesized a series of Snail/HDAC dual inhibitors. Compound 9n displayed the most potent inhibitory activity against HDAC1 with an IC50 of 0.405 µM, potent inhibition against Snail with a Kd of 0.180 µM, and antiproliferative activity in HCT-116 cell lines with an IC50 of 0.0751 µM. Compound 9n showed a good inhibitory effect on NCI-H522 (GI50 = 0.0488 µM), MDA-MB-435 (GI50 = 0.0361 µM), and MCF7 (GI50 = 0.0518 µM). Docking studies showed that compound 9n can be well docked into the active binding sites of Snail and HDAC. Further studies showed that compound 9n increased histone H4 acetylation in HCT-116 cells and decreased the expression of Snail protein to induce cell apoptosis. These findings highlight the potential for the development of Snail/HDAC dual inhibitors as anti-solid tumour cancer drugs.


Assuntos
Aminopiridinas/química , Antineoplásicos/síntese química , Benzamidas/química , Inibidores Enzimáticos/síntese química , Histona Desacetilases/metabolismo , Fatores de Transcrição da Família Snail/síntese química , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Benzamidas/farmacocinética , Biomarcadores Tumorais , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacocinética , Células HCT116 , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Ratos , Fatores de Transcrição da Família Snail/farmacocinética , Relação Estrutura-Atividade
16.
Int J Biol Sci ; 18(1): 82-95, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34975319

RESUMO

HCC has remained one of the challenging cancers to treat, owing to the paucity of drugs targeting the critical survival pathways. Considering the cancer cells are deficient in DNase activity, the increase of an autonomous apoptisis endonuclease should be a reasonable choice for cancer treatment. In this study, we investigated whether DNASE1L3, an endonuclease implicated in apoptosis, could inhibit the progress of HCC. We found DNASE1L3 was down-regulated in HCC tissues, whereas its high expression was positively associated with the favorable prognosis of patients with HCC. Besides, serum DNASE1L3 levels were lower in HCC patients than in healthy individuals. Functionally, we found that DNASE1L3 inhibited the proliferation of tumor cells by inducing G0/G1 cell cycle arrest and cell apoptosis in vitro. Additionally, DNASE1L3 overexpression suppressed tumor growth in vivo. Furthermore, we found that DNASE1L3 overexpression weakened glycolysis in HCC cells and tissues via inactivating the rate-limiting enzymes involved in PTPN2-HK2 and CEBPß-p53-PFK1 pathways. Finally, we identified the HBx to inhibit DNASE1L3 expression by up-regulating the expression of ZNF384. Collectively, our findings demonstrated that DNASE1L3 could inhibit the HCC progression through inducing cell apoptosis and weakening glycolysis. We believe DNASE1L3 could be considered as a promising prognostic biomarker and therapeutic target for HCC.


Assuntos
Apoptose , Carcinoma Hepatocelular/metabolismo , Desoxirribonucleases/metabolismo , Glicólise , Neoplasias Hepáticas/metabolismo , Animais , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Regulação para Baixo , Xenoenxertos , Hexoquinase/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfofrutoquinase-1/metabolismo
17.
J Neurooncol ; 156(1): 123-137, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34797524

RESUMO

PURPOSE: Autophagy-dependent tumorigenic growth is one of the most commonly reported molecular mechanisms in glioblastoma (GBM) progression. However, the mechanistic correlation between autophagy and GBM is still largely unexplored, especially the roles of autophagy-related genes involved in GBM oncogenesis. In this study, we aimed to explore the genetic alterations that interact with both autophagic activity and GBM tumorigenesis, and to investigate the molecular mechanisms of autophagy involved in GBM cell death and survival. METHOD: For this purpose, we systematically explored the alterations of autophagic molecules at the genome level in human GBM samples through deep RNA sequencing. The effect of genetic and pharmacologic inhibition of ERK on GBM growth in vitro and in vivo was researched. An image-based tracking analysis of LC3 using mCherry-eGFP-LC3 plasmid, and transmission electron microscopy were utilized to monitor autophagic flux. Immunoblot analysis was used to measure the related proteins. RESULTS: MAPK ERK expression was identified as one of the most probable autophagy-related transcriptional responses during GBM growth. The genetic and pharmacologic inhibition of ERK in vivo and in vitro led to cell death, demonstrating its critical role for GBM proliferation and survival. To our surprise, autophagic activities were excessively activated and resulted in cytodestructive effects on GBM cells upon ERK inhibitor treatment. Furthermore, based on the observation of downregulation of mTOR signaling, we speculated the ERK inhibitor-induced GBM cells death might depend on mTOR-mediated pathway, leading to autophagy dysregulation. Accordingly, the in vivo and in vitro experiments revealed that the mTOR inhibitor rapamycin further increased cell mortality and exhibited enhanced antitumor effect on GBM cells when co-treated with the ERK inhibitor. CONCLUSION: Our data creatively demonstrated that the autophagy-related regulator ERK maintains autophagic activity during GBM tumorigenesis via mTOR signaling pathway. The pharmacologic inhibition of both mTOR and ERK signaling exhibited synergistic therapeutic effect on GBM growth in vivo and in vitro, which has certain novelty and may provide a potential therapeutic approach for GBM treatment in the future.


Assuntos
Autofagia , Neoplasias Encefálicas , Carcinogênese , Glioblastoma , Inibidores de Proteínas Quinases , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Carcinogênese/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
18.
Environ Sci Pollut Res Int ; 29(4): 5798-5811, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34431046

RESUMO

In Tangshan Mine, there are four engineering problems, including the layout of multiple seam mining system, serious environmental damages caused by gangue accumulation and surface collapse, nearly 100 million tons of three under coal (coal trapped under buildings, water bodies, and railways) to be released, and the control accuracy of stratum formations to be improved. The work developed the integrated green mining technology of coal mining, gangue washing-backfilling, strata control, and system monitoring. First, a production system was designed for surface-underground transportation of backfilling materials, underground gangue separation, multiple-seam combined backfilling, and mining. Second, key backfilling equipment was developed at mining heights of 2.2 and 3.5 m by backfilling system layout and precise stratum control methods in Tangshan Mine. After real-time monitoring of stope pressure, backfilling effect, and surface deformation, we evaluated the implementation effect of mining, washing, and backfilling technology. The integrated coal mining in seams 5, 8, and 9 of Tangshan Mine showed that the four backfilling surfaces of T3281, T3292, F5001, and F5002 recovered 946,000 t of raw coal and 1.18 million tons of filled gangue, with a net profit of 363.20 million yuan. The maximum land subsidence values (18, 119, 64, and 47mm) were far lower than the deformation extremes based on the requirements of surface building protection.


Assuntos
Minas de Carvão , China , Carvão Mineral , Tecnologia
20.
Chin J Nat Med ; 20(4): 301-308, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35487600

RESUMO

Chemical fractionation of the n-BuOH partition, which was generated from the EtOH extract of the flower buds of Tussilago farfara, afforded a series of polar constituents including four new sesquiterpenoids (1-4), one new sesquiterpenoid glucoside (5) and one known analogue (6) of the eudesmane type, as well as five known quinic acid derivatives (7-11). Structures of the new compounds were unambiguously characterized by detailed spectroscopic analyses, with their absolute configurations being established by X-ray crystallography, electronic circular dichroism (ECD) calculation and induced ECD experiments. The inhibitory effect of all the isolates against LPS-induced NO production in murine RAW264.7 macrophages was evaluated, with isochlorogenic acid A (7) showing significant inhibitory activity.


Assuntos
Sesquiterpenos de Eudesmano , Sesquiterpenos , Tussilago , Animais , Flores/química , Glucosídeos/análise , Glucosídeos/farmacologia , Camundongos , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Sesquiterpenos de Eudesmano/análise , Sesquiterpenos de Eudesmano/farmacologia , Tussilago/química
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