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YM201636 is the potent PIKfyve inhibitor that is being actively investigated for liver cancer efficacy. In this study, computer simulations and experiments were conducted to investigate the interaction mechanism between YM201636 and the transport protein HSA. Results indicated that YM201636 is stably bound between the subdomains IIA and IIIA of HSA, supported by site marker displacement experiments. YM201636 quenched the endogenous fluorescence of HSA by static quenching since a decrease in quenching constants was observed from 7.74 to 2.39 × 104 M-1. UV-vis and time-resolved fluorescence spectroscopy confirmed the YM201636-HSA complex formation and this binding followed a static mechanism. Thermodynamic parameters ΔG, ΔH, and ΔS obtained negative values suggesting the binding was a spontaneous process driven by Van der Waals interactions and hydrogen binding. Binding constants ranged between 5.71 and 0.33 × 104 M-1, which demonstrated a moderately strong affinity of YM201636 to HSA. CD, synchronous, and 3D fluorescence spectroscopy revealed that YM201636 showed a slight change in secondary structure. The increase of Kapp and a decrease of PSH with YM201636 addition showed that YM201636 changed the surface hydrophobicity of HSA. The research provides reasonable models helping us further understand the transportation and distribution of YM201636 when it absorbs into the blood circulatory system.
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Sérum-albumine humaine , Spectrométrie de fluorescence , Humains , Sérum-albumine humaine/composition chimique , Sérum-albumine humaine/métabolisme , Thermodynamique , Phosphatidylinositol 3-kinases/métabolisme , Phosphatidylinositol 3-kinases/composition chimique , Modèles moléculaires , Inhibiteurs des phosphoinositide-3 kinases/composition chimique , Inhibiteurs des phosphoinositide-3 kinases/pharmacologie , Inhibiteurs des phosphoinositide-3 kinases/métabolisme , Pyrimidines/composition chimiqueRÉSUMÉ
Cadaverine is an endogenous metabolite produced by the gut microbiome with various activity in physiological and pathological conditions. However, whether cadaverine regulates pain or itch remains unclear. In this study, we first found that cadaverine may bind to histamine 4 receptor (H4R) with higher docking energy score using molecular docking simulations, suggesting cadaverine may act as an endogenous ligand for H4R. We subsequently found intradermal injection of cadaverine into the nape or cheek of mice induces a dose-dependent scratching response in mice, which was suppressed by a selective H4R antagonist JNJ-7777120, transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine and PLC inhibitor U73122, but not H1R antagonist or TRPA1 antagonist or TRPV4 antagonist. Consistently, cadaverine-induced itch was abolished in Trpv1-/- but not Trpa1-/- mice. Pharmacological analysis indicated that mast cells and opioid receptors were also involved in cadaverine-induced itch in mice. scRNA-Seq data analysis showed that H4R and TRPV1 are mainly co-expressed on NP2, NP3 and PEP1 DRG neurons. Calcium imaging analysis showed that cadaverine perfusion enhanced calcium influx in the dissociated dorsal root ganglion (DRG) neurons, which was suppressed by JNJ-7777120 and capsazepine, as well as in the DRG neurons from Trpv1-/- mice. Patch-clamp recordings found that cadaverine perfusion significantly increased the excitability of small diameter DRG neurons, and JNJ-7777120 abolished this effect, indicating involvement of H4R. Together, these results provide evidences that cadaverine is a novel endogenous pruritogens, which activates H4R/TRPV1 signaling pathways in the primary sensory neurons.
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Cadavérine , Ganglions sensitifs des nerfs spinaux , Souris de lignée C57BL , Prurit , Canaux cationiques TRPV , Animaux , Prurit/métabolisme , Prurit/induit chimiquement , Canaux cationiques TRPV/métabolisme , Ganglions sensitifs des nerfs spinaux/métabolisme , Ganglions sensitifs des nerfs spinaux/effets des médicaments et des substances chimiques , Mâle , Cadavérine/analogues et dérivés , Cadavérine/pharmacologie , Cadavérine/métabolisme , Souris , Souris knockout , Humains , Mastocytes/métabolisme , Mastocytes/effets des médicaments et des substances chimiques , Membre-1 de la sous-famille A de canaux cationiques à potentiel de récepteur transitoire/métabolisme , Cellules réceptrices sensorielles/métabolisme , Cellules réceptrices sensorielles/effets des médicaments et des substances chimiques , Récepteurs couplés aux protéines G/métabolisme , Capsaïcine/analogues et dérivésRÉSUMÉ
Novel brominated flame retardants (NBFRs) have been developed as replacements for legacy brominated flame retardants (BFRs) such as polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecanes (HBCDs). The prevalence of NBFRs in aquatic environments has initiated intense concerns that they resemble to BFRs. To comprehensively elucidate the fate of NBFRs in aquatic environments, this review summarizes the physico-chemical properties, distribution, bioaccumulation, and fates in aquatic environments. 1,2-bis(2,3,4,5,6-pentabromophenyl) ethane (DBDPE) as the major substitute for PBDEs is the primary NBFR. The release from industrial point sources such as e-waste recycling stations is the dominant way for NBFRs to enter the environment, which results in significant differences in the regional distribution of NBFRs. Sediment is the major sink of NBFRs attributed to the high hydrophobicity. Significantly, there is no decreasing trend of NBFRs concentrations, while PBDEs achieved the peak value in 1970-2000 and decreased gradually. The bioaccumulation of NBFRs is reported in both field studies and laboratory studies, which is regulated by the active area, lipid contents, trophic level of aquatic organisms, and the log KOW of NBFRs. The biotransformation of NBFRs showed similar metabolism patterns to that of BFRs, including debromination, hydroxylation, methoxylation, hydrolysis, and glycosylation. In addition, NBFRs show great potential in trophic magnification along the aquatic food chain, which could pose a higher risk to high trophic-level species. The passive uptake by roots dominates the plant uptake of NBFRs, followed by acropetal and basipetal bidirectional transportation between roots and leaves in plants. This review will provide the support to understand the current pollution characteristics of NBFRs and highlight perspectives for future research.
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Surveillance de l'environnement , Ignifuges , Éthers de polyhalogénophényle , Hydrocarbures bromés , Polluants chimiques de l'eau , Ignifuges/métabolisme , Ignifuges/analyse , Polluants chimiques de l'eau/analyse , Polluants chimiques de l'eau/métabolisme , Éthers de polyhalogénophényle/métabolisme , Éthers de polyhalogénophényle/analyse , Hydrocarbures bromés/métabolisme , Hydrocarbures bromés/analyse , BioaccumulationRÉSUMÉ
BACKGROUND: Ischemic stroke (IS) is more common every year, the condition is serious, and have a poor prognosis. New, efficient, and safe therapeutic targets are desperately needed as early treatment especially prevention and reperfusion is the key to lowering the occurrence of poorer prognosis. Generally circulating proteins are attractive therapeutic targets, this study aims to identify potential pharmacological targets among plasma and cerebrospinal fluid (CSF) proteins for the prevention and treatment of IS using a multicenter Mendelian randomization (MR) approach. METHODS: First, the genetic instruments of 734 plasma and 151 CSF proteins were assessed for causative connections with IS from MEGASTROKE consortium by MR to identify prospective therapeutic targets. Then, for additional validation, plasma proteins from the deCODE consortium and the Fenland consortium, as well as IS GWAS data from the FinnGen cohort, the ISGC consortium and UK biobank, were employed. A thorough evaluation of the aforementioned possible pharmacological targets was carried out using meta-analysis. The robustness of MR results was then confirmed through sensitivity analysis using several techniques, such as bidirectional MR analysis, Steiger filtering, and Bayesian colocalization. Finally, methods like Protein-Protein Interaction (PPI) Networking were utilized to investigate the relationship between putative drug targets and therapeutic agents. RESULTS: The authors discovered three proteins that may function as promising therapeutic targets for IS and meet the Bonferroni correction ( P <0.05/885=5.65×10 -5 ). Prekallikrein (OR=0.41, 95% CI: 0.27-0.63, P =3.61×10 -5 ), a protein found in CSF, has a 10-fold protective impact in IS, while the plasma proteins SWAP70 (OR=0.85, 95% CI: 0.80-0.91, P =1.64×10 -6 ) and MMP-12 (OR=0.92, 95% CI: 0.89-0.95, P =4.49×10 -6 ) of each SD play a protective role in IS. Prekallikrein, MMP-12, SWAP70 was replicated in the FinnGen cohort and ISGC database. MMP-12 (OR=0.93, 95% CI: 0.91-0.94, P <0.001), SWAP70 (OR=0.92, 95% CI: 0.90-0.94, P <0.001), and prekallikrein (OR=0.53, 95% CI: 0.33-0.72, P <0.001) may all be viable targets for IS, according to the combined meta-analysis results. Additionally, no evidence of reverse causality was identified, and Bayesian colocalization revealed MMP-12 (PPH 4 =0.995), SWAP70 (PPH 4 =0.987), and prekallikrein (PPH 4 =0.894) shared the same variant with IS, supporting the robustness of the aforementioned causation. Prekallikrein and MMP-12 were associated with the target protein of the current treatment of IS. Among them, Lanadelumab, a new drug whose target protein is a prekallikrein, may be a promising new drug for the treatment of IS. CONCLUSION: The prekallikrein, MMP-12, and SWAP70 are causally associated with the risk of IS. Moreover, MMP-12 and prekallikrein may be treated as promising therapeutic targets for medical intervention of IS.
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Accident vasculaire cérébral ischémique , Protéome , Humains , Théorème de Bayes , Matrix metalloproteinase 12 , Analyse de randomisation mendélienne , Prékallicréine , Études multicentriques comme sujetRÉSUMÉ
This study investigated the feasibility of alleviating the negative influence of long-chain fatty acids (LCFAs) on anaerobic digestion by biochar, micron zero-valent iron, micron-magnetite (mFe3O4) and their combination. The results demonstrate that co-addition of biochar and 6 g/L mFe3O4 (BC+6 g/L mFe3O4) increased cumulative methane production by 50% as suffered from LCFAs inhibition exerted by 2 g/L glycerol trioleate. The BC+6 g/L mFe3O4 did best in accelerating total organic carbon degradation and volatile fatty acids conversion, through successively enriching Bacteroides, Corynebacterium, and DMER64 to dominant the bacterial community. The proportion of acetotrophic Methanothrix that could alternatively reduce CO2 to methane by accepting electrons via direct interspecies electron transfer (DIET) was 0.09% with BC+6 g/L mFe3O4, nine times more than the proportion in control. Prediction of functional genes revealed the enrichment of the bacterial secretion system, indicating that BC+6 g/L mFe3O4 promoted DIET by stimulating the secretion of extracellular polymeric substances. This study provided novel insights into combining biochar and iron-based conductive materials to enhance AD performance under LCFAs inhibition.
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Acides gras volatils , Fer , Anaérobiose , Méthane , Bioréacteurs , Eaux d'égoutRÉSUMÉ
Optical frequency combs with more than 10 W have paved the way for extreme ultraviolet combs generation by interaction with inert gases, leading to extreme nonlinear spectroscopy and the ultraviolet nuclear clock. Recently, the demand for an ultra-long-distance time and frequency space transfer via optical dual-comb proposes a new challenge for high power frequency comb in respect of power scaling and optical frequency stability. Here we present a frequency comb based on fiber chirped pulse amplification (CPA), which can offer more than 20 W output power. We further characterize the amplifier branch noise contribution by comparing two methods of locking to an optical reference and measure the out-of-loop frequency instability by heterodyning two identical high-power combs. Thanks to the low noise CPA, reasonable locking method, and optical path-controlled amplifiers, the out-of-loop beat note between two combs demonstrates the unprecedented frequency stability of 4.35 × 10-17 at 1s and 6.54 × 10-19 at 1000 s.
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In this work, integrated transcriptome and proteome to offer a new insight of the molecular mechanisms linked to the nutritional quality of Koroneiki and Chenggu-32 by RNA sequencing and 4D Label-free quantitative proteomics technology. Physical and chemical properties studies showed that the main nutrient content of Koroneiki was significantly higher than Chenggu-32, proved the quality of Koroneiki was better. Compared to Koroneiki, there were differences in expression levels of 10,115 genes and 723 proteins in Chenggu-32, mainly related to enzymes in lipid metabolism and lipid biosynthesis. Through the joint analysis of transcriptome and proteome, it was found that the differentially expressed genes and differentially expressed proteins on the association were mainly enriched in starch and sucrose metabolism and α-linolenic acid metabolism pathways, indicated that the nutritional quality of olive fruits was related to the two metabolic pathways. The results of this study identified key genes and proteins related to nutrient metabolism and accumulation in olive fruits, provided transcriptomic and proteomic information for the molecular mechanism of nutritional changes in olive fruit, it helps to develop higher quality olive trees.
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Olea , Protéome , Transcriptome , Olea/génétique , Fruit/génétique , Protéomique , Valeur nutritiveRÉSUMÉ
Background: Olive (Olea europaea L.) oil accumulate more diacylglycerols (DAG) than mostly vegetable oils. Unsaturated fatty acids-enriched DAG consumption enhanced wellness in subjects. However, the mechanism of DAG accumulation is not yet fully understood. Methods: In this study, gene network of DAG accumulation and fatty acid composition in the two olive mesocarps ("Chenggu 32" (CG) and "Koroneiki" (QJ)) were investigated by integrating lipidome and transcriptome techniques. Results: A total of 1,408 lipid molecules were identified by lipidomic analysis in olive mesocarp, of which DAG (DAG36:3, DAG36:4 and DAG36:5) showed higher content, and triacylglycerols (TAG54:3, TAG54:4) exhibited opposite trend in CG. Specifically, DAG was rich in polyunsaturated fatty acids (especially C18:2) at the sn-2 position, which was inconsistent with TAG at the same positions (Primarily C18:1). Transcriptomic analysis revealed that phospholipase C (NPC, EC 3.1.4.3) were up-regulated relative to QJ, whereas diacylglycerol kinase (ATP) (DGK, EC 2.7.1.107), diacylglycerol acyltransferase (DGAT, EC 2.3.1.20), and phospholipid: diacylglycerol acyltransferase (PDAT, EC 2.3.1.158) were down-regulated. Conclusion: We speculated that the non-acyl coenzyme A pathway played a significant role in DAG biosynthesis. Additionally, fatty acyl-ACP thioesterase B (FATB, EC 3.1.2.14), stearoyl [acyl-carrier-protein] 9-desaturase (SAD, EC 1.14.19.2) and omega-6 fatty acid desaturase (FAD2, EC 1.14.19.6) were highly expressed in CG and may be involved in regulating fatty acid composition. Meanwhile, phospholipase A1 (LCAT, EC 3.1.1.32) involved in the acyl editing reaction facilitated PUFA linkage at the sn-2 position of DAG. Our findings provide novel insights to increase the DAG content, improve the fatty acid composition of olive oil, and identify candidate genes for the production of DAG-rich oils.
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Olea , Humains , Olea/génétique , Lipidomique , Diacylglycerol O-acyltransferase/génétique , Diglycéride/métabolisme , Transcriptome/génétique , Acides gras , Acides gras insaturésRÉSUMÉ
Lappaconitine (LA), a diterpenoid alkaloid extracted from the root of Aconitum sinomontanum Nakai, exhibits broad pharmacological effects, including anti-tumor activity. The inhibitory effect of lappaconitine hydrochloride (LH) on HepG2 and HCT-116 cells and the toxicity of lappaconitine sulfate (LS) on HT-29, A549, and HepG2 cells have been described. But the mechanisms of LA against human cervical cancer HeLa cells still need to be clarified. This study was designed to investigate the effects and molecular mechanisms of lappaconitine sulfate (LS) on the growth inhibition and apoptosis in HeLa cells. The cell viability and proliferation were evaluated using the Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2´-deoxyuridine (EdU) assay, respectively. The cell cycle distribution and apoptosis were detected by flow cytometry analysis and 4', 6-diamidino-2-phenylindole (DAPI) staining. The mitochondrial membrane potential (MMP) was determined through the 5, 5', 6, 6'-tetrachloro-1, 1', 3, 3'-tetraethylbenzimi-dazolyl carbocyanine iodide (JC-1) staining. The cell cycle arrest-, apoptosis-, and the phosphatidylinositol-3-kinase/protein kinase B/glycogen synthase kinase 3ß (PI3K/AKT/GSK3ß) pathway-related proteins were estimated by western blot analysis. LS markedly reduced the viability and suppressed the proliferation of HeLa cells. LS induced G0/G1 cell cycle arrest through the inhibition of Cyclin D1, p-Rb, and induction of p21 and p53. Furthermore, LS triggered apoptosis through the activation of mitochondrial-mediated pathway based on decrease of Bcl-2/Bax ratio and MMP and activation of caspase-9/7/3. Additionally, LS led to constitutive downregulation of the PI3K/AKT/GSK3ß signaling pathway. Collectively, LS inhibited cell proliferation and induced apoptosis through mitochondrial-mediated pathway by suppression of the PI3K/AKT/GSK3ß signaling pathway in HeLa cells.
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Phosphatidylinositol 3-kinases , Protéines proto-oncogènes c-akt , Humains , Protéines proto-oncogènes c-akt/métabolisme , Phosphatidylinositol 3-kinases/métabolisme , Cellules HeLa , Glycogen synthase kinase 3 beta/métabolisme , Sulfates/pharmacologie , Transduction du signal , Apoptose , Prolifération cellulaire , Lignée cellulaire tumoraleRÉSUMÉ
The extension application of perovskites in aqueous media such as bioassays requires the development of a water-stable perovskite with a simple preparation process and low cost. However, the degradation of perovskites in aqueous solution is still a thorny problem. Here, we develop a methylimidazole-assisted two-step synthesis protocol to prepare CsPbBr3@PbBrOH nanorods with superior water stability and remarkable optical properties at room temperature. The synergy of 2-methylimidazole (2-MIM), an N-donor ligand, with water can not only facilitate CsPbBr3 formation and suppress CsPb2Br5 or Cs4PbBr6 formation, but also promote the formation of a PbBrOH shell capping CsPbBr3. 2-MIM is ionized into 2-MIM- in DMF and 2-MIM+ in water. They passivated the surface defects and changed the crystallization environment, leading to water-stable CsPbBr3@PbBrOH. The obtained CsPbBr3@PbBrOH nanorods can still maintain 91% PL intensity after being stored in water for more than 2 months. Furthermore, the CsPbBr3@PbBrOH nanorods show excellent stability in polar solvents, water, and phosphate buffer solution in a wide pH range, as well as better thermal and irradiation stability. In addition, the CsPbBr3@PbBrOH nanorods are further functionalized with polydopamine (PDA) for biomolecular immobilization and immunoassay studies. The resulting assay shows a detection limit of 0.003 ng mL-1 for IgG detection, illustrating important progress towards expanding fluorescence labeling application of perovskite nanomaterials for immunoassays.
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Nanostructures , Nanotubes , Oxydes , EauRÉSUMÉ
Aim: Atherosclerosis is the major cause of acute coronary syndrome (ACS) which is a significant contributor to both morbidity and mortality in the world. The microbiome-derived metabolite trimethylamine-N-oxide (TMAO) has aroused great interest and controversy as a risk factor of atherosclerosis. Therefore, in this study, we aimed at investigating whether plasma TMAO can be a risk factor of atherosclerosis in coronary artery of patients with ACS and how this relates to lipids and proinflammatory cytokines in plasma. Methods: We enrolled consecutive patients with ACS who underwent percutaneous coronary intervention (PCI). Gensini scoring was used to evaluate angiographic atherosclerosis in the coronary artery of the patients. 13 patients were divided into low (Gensini score < 25), 33 into intermediate (Gensini score 25-50), and 81 into severe atherosclerosis (Gensini score ≥50). Plasma TMAO, vasculitis factors, and cardiovascular biomarkers were measured by clinical biochemistry, intima-media thickness (IMT) of carotid artery was determined by the Color Doppler ultrasound, and the atherosclerotic lesion in coronary artery was assessed in PCI. Results: Plasma TMAO concentrations were positively associated with Gensini score (OR = 0.629, p < 0.001) and Gensini subgroup (R = 0.604, p < 0.001). Plasma TMAO concentrations in patients with severe coronary atherosclerosis were higher than those of patients with moderate coronary atherosclerosis, and the plasma TMAO concentrations of patients with moderate coronary atherosclerosis were higher than those of patients with mild coronary atherosclerosis, the difference was statistically significant [4.73 (3.13, 4.62) versus 1.13 (0.63, 3.34) versus 0.79 (0.20, 1.29), p < 0.001], respectively. Furthermore, ROC analysis showed that plasma TMAO could identify the severity of atherosclerosis (p < 0.001). The AUC of TMAO for severe atherosclerosis was 0.852 (95%CI = 0.779 - 0.925). The sensitivity and specificity of TMAO for identifying severe atherosclerosis are 96.3% and 63.0% when the cut-off value of TMAO was set at 1.2715 pg/ml. Furthermore, logistic regression analysis showed plasma TMAO concentrations were positively associated with severity of atherosclerosis in coronary artery (OR = 1.934, 95%CI = 1.522 - 2.459, p < 0.001). For all that, negatively association was observed between TMAO and age (OR = -0.224, p < 0.05), B-type natriuretic peptide (BNP) (OR = -0.175, p < 0.05), and interleukin-8 (IL-8) (OR = -0.324, p < 0.001), while positive association was observed between TMAO and nitric oxide (NO) (OR = 0.234, p < 0.01). However, there is no obvious association was observed between Gensini score and cardiovascular biomarkers, vasculitis factors, and carotid IMT, respectively. Conclusion: Our cross-sectional observation suggested that plasma TMAO concentrations positively associated with coronary atherosclerosis in ACS patients and serve as a risk factor for severe atherosclerosis. Plasma TMAO also correlated with age, BNP, IL-8, and NO. However, no obvious association was found between atherosclerosis with vasculitis factors and cardiovascular biomarkers in this study, and there was no conclusive evidence showing TMAO enhance atherosclerosis via regulation of inflammation or lipid.
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Syndrome coronarien aigu , Athérosclérose , Maladie des artères coronaires , Intervention coronarienne percutanée , Vascularite , Humains , Syndrome coronarien aigu/imagerie diagnostique , Syndrome coronarien aigu/thérapie , Interleukine-8 , Maladie des artères coronaires/imagerie diagnostique , Maladie des artères coronaires/thérapie , Épaisseur intima-média carotidienne , Études transversales , Peptide natriurétique cérébral , OxydesRÉSUMÉ
Pancreatic cancer is the seventh leading cause of cancer-related death worldwide and is known as "the king of cancers". Currently, gemcitabine (GEM) as the clinical drug of choice for chemotherapy of advanced pancreatic cancer has poor drug sensitivity and ineffective chemotherapy. Nardoguaianone L (G-6) is a novel guaiane-type sesquiterpenoid isolated from Nardostachys jatamansi DC., and it exhibits anti-tumor activity. Based on the newly discovered G-6 with anti-pancreatic cancer activity in our laboratory, this paper aimed to evaluate the potential value of the combination of G-6 and GEM in SW1990 cells, including cell viability, cell apoptosis, colony assay and tandem mass tags (TMT) marker-based proteomic technology. These results showed that G-6 combined with GEM significantly inhibited cell viability, and the effect was more obvious than that with single drug. In addition, the use of TMT marker-based proteomic technology demonstrated that the AGE-RAGE signaling pathway was activated after medication-combination. Furthermore, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) assays were used to validate the proteomic results. Finally, apoptosis was detected by flow cytometry. In conclusion, G-6 combined with GEM induced an increase in ROS level and a decrease in MMP in SW1990 cells through the AGE-RAGE signaling pathway, ultimately leading to apoptosis. G-6 improved the effect of GEM chemotherapy and may be used as a potential combination therapy for pancreatic cancer.
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Nardostachys , Tumeurs du pancréas , Espèces réactives de l'oxygène/pharmacologie , Protéomique , Lignée cellulaire tumorale , Tumeurs du pancréas/anatomopathologie , Transduction du signal , Apoptose , Prolifération cellulaire , , Tumeurs du pancréasRÉSUMÉ
Background: Intracerebral hemorrhage (ICH) is associated with high mortality and disability rates. This study aimed to investigate the relationship between sex, age, study year, risk factors, bleeding site, median year of study, and the incidence of ICH. Method: Literature on the incidence of ICH published on 1 January 1980 and 1 January 2020, was systematically retrieved from PubMed and Embase databases. The random-effects model and subgroup analysis were used to explore the relationship between the incidence of ICH and different ages, sex, bleeding sites, and risk factors. Results: We summarized the epidemiological changes in ICH in the past 40 years according to 52 studies and found that the total incidence of ICH is 29.9 per 100,000 person-years (95% CI: 26.5-33.3), which has not decreased worldwide. The incidence of ICH in the Asian population is much higher than in other continents. In addition, the incidence of ICH increases with age and differs at the 85-year-old boundary. Men are more likely to develop ICH than women, and the basal ganglia region is the most common area for ICH. Of the 10 risk factors examined in this study, those with hypertension had the highest incidence of ICH, followed by those with excessive alcohol consumption and heart disease. Conclusion: The prevention and treatment of ICH still need to be improved continuously according to age, sex, risk factors, and other factors, and targeted and normative strategies should be gradually developed in the future.
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Aims: This research aimed to explore alterations in the local gyrification index (GI) and resting-state functional connectivity (RSFC) in type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment (MCI). Methods: In this study, 126 T2DM patients with MCI (T2DM-MCI), 154 T2DM patients with normal cognition (T2DM-NC), and 167 healthy controls (HC) were recruited. All subjects underwent a battery of neuropsychological tests. A multimodal approach combining surface-based morphometry (SBM) and seed-based RSFC was used to determine the structural and functional alterations in patients with T2DM-MCI. The relationships among the GI, RSFC, cognitive ability, and clinical variables were characterized. Results: Compared with the T2DM-NC group and HC group, T2DM-MCI patients showed significantly reduced GI in the bilateral insular cortex. Decreased RSFC was found between the left insula and right precuneus, and the right superior frontal gyrus (SFG). The altered GI was correlated with T2DM duration, global cognition, and episodic memory. The mediation effects of RSFC on the association between GI and cognition were not statistically significant. Conclusion: Our results suggest that GI may serve as a novel neuroimaging biomarker to predict T2DM-related MCI and help us to improve the understanding of the neuropathological effects of T2DM-related MCI.
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Foliar-application of nano-particles enhanced the foliar nutrient status and crop growth and yield. It is hypothesized that being second messenger molecule, supplementation of Ca2+ via calcium nanoparticles (Ca-NPs) can trigger various signaling pathways of physiological processes which can lead to alleviate the adverse effects of drought stress on the growth of canola (Brassica napus L.). Nano-enabled foliar-application could be an ideal strategy for advancing agricultural productivity. The present study explored the role of calcium nanoparticles (Ca-NPs) in alleviating drought stress in hydroponic Brassica napus (B. napus) plants. The foliar applied Ca-NPs were spherically shaped with an average size of 86 nm. Foliar application of 100 mg L-1 Ca-NPs enhanced biomass of canola plants and considered as optimal dose. Ca-NPs at 100 mg L-1 has a greater favorable impact on mesophyll ultrastructure, PSI and PSII efficacy, gas exchange parameters, chlorophyll content, and mineral absorption. The Ca-NPs treatment increased NPQ and Y(NPQ) under drought condition, indicating a higher PSII protective response to stressed conditions with better heat dissipation as a photoprotective component of NPQ. Ca-NPs application also reduced oxidative stress damage as measured by a reduction in reactive oxygen species (ROS) generation in terms of hydrogen peroxide and malondialdehyde (H2O2 and MDA). Furthermore, Ca-NPs induced drought tolerance response corresponded to an increased in key antioxidative defense enzymes (SOD, POD, CAT, APX), as well as non-enzymatic components (protease, lipoxygenase, proline, total soluble protein contents, endogenous hormonal biosynthesis), and secondary metabolite expression in B. napus plants. Taken together, the results of this study offer new insights into the physiological and molecular mechanisms by which B. napus responds to Ca-NPs exposure.
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Brassica napus , Complexe protéique du photosystème II , Calcium , Antioxydants/pharmacologie , Peroxyde d'hydrogèneRÉSUMÉ
Pancreatic cancer has an extremely poor prognosis, and the clinical drugs for the treatment of pancreatic cancer are usually multi-drug combinations. Therefore, it is necessary to search for and find specific new bioactive agents against pancreatic cancer. Carabrone is a carabrane-type sesquiterpenolide extracted from Carpesium cernuum L., and this natural compound has been reported to be a potential anti-tumor agent. However, there are few reports on the function of carabrone related to anti-tumor activity in pancreatic cancer. Herein, cell experiments indicated that carabrone had anti-proliferation inhibition and anti-migration and anti-invasion activity against SW1990 cells. Furthermore, the tandem mass spectrometry and network pharmacology analysis showed that this activity may be related to the ferroptosis and Hippo signaling pathway. Taken together, our results demonstrated that carabrone exhibited prominent anti-pancreatic cancer activity and could be a promising agent against pancreatic cancer.
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Asteraceae , Ferroptose , Tumeurs du pancréas , Asteraceae/composition chimique , Lignée cellulaire tumorale , Prolifération cellulaire , Humains , Pancréas/métabolisme , Tumeurs du pancréas/anatomopathologie , Tumeurs du pancréasRÉSUMÉ
Pictilisib (GDC-0941) is a well-known dual inhibitor of class I PI3K and mTOR and is presently undergoing phase 2 clinical trials for cancer treatment. The present work investigated the dynamic behaviors and interaction mechanism between GDC-0941 and human serum albumin (HSA). Molecular docking and MD trajectory analyses revealed that GDC-0941 bound to HSA and that the binding site was positioned in subdomain IIA at Sudlow's site I of HSA. The fluorescence intensity of HSA was strongly quenched by GDC-0941, and results showed that the HSA-GDC-0941 interaction was a static process caused by ground-state complex formation. The association constant of the HSA-GDC-0941 complex was approximately 105 M-1, reflecting moderate affinity. Thermodynamic analysis conclusions were identical with MD simulation results, which revealed that van der Waals interactions were the vital forces involved in the binding process. CD, synchronous, and 3D fluorescence spectroscopic results revealed that GDC-0941 induced the structural change in HSA. Moreover, the conformational change of HSA affected its molecular sizes, as evidenced by AFM. This work provides a useful research strategy for exploring the interaction of GDC-0941 with HSA, thus helping in the understanding of the transport and delivery of dual inhibitors in the blood circulation system.
Sujet(s)
Phosphatidylinositol 3-kinases , Sérum-albumine humaine , Sites de fixation , Dichroïsme circulaire , Humains , Indazoles , Simulation de docking moléculaire , Simulation de dynamique moléculaire , Inhibiteurs des phosphoinositide-3 kinases , Liaison aux protéines , Sérum-albumine humaine/composition chimique , Spectrométrie de fluorescence , Sulfonamides , Sérine-thréonine kinases TOR , ThermodynamiqueRÉSUMÉ
Background: The role of brain atrophy in cognitive decline related to cerebral small vessel disease (CSVD) remains unclear. This study used AccuBrain™ to identify major CSVD-related brain changes and verified the relationship between brain atrophy and different cognition domains in CSVD patients. Methods: All enrolled 242 CSVD patients and 76 healthy participants underwent magnetic resonance imaging examinations and detailed neuropsychological scale assessments were collected at the same time. The AccuBrain™ technology was applied to fully automated image segmentation, measurement, and calculation of the acquired imaging results to obtain the volumes of different brain partitions and the volume of WMH for quantitative analysis. Correlation analyses were used to estimate the relationship between MRI features and different cognitive domains. Multifactor linear regression models were performed to analyze independent predictors of MTA and cognitive decline. Results: CSVD patients exhibited multiple gray matter nucleus volume decreases in the basal ganglia regions and brain lobes, including the temporal lobe (P = 0.019), especially in the medial temporal lobe (p < 0.001), parietal lobe (p = 0.013), and cingulate lobe (p = 0.036) compare to HC. The volume of PWMH was an independent predictor of MTA for CSVD patients. Both medial temporal atrophy (MTA) and PWMH were associated with cognition impairment in CSVD-CI patients. MTA mediated the effect of PWMH on executive function in CSVD-CI patients. Conclusions: Our results showed that MTA was related to cognition impairment in CSVD patients, which might become a potential imaging marker for CSVD-CI.
RÉSUMÉ
This study systematically evaluated the effects of bentonite as a possible additive to alleviate the "inhibited steady-state" induced by ammonia and acid accumulation during anaerobic digestion. Continuous stirred tank reactors fed with poultry manure were operated at 35 ± 1 °C either with bentonite or not. The results demonstrate that bentonite amendment increased average specific methane production by 35% as suffered from steady-state at an organic loading rate of 6.25 g VS/L·d. 16S rRNA gene amplicon sequencing revealed that the relative abundance of electron-donating Sedimentibacter and Syntrophomonas, and electrophilic Methanosarcina was increased by 110%, 91%, and 49%, respectively. The genera were identified as crucial for alleviating "inhibited steady-state", through establishment of a more robust syntrophic pathway of methanogenic acetate degradation. The enhancement might result from the accelerated electron transfer by bentonite, which is qualified for serving as an exogenetic electron mediator due to containing abundant redox-active metal elements.
Sujet(s)
Fumier , Volaille , Anaérobiose , Animaux , Bentonite , Bioréacteurs , Méthane/métabolisme , Volaille/génétique , Volaille/métabolisme , ARN ribosomique 16S/génétique , ARN ribosomique 16S/métabolismeRÉSUMÉ
Purpose: Combined the number, volume, and location of cerebral microbleeds (CMBs), this study aimed to explore the different features of CMBs and their correlation with cognitive ability in patients with type 2 diabetes mellitus (T2DM). Methods: This study recruited 95 patients with T2DM and 80 healthy control (HC) individuals. AccuBrain®, an automated tool, was used to obtain the number and volume of CMBs. The scores on global cognition and five cognitive domains were derived from a battery of cognitive tests. The logistic regression and multivariate linear regression were conducted to determine the relationship between the CMBs (number, volume, and location) and cognitive ability in patients with T2DM. Results: After adjusting for several variables, the total volume of CMBs (OR = 0.332, 95%CI: 0.133-0.825, and p = 0.018) was independent risk factor for cognitive impairment, whereas the total number of CMBs was not (OR = 0933, 95%CI: 0.794-1.097, and p = 0.400). Furthermore, the volume of CMBs in lobar regions was independently associated with working memory (ß = -0.239, 95%CI: -0.565 to -0.035, and p = 0.027). However, no significant correlation between the number of CMBs (both lobar and deep/infratentorium) and any cognitive domains was observed. Conclusions: Lobar CMBs was related with cognitive impairment in patients with T2DM and might be a potential early warning signal. Compared with the counting analysis, the quantitative method offered a more sensitive and objective measurement for studying imaging features of CMBs.