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1.
Clin Exp Hypertens ; 45(1): 2228517, 2023 Dec 31.
Article in English | MEDLINE | ID: mdl-37358029

ABSTRACT

OBJECTIVE: To investigate coronary artery disease (CAD) and its correlation with the ambulatory arterial stiffness index (AASI) in patients with H-type hypertension (essential hypertension combined with hyper-homocysteinemia) and coronary heart disease (CHD). METHODS: Patients with essential hypertension and CHD who were undergoing coronary angiography were enrolled. The general clinical data, biochemical indicators, ambulatory blood pressure monitoring results and coronary angiography results of the selected patients were collected, and the AASI and Gensini scores were calculated. According to homocysteine (Hcy) levels, the patients were divided into two groups: a study group and a control group. The differences in general clinical data, biochemical indexes, AASI scores and degree of coronary artery lesions between the two groups were compared. The correlation between the AASI and the Gensini score and the relationship between the AASI and the Gensini score of CAD and various factors were analyzed. RESULTS: Compared with the control group, the Hcy level in the study group was significantly increased (8.16 ± 2.33 vs 19.20 ± 2.36, P = .001). The 24-h diastolic blood pressure (DBP) in the study group was significantly lower than that in the control group (76.38 ± 9.33 vs 79.91 ± 9.25, P = .002), and the AASI was significantly higher than in the control group (0.62 ± 0.81 vs 0.420 ± 0.70, P = .001). The number of patients having coronary stenoses with a Gensini score of ≤ 38 was significantly lower in the study group than in the control group (21.3% vs 49.4%, P < .001). The number of patients with a Gensini score of ≥ 51 in the study group was significantly higher than in the control group (22.0% vs 18.8%, P < .001). There was a significant positive correlation between the AASI and the Gensini score in the study group (R = 0.732, P < .001). Hypertension duration (ß = 0.168), diabetes history (ß = 0.236), 24-h SBP (ß = 0.122), 24-h DBP (ß = -0.131), low-density lipoprotein cholesterol (ß = 0.134) and Hcy (ß = 0.233) were the influencing factors for AASI (P < .05). Both Hcy * AASI (ß = 0.356) and Hcy × 24-h HR (ß = 0.331) had a synergistic effect on the Gensini score (P = .017), with Hcy * AASI having a more significant effect on the Gensini score (P < .001). CONCLUSION: The AASI was significantly increased in patients with H-type hypertension and CHD, which was associated with the severity of CAD. Therefore, Hcy levels and the AASI have a synergistic effect when evaluating the severity of CAD in patients with hypertensive CHD.


Subject(s)
Atherosclerosis , Coronary Artery Disease , Hypertension , Vascular Stiffness , Humans , Coronary Artery Disease/diagnosis , Coronary Artery Disease/diagnostic imaging , Vascular Stiffness/physiology , Blood Pressure Monitoring, Ambulatory , Hypertension/complications , Essential Hypertension/complications , Atherosclerosis/complications
2.
Anal Chem ; 94(48): 16864-16870, 2022 12 06.
Article in English | MEDLINE | ID: mdl-36394960

ABSTRACT

Rationally designed new materials for the selective detection and adsorption of 99Tc, a problematic element in nuclear waste, are important and challenging in environmental monitoring. Here, we utilize an interpenetration approach to develop a cationic fluorescent metal-organic framework (NCU-2), which was constructed by a flexible tridentate nitrogen-containing ligand and Ag+ metal ions. The NCU-2 is a scarce case of 14-fold interpenetrated with excellent chemical stability even under 0.5 M HNO3, which is helpful for the detection and removal of ReO4-/TcO4- from nuclear waste. Excitingly, the fluorescence signal of NCU-2 was obviously quenched in the presence of ReO4- (a nonradioactive surrogate of TcO4-) due to the robust interaction between ReO4- and the host for the formation of a non-fluorescent complex. Furthermore, the NCU-2 exhibits a high selectivity sensing of ReO4- in the presence of excess competitive ions. The superior response of NCU-2 toward ReO4- is ascribed to the high-fold structure and the luxuriant unsaturated Ag metal sites on the wall of 1D pore channels, which can enhance the framework positive charge and accelerate the transport of guest molecules to strengthen the interaction between them. Notably, NCU-2 successfully quantified trace levels of ReO4- in simulated Hanford waste with a broad linear range (0.2-200 µM) and a low detection limit of 66.7 nM. Moreover, NCU-2 also shows a high adsorption capacity to ReO4- (541 mg/g) and rapid sorption kinetics, making it extremely attractive for waste monitoring and emergency remediation.


Subject(s)
Metal-Organic Frameworks , Radioactive Waste , Adsorption , Cations , Metals
3.
Mol Pharm ; 18(2): 667-678, 2021 02 01.
Article in English | MEDLINE | ID: mdl-32579365

ABSTRACT

Gasdermin D (GSDMD) plays a causal role in NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis eruption, which has been regarded as a potential therapeutic target for pyroptosis-related diseases including acute gouty arthritis. In the present study, the synthesized PEI-Chol (cholesterol grafted polyethylenimine) was assembled with GSDMD small interfering RNA (siRNA) to form PEI-Chol/siGSDMD polyplexes, which provided high transfection efficiency for siRNA-mediated GSDMD knockdown. Then we evaluated the effect of GSDMD siRNA-loaded PEI-Chol on inflammatory cascades in bone-marrow-derived macrophages (BMDMs) and acute gouty arthritis animal models under MSU exposure. When accompanied by pyroptosis blockade and decreased release of interleukin-1 beta (IL-1ß), NLRP3 inflammasome activation was also suppressed by GSDMD knockdown in vivo and in vitro. Moreover, in MSU-induced acute gouty arthritis mice, blocking GSDMD with siRNA significantly improved ankle swelling and inflammatory infiltration observed in histopathological analysis. Furthermore, investigation using a mouse air pouch model verified the effect of siGSDMD-loaded PEI-Chol on pyroptosis of recruited macrophages and related signaling pathways in response to MSU. These novel findings exhibited that GSDMD knockdown relieved acute gouty arthritis through inhibiting pyroptosis, providing a possible therapeutic approach for MSU-induced acute gouty arthritis molecular therapy using PEI-Chol as a nucleic acid delivery carrier.


Subject(s)
Arthritis, Gouty/drug therapy , Drug Carriers/chemistry , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Phosphate-Binding Proteins/antagonists & inhibitors , Pyroptosis/drug effects , RNA, Small Interfering/administration & dosage , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Arthritis, Experimental/immunology , Arthritis, Experimental/pathology , Arthritis, Gouty/chemically induced , Arthritis, Gouty/immunology , Arthritis, Gouty/pathology , Cells, Cultured , Cholesterol , Gene Knockdown Techniques/methods , Humans , Inflammasomes/drug effects , Inflammasomes/immunology , Inflammasomes/metabolism , Interleukin-1beta/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Male , Mice , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Phosphate-Binding Proteins/genetics , Phosphate-Binding Proteins/metabolism , Polyethyleneimine/chemistry , Primary Cell Culture , Signal Transduction/drug effects , Signal Transduction/immunology , Uric Acid/administration & dosage , Uric Acid/toxicity
4.
Horm Behav ; 105: 95-103, 2018 09.
Article in English | MEDLINE | ID: mdl-30096284

ABSTRACT

Estrogen receptors (ERs) are thought to be associated with the onset and progression of neurodegenerative injuries and diseases, but the relationship and mechanisms underlying between ERs and cognition in type 1 diabetes remain elusive. In the current study, we investigated the effects of ERα and ERß on the memory impairment and apoptosis in streptozotocin-induced diabetic mice. We found that ERα and/or ERß activation using their agonists (0.5 mg/kg E2, PPT or DPN) ameliorate memory impairment in the Morris water maze (MWM) and Y-maze tests and suppress apoptosis as evidenced by decreased caspase-3 activity and increased ratio of Bcl-2/Bax. Importantly, treatment with the pharmacologic ERs agonists caused significant increases in the membrane ERα and ERß expression and subsequent PI3K/Akt, CREB and BDNF activation in the hippocampus of diabetic mice. Our data indicate that ERα and ERß are involved in the cognitive impairment of type 1 diabetes and that activation of ERs via administration of ERs agonists could be a novel and promising strategy for the treatment of diabetic cognitive impairment.


Subject(s)
Cognitive Dysfunction/drug therapy , Diabetes Mellitus, Experimental/drug therapy , Neuroprotective Agents/therapeutic use , Animals , Apoptosis/drug effects , Cognitive Dysfunction/etiology , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/psychology , Estradiol/pharmacology , Estradiol/therapeutic use , Estrogen Receptor alpha/agonists , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/agonists , Estrogen Receptor beta/metabolism , Female , Hippocampus/drug effects , Maze Learning/drug effects , Mice , Mice, Inbred ICR , Neuroprotective Agents/pharmacology , Nitriles/pharmacology , Nitriles/therapeutic use , Ovariectomy , Phenols/pharmacology , Phenols/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Streptozocin
5.
Bioorg Med Chem ; 25(1): 166-174, 2017 01 01.
Article in English | MEDLINE | ID: mdl-28340987

ABSTRACT

A series of curcumin derivatives as potent dual inhibitors of xanthine oxidase (XOD) and urate transporter 1 (URAT1) was discovered as anti-hyperuricemic agents. These compounds proved efficient effects on anti-hyperuricemic activity and uricosuric activity in vivo. More importantly, some of them exhibited proved efficient effects on inhibiting XOD activity and suppressing uptake of uric acid via URAT1 in vitro. Especially, the treatment of 4d was demonstrated to improve uric acid over-production and under-excretion in oxonate-induced hyperuricemic mice through regulating XOD activity and URAT1 expression. Docking study was performed to elucidate the potent XOD inhibition of 4d. Compound 4d may serve as a tool compound for further design of anti-hyperuricemic drugs targeting both XOD and URAT1.


Subject(s)
Curcumin/analogs & derivatives , Curcumin/therapeutic use , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Hyperuricemia/drug therapy , Organic Anion Transporters/antagonists & inhibitors , Organic Cation Transport Proteins/antagonists & inhibitors , Xanthine Oxidase/antagonists & inhibitors , Animals , Curcumin/pharmacology , Enzyme Inhibitors/pharmacology , HEK293 Cells , Humans , Hyperuricemia/metabolism , Male , Mice , Models, Molecular , Organic Anion Transporters/metabolism , Organic Cation Transport Proteins/metabolism , Uric Acid/metabolism , Xanthine Oxidase/metabolism
6.
Zhongguo Dang Dai Er Ke Za Zhi ; 19(12): 1278-1284, 2017 Dec.
Article in Zh | MEDLINE | ID: mdl-29237530

ABSTRACT

OBJECTIVE: To investigate the molecular mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice. METHODS: A total of 24 mice were randomly divided into control group, ovalbumin (OVA)-induced asthma group (OVA group), and JQ1 intervention group (JQ1+OVA group), with 8 mice in each group. OVA sensitization/challenge was performed to establish a mouse model of asthma. At 1 hour before challenge, the mice in the JQ1+OVA group were given intraperitoneal injection of JQ1 solution (50 µg/g). Bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected at 24 hours after the last challenge, and the total number of cells and percentage of eosinophils in BALF were calculated. Pathological staining was performed to observe histopathological changes in lung tissue. RT-PCR and Western blot were used to measure the mRNA and protein expression of E-cadherin and vimentin during epithelial-mesenchymal transition (EMT). RESULTS: Compared with the control group, the OVA group had marked infiltration of inflammatory cells in the airway, thickening of the airway wall, increased secretion of mucus, and increases in the total number of cells and percentage of eosinophils in BALF (P<0.01). Compared with the OVA group, the JQ1+OVA group had significantly alleviated airway inflammatory response and significant reductions in the total number of cells and percentage of eosinophils in BALF (P<0.01). Compared with the control group, the OVA group had significant reductions in the mRNA and protein expression of E-cadherin and significant increases in the mRNA and protein expression of vimentin (P<0.01); compared with the OVA group, the JQ1+OVA group had significant increases in the mRNA and protein expression of E-cadherin and significant reductions in the mRNA and protein expression of vimentin (P<0.01); there were no significant differences in these indices between the JQ1+OVA group and the control group (P>0.05). CONCLUSIONS: Mice with OVA-induced asthma have airway remodeling during EMT. BET bromodomain inhibitor JQ1 can reduce airway inflammation, inhibit EMT, and alleviate airway remodeling, which provides a new direction for the treatment of asthma.


Subject(s)
Airway Remodeling/drug effects , Asthma/drug therapy , Azepines/pharmacology , Triazoles/pharmacology , Animals , Cadherins/analysis , Cadherins/genetics , Epithelial-Mesenchymal Transition , Female , Mice , Nuclear Proteins/antagonists & inhibitors , Ovalbumin/immunology , RNA, Messenger/analysis , Transcription Factors/antagonists & inhibitors , Vimentin/analysis , Vimentin/genetics
7.
Curr Microbiol ; 73(4): 498-502, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27344596

ABSTRACT

Staphylococcus aureus is a well-known organism which is responsible for a variety of human infectious diseases including skin infections, pneumonia, bacteremia, and endocarditis. Few of the microorganisms can be transmitted from mother to the newborn or infant by milk breastfeeding. This study aims to identify transmission of S. aureus from healthy, lactating mothers to their infants by breastfeeding. Stool specimens of diarrheal infants and breast milk of their mother (totally three pairs) were collected and six Staphylococcus aureus isolates were cultured positively. Homology and molecular characters of isolated strains were tested using pulsed-field gel electrophoresis (PFGE), spa typing, and multilocus sequence typing. Furthermore, toxin genes detection was also performed. Each pair of isolates has the same PFGE type and spa type. Four Sequence types (STs) were found among all the isolates; they are ST15, ST188, and ST59, respectively. Among the strains, seb, sec, and tst genes were found, and all were negative for pvl gene. The homology of the S. aureus strains isolated from the infants' stool and the mothers' milk was genetically demonstrated, which indicated that breastfeeding may be important in the transmission of S. aureus infection, and the character of S. aureus needed to be further evaluated.


Subject(s)
Diarrhea, Infantile/microbiology , Milk, Human/microbiology , Staphylococcal Infections/microbiology , Staphylococcus aureus/physiology , Adult , Breast Feeding/adverse effects , China , Diarrhea, Infantile/etiology , Feces/microbiology , Female , Humans , Infant , Infant, Newborn , Infectious Disease Transmission, Vertical , Male , Multilocus Sequence Typing , Staphylococcal Infections/etiology , Staphylococcal Infections/transmission , Staphylococcus aureus/classification , Staphylococcus aureus/genetics , Staphylococcus aureus/isolation & purification , Young Adult
8.
Int J Neuropsychopharmacol ; 19(1)2015 Sep 10.
Article in English | MEDLINE | ID: mdl-26362775

ABSTRACT

BACKGROUND: Emerging data have demonstrated that peroxisome proliferator-activated receptor δ (PPARδ) activation confers a potentially neuroprotective role in some neurodegenerative diseases. However, whether PPARδ is involved in depression is unknown. METHODS: In this study, PPARδ was firstly investigated in the chronic mild stress (CMS) and learned helplessness (LH) models of depression. The changes in depressive behaviors and hippocampal neurogenesis were investigated after PPARδ overexpression by microinfusion of the lentiviral vector, containing the coding sequence of mouse PPARδ (LV-PPARδ), into the bilateral dentate gyri of the hippocampus or PPARδ activation by repeated systemic administration of PPARδ agonist GW0742 (5 or 10mg/kg.d, i.p., for 21 d). RESULTS: We found that both CMS and LH resulted in a significant decrease in the PPARδ expression in the hippocampi of mice, and this change was reversed by treatment with the antidepressant fluoxetine. PPARδ overexpression and PPARδ activation each suppressed the CMS- and LH-induced depressive-like behavior and produced an antidepressive effect. In vivo or in vitro studies also showed that both overexpression and activation of PPARδ enhanced proliferation or differentiation of neural stem cells in the hippocampi of mice. CONCLUSIONS: These results suggest that hippocampal PPARδ upregulation represses stress-induced depressive behaviors, accompanied by enhancement of neurogenesis.


Subject(s)
Depression/complications , Depression/pathology , Hippocampus/metabolism , Neurogenesis/physiology , PPAR delta/metabolism , Stress, Psychological/complications , Animals , Cell Differentiation , Disease Models, Animal , Gene Expression Regulation/physiology , Glial Fibrillary Acidic Protein/metabolism , Hindlimb Suspension , Male , Mice , Mice, Inbred ICR , Neural Stem Cells/physiology , PPAR delta/genetics , Phosphopyruvate Hydratase/metabolism , Sincalide/metabolism , Thiazoles/pharmacology , Time Factors , Transduction, Genetic
9.
Nucleic Acids Res ; 41(3): 1859-72, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-23268443

ABSTRACT

The C-terminal extension of prokaryotic leucyl-tRNA synthetase (LeuRS) has been shown to make contacts with the tertiary structure base pairs of tRNA(Leu) as well as its long variable arm. However, the precise role of the flexibly linked LeuRS C-terminal domain (CTD) in aminoacylation and editing processes has not been clarified. In this study, we carried out aspartic acid scanning within the CTD of Mycobacterium tuberculosis LeuRS (MtbLeuRS) and studied the effects on tRNA(Leu)-binding capacity and enzymatic activity. Several critical residues were identified to impact upon the interactions between LeuRS and tRNA(Leu) due to their contributions in the maintenance of structural stability or a neutral interaction interface between the CTD platform and tRNA(Leu) elbow region. Moreover, we propose Arg921 as a crucial recognition site for the tRNA(Leu) long variable arm in aminoacylation and tRNA-dependent pre-transfer editing. We also show here the CTD flexibility conferred by Val910 in regulation of LeuRS-tRNA(Leu) interaction. Taken together, our results suggest the structural importance of the CTD in modulating precise interactions between LeuRS and tRNA(Leu) during the quality control of leucyl-tRNA(Leu) synthesis. This system for the investigation of the interactions between MtbLeuRS and tRNA(Leu) provides a platform for the development of novel antitubercular drugs.


Subject(s)
Leucine-tRNA Ligase/chemistry , Mycobacterium tuberculosis/enzymology , RNA Editing , Transfer RNA Aminoacylation , Amino Acid Sequence , Leucine-tRNA Ligase/genetics , Leucine-tRNA Ligase/metabolism , Molecular Sequence Data , Mutagenesis , Protein Structure, Tertiary , RNA, Transfer, Leu/metabolism , Two-Hybrid System Techniques
10.
Nat Commun ; 15(1): 1558, 2024 Feb 20.
Article in English | MEDLINE | ID: mdl-38378705

ABSTRACT

Extracting rare earth elements (REEs) from wastewater is essential for the growth and an eco-friendly sustainable economy. However, it is a daunting challenge to separate individual rare earth elements by their subtle differences. To overcome this difficulty, we report a unique REE nanotrap that features dense uncoordinated carboxyl groups and triazole N atoms in a two-fold interpenetrated metal-organic framework (named NCU-1). Notably, the synergistic effect of suitable pore sizes and REE nanotraps in NCU-1 is highly responsive to the size variation of rare-earth ions and shows high selectivity toward light REE. As a proof of concept, Pr/Lu and Nd/Er are used as binary models, which give a high separation factor of SFPr/Lu = 796 and SFNd/Er = 273, demonstrating highly efficient separation over a single step. This ability achieves efficient and selective extraction and separation of REEs from mine tailings, establishing this platform as an important advance for sustainable obtaining high-purity REEs.

11.
J Med Chem ; 67(14): 11989-12011, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-38959216

ABSTRACT

The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.


Subject(s)
Inflammatory Bowel Diseases , Receptors, Purinergic P2 , Thiophenes , Animals , Thiophenes/pharmacology , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/therapeutic use , Humans , Mice , Inflammatory Bowel Diseases/drug therapy , Receptors, Purinergic P2/metabolism , Structure-Activity Relationship , Purinergic P2 Receptor Antagonists/pharmacology , Purinergic P2 Receptor Antagonists/chemistry , Purinergic P2 Receptor Antagonists/chemical synthesis , Purinergic P2 Receptor Antagonists/therapeutic use , Male , Drug Discovery , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Amides/therapeutic use , Microsomes, Liver/metabolism , Molecular Dynamics Simulation , Colitis/drug therapy
12.
Bioorg Med Chem ; 21(19): 6084-91, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23962660

ABSTRACT

Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR-TK inhibitory activity. Especially, N(6)-((5-bromothiophen-2-yl)methyl)-N(4)-(3-chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC50=3.11µM for Hep G2, IC50=0.82µM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells.


Subject(s)
Aniline Compounds/chemical synthesis , Antineoplastic Agents/chemical synthesis , Drug Discovery , ErbB Receptors/antagonists & inhibitors , Quinazolines/chemical synthesis , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Hep G2 Cells , Humans , Inhibitory Concentration 50 , Molecular Structure , Protein Binding/drug effects , Quinazolines/chemistry , Quinazolines/pharmacology , Structure-Activity Relationship
13.
Nucleic Acids Res ; 39(1): 235-47, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20805241

ABSTRACT

To prevent potential errors in protein synthesis, some aminoacyl-transfer RNA (tRNA) synthetases have evolved editing mechanisms to hydrolyze misactivated amino acids (pre-transfer editing) or misacylated tRNAs (post-transfer editing). Class Ia leucyl-tRNA synthetase (LeuRS) may misactivate various natural and non-protein amino acids and then mischarge tRNA(Leu). It is known that the fidelity of prokaryotic LeuRS depends on multiple editing pathways to clear the incorrect intermediates and products in the every step of aminoacylation reaction. Here, we obtained human cytoplasmic LeuRS (hcLeuRS) and tRNA(Leu) (hctRNA(Leu)) with high activity from Escherichia coli overproducing strains to study the synthetic and editing properties of the enzyme. We revealed that hcLeuRS could adjust its editing strategy against different non-cognate amino acids. HcLeuRS edits norvaline predominantly by post-transfer editing; however, it uses mainly pre-transfer editing to edit α-amino butyrate, although both amino acids can be charged to tRNA(Leu). Post-transfer editing as a final checkpoint of the reaction was very important to prevent mis-incorporation in vitro. These results provide insight into the modular editing pathways created to prevent genetic code ambiguity by evolution.


Subject(s)
Amino Acyl-tRNA Synthetases/metabolism , Aminobutyrates/metabolism , Leucine-tRNA Ligase/metabolism , Transfer RNA Aminoacylation , Valine/analogs & derivatives , Amino Acyl-tRNA Synthetases/genetics , Escherichia coli/genetics , Humans , Leucine-tRNA Ligase/genetics , Mutation , RNA, Transfer, Leu/metabolism , Valine/metabolism
14.
Pharmacology ; 92(1-2): 75-83, 2013.
Article in English | MEDLINE | ID: mdl-23942050

ABSTRACT

AIMS: The aim of the present study was to investigate the effects of rutin on potassium oxonate-induced hyperuricemia and renal dysfunction in mice. METHODS: Rutin was administered orally 1 h after oxonate at doses of 25, 50 and 100 mg·kg(-1). Serum uric acid levels and kidney function parameters were assayed. Mouse uromodulin levels in serum, urine and kidney were determined by the ELISA method. Simultaneously, the expression levels of renal organic ion transporters were detected. RESULTS: Rutin significantly decreased serum urate, creatinine and blood urea nitrogen, serum and kidney uromodulin levels, and increased urine uromodulin, urate and creatinine excretion in hyperuricemic mice. Rutin at 50 and 100 mg·kg(-1) significantly downregulated mRNA and protein levels of mouse glucose transporter 9 and urate transporter 1, and upregulated mRNA and protein levels of organic anion transporter 1 and organic cation/carnitine transporters in the kidney of hyperuricemic mice. CONCLUSIONS: Rutin exerted its hypouricemic action and renal function improvement by the regulation of renal organic ion transporters.


Subject(s)
Hyperuricemia/drug therapy , Kidney Diseases/drug therapy , Rutin/therapeutic use , Animals , Carrier Proteins/metabolism , Glucose Transport Proteins, Facilitative/genetics , Glucose Transport Proteins, Facilitative/metabolism , Hyperuricemia/chemically induced , Hyperuricemia/metabolism , Kidney Diseases/chemically induced , Kidney Diseases/metabolism , Male , Membrane Proteins/metabolism , Mice , Octamer Transcription Factor-1/metabolism , Organic Anion Transport Protein 1/genetics , Organic Anion Transport Protein 1/metabolism , Organic Anion Transporters/genetics , Organic Anion Transporters/metabolism , Organic Cation Transport Proteins/metabolism , Organic Cation Transporter 2 , Oxonic Acid , RNA, Messenger/metabolism , Rutin/pharmacology , Solute Carrier Family 22 Member 5 , Symporters , Uromodulin/genetics , Uromodulin/metabolism
15.
Molecules ; 18(8): 8976-93, 2013 Jul 29.
Article in English | MEDLINE | ID: mdl-23899832

ABSTRACT

The potent anti-hyperuricemia activities of Fructus Gardenia Extract (FGE) have been well reported. The aim of this study was to evaluate the uricosuric and nephro-protective effects of FGE and explore its possible mechanisms of action in oxonate-induced hyperuricemic mice. FGE was orally administered to hyperuricemic and normal mice for 1 week. Serum and urinary levels of uric acid, creatinine and blood urea nitrogen (BUN), and fractional excretion of uric acid (FEUA) were measured. The mRNA and protein levels of mouse urate transporter 1 (mURAT1), glucose transporter 9 (mGLUT9), ATP-binding cassette, subfamily G, 2 (mABCG2), organic anion transporter 1 (mOAT1), mOAT3, oncoprotein induced transcript 3 (mOIT3), organic cation/carnitine transporters in the kidney were analyzed. Simultaneously, Tamm-Horsfall glycoprotein (THP) levels in urine and kidney were detected. FGE significantly reduced serum urate levels and increased urinary urate levels and FEUA in hyperuricemic mice. It could also effectively reverse oxonate-induced alterations in renal mURAT1, mGLUT9, mOAT1 and mOIT3 expressions, as well as THP levels, resulting in the enhancement of renal uric acid excretion. Moreover, FGE decreased serum creatinine and BUN levels, and up-regulated expression of organic cation/carnitine transporters, improving renal dysfunction in this model. Furthermore, FGE decreased renal mABCG2 expressions in hyperuricemic mice, contributing to its beneficial actions. However, further investigation is needed in clinical trials of FGE and its bioactive components.


Subject(s)
Gene Expression Regulation/drug effects , Hyperuricemia/drug therapy , Plant Extracts/administration & dosage , Renal Insufficiency/drug therapy , Animals , Blood Urea Nitrogen , Gardenia/chemistry , Humans , Hyperuricemia/chemically induced , Hyperuricemia/pathology , Mice , Oxonic Acid/toxicity , Renal Insufficiency/chemically induced , Renal Insufficiency/pathology , Uric Acid/metabolism
16.
J Hazard Mater ; 446: 130744, 2023 Mar 15.
Article in English | MEDLINE | ID: mdl-36630874

ABSTRACT

Effective and selective removal of 99TcO4-, one of the most nuisance radionuclides in nuclear waste, is highly desirable but remains a significant challenge. Herein, two isostructural MOFs, NCU-3-X (X = Cl, Br) were constructed by ZnX2 coordinated to nitrogen-containing neutral ligand tri(4-(1H-imidazole-1-l) phenyl) amine for efficient adsorption ReO4-/TcO4-. Owning to the twofold interpenetrating structure, both of them exhibit strong alkaline resistance. Consequently, NCU-3-Br exhibited superior adsorption performances with a maximum capacity as high as 483 mg/g, which is 2.23 times larger than that of NCU-3-Cl. The primary reasons accounting for the enhanced adsorption performances of NCU-3-Br are that compared to chlorine atoms, the smaller electronegativity of bromine atoms as halogen bonds donor can facilitate the formation of σ-holes, enhance positively charged skeleton, and reduce the adsorption energy associated with ReO4-/TcO4-. In addition, the one-dimensional hydrophobic channels in the NCU-3-Br framework enable NCU-3-Br to have highly selective toward ReO4-, which has a low relative charge density against interfering ions. The SRS simulation removal experiment further confirmed the excellent adsorption capacity of NCU-3-Br to ReO4-/TcO4-. This work illustrated that the halogenated new strategy incorporated different halogen atoms into MOF skeletons can dramatically modulate the adsorption performances for ReO4-/TcO4-.

17.
J Hazard Mater ; 443(Pt B): 130325, 2023 02 05.
Article in English | MEDLINE | ID: mdl-36372023

ABSTRACT

The elimination of anion is of great importance from radioactive nuclear waste containing 99TcO4- by rationally designing anion-scavenging materials with high density of charge and more accessible adsorption sites. Herein, a tailor-made cationic organic polymer with donor-acceptor (D-A) structure, namely TrDCPN, was successfully synthesized by rationally modifying the benzimidazole unit for efficient trapping the perrhenate (ReO4-) as a 99Tc surrogate. Systematic control of the skeleton affect enables the material to integrate a variety of features, surmounting the long-term challenge of 99TcO4-/ReO4- remediation under extreme conditions of high acid/base and high ionic strength. Furthermore, the TrDCPN shows excellent affinity toward ReO4- in the existence of large excess of competitive anions (SO42-, NO3- and PO43-etc.) as well as promising reusability for trapping ReO4-. The excellent stability and separation were derived from the introduction of large conjugated modules, triazine core and hydrophobic. More importantly, the synthetic cationic organic polymer with D-A feature was first proved that the introduction of halogen can effectively enhance the backbone charge, and increase the adsorption capacity by synergy of ion exchange, electrostatic interaction and δ hole-anion interaction. The adsorption capacity of TrDCPN can be up to 420.3 mg/g and reach equilibrium within 20 min. It is noteworthy that TrDCPN successfully immobilizes ReO4- from simulated Hanford waste with a high separation efficiency of 93 %, providing a new paradigm for material design to dispose of the problem of radioactive pollutants in the environment.


Subject(s)
Halogens , Radioactive Waste , Polymers , Cations , Adsorption , Ion Exchange
18.
Front Cell Infect Microbiol ; 13: 1254379, 2023.
Article in English | MEDLINE | ID: mdl-37692161

ABSTRACT

Vibrio vulnificus, a foodborne pathogen, has a high mortality rate. Despite its relevance to public health, the identification of virulence genes associated with the pathogenicity of currently known clinical isolates of V. vulnificus is incomplete and its synergistic pathogenesis remains unclear. Here, we integrate whole genome sequencing (WGS), genome-wide association studies (GWAS), and genome-wide epistasis studies (GWES), along with phenotype characterization to investigate the pathogenesis and survival strategies of V. vulnificus. GWAS and GWES identified a total of six genes (purH, gmr, yiaV, dsbD, ramA, and wbpA) associated with the pathogenicity of clinical isolates related to nucleotide/amino acid transport and metabolism, cell membrane biogenesis, signal transduction mechanisms, and protein turnover. Of these, five were newly discovered potential specific virulence genes of V. vulnificus in this study. Furthermore, GWES combined with phenotype experiments indicated that V. vulnificus isolates were clustered into two ecological groups (EGs) that shared distinct biotic and abiotic factors, and ecological strategies. Our study reveals pathogenic mechanisms and their evolution in V. vulnificus to provide a solid foundation for designing new vaccines and therapeutic targets.


Subject(s)
Metagenomics , Vibrio vulnificus , Vibrio vulnificus/genetics , Genome-Wide Association Study , Amino Acids , Biological Transport
19.
J Thorac Dis ; 15(6): 3372-3385, 2023 Jun 30.
Article in English | MEDLINE | ID: mdl-37426151

ABSTRACT

Background: Data are quite sparse on the comprehensive analyses of pulmonary hypertension (PH) clinical trials worldwide. Methods: Information including participating countries (developed or developing), intervention type, trial size, PH categories, sponsorship, study phase, design strategies, and participants' demographic characteristics was extracted from PH trials registered on ClinicalTrials.gov from 1999 to 2021. Results: A total of 203 eligible clinical PH trials were screened, involving 23,402 participants, 67.8% of whom were females. Major clinical trials were designed to test drug interventions (95.6%), sponsored solely by industries in 59.5%, and targeting Group 1 PH patients in 76.3%. A large number of countries participated in PH clinical trials; however, most clinical trials were conducted in developed countries (84.2%). Developing countries were involved in clinical trials with larger sample sizes (P<0.01). Additionally, the differences between developed and developing countries centered on interventions, sponsors, PH groups, and design strategies. Furthermore, developing countries participated in multinational clinical trials with good quality, homogeneity, reliability, and data authenticity. All pediatric participants were diagnosed with Group 1 PH and were only involved in drug intervention trials. Children participated in far fewer clinical trials than adults (P<0.01), and most were enrolled in PH clinical trials in developed countries. Among the entire clinical trial population, younger patients with Group 1 PH had a much higher participation to prevalence ratio (PPR). There was no difference in women's PPRs between developed and developing countries. However, developing countries had higher PPRs for PH Groups I and IV (1.28 vs. 1.22, P<0.01), while developed countries had a lower PPR for Group III (P=0.02). Conclusions: PH is attracting increasing global attention, which is not at the same level of progress in developed and developing countries. Women and children with this disease have unique characteristics and require more attention.

20.
J Gastroenterol ; 58(7): 668-681, 2023 07.
Article in English | MEDLINE | ID: mdl-37150773

ABSTRACT

BACKGROUND: The activation of hepatic stellate cells (HSCs) is the key step in the pathogenesis of liver fibrosis, which directly leads to fibrotic pathological changes in the hepatic tissue. Mitochondrial stress exacerbates inflammatory diseases by inducing pathogenic shifts in normal cells. However, the role of mitochondrial stress in HSC activation remains to be elucidated.  METHODS: We analyzed the effect of mitochondrial stress on HSC activation. An in vivo hepatic fibrosis model was established by intraperitoneal injection of 40% carbon tetrachloride (CCl4) for 12 weeks. Additionally, using in vitro approach, HSC-T6 cells were treated with 10 ng/mL platelet-derived growth factor-BB (PDGF-BB) for 24 h. RESULTS: Transcriptional activator 4 (ATF4) is highly expressed in fibrotic liver tissue samples and activated HSCs. We found that AAV8-shRNA-Atf4 alleviated liver fibrosis in rats. ATF4 promoted the activation of HSCs, which was induced by mitochondrial stress. The mechanisms involved ATF4 binding to a specific region of the tribble homologue 3 (TRIB3) promoter. Further, TRIB3 promoted HSCs activation mediated by mitochondrial stress. CONCLUSIONS: ATF4 induces mitochondrial stress by upregulating TRIB3, leading to the activation of HSCs. Therefore, the inhibition of ATF4 during mitochondrial stress may be a promising therapeutic target for liver fibrosis.


Subject(s)
Hepatic Stellate Cells , Liver , Rats , Animals , Hepatic Stellate Cells/metabolism , Liver/pathology , Liver Cirrhosis/pathology , Becaplermin/adverse effects , Becaplermin/metabolism , Fibrosis
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