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1.
Int J Biol Macromol ; : 123473, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36731707

RESUMO

Uncontrolled hemorrhage is a main cause of pre-hospital death. Given the importance of hemostatic wound dressings in pre-hospital emergency treatment, novel composite materials are required for fast hemostasis, synergistic bacterial ablation with negligible resistance and wound healing acceleration. Herein, multifunctional SCTF cryogels were fabricated by the simultaneous cross-linking of sodium alginate (SA) and tannic acid (TA) with Fe3+ ions. As a result, the prepared SCTF cryogels consisted of Fe3+/TA-based metal phenolic networks (MPNs) and Fe3+/SA-based 3D skeleton for collagen (CA). MPNs endowed the cryogels with photothermal effect, photothermal-enhanced Fenton activity and pH/photothermal dual-responsive release property of TA and Fe2+, which were beneficial for the antibacterial capacity. Due to the intrinsic high porosity, in vitro and in vivo assays demonstrated that SCTF cryogels possessed good hemostatic capacity. Moreover, the synergistic photothermal therapy (PTT), chemodynamic therapy (CDT) and pH/photothermal responsive chemo-therapy dramatically enhanced the bactericidal efficacy of SCTF cryogels both in vitro and in vivo. Eventually, their outstanding healing-accelerating effects were confirmed via animal experiments, which were attributed to the presence of CA and TA. Therefore, the developed composite materials could offer new strategy on exploiting multifunctional wound dressing for clinical applications in the future.

2.
J Colloid Interface Sci ; 635: 265-272, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36587578

RESUMO

With the proposal of carbon peaking and carbon neutrality goals, clean energy storage is attracting more and more attentions. In view of the lack of lithium resource in our earth, sodium-ion batteries are considered as the emerging and promising next-generation energy storage devices. Appropriate high-performance anode materials play a vital role in the development of sodium-ion batteries. Here, a core-shell hollow Ni-Co-P nanopolyhedron interconnected by oxygen defect TiO2 (Ni-Co-P@TiO2-x) is reported, which is synthesized by ion etching-hydrolysis and subsequent phosphatization/hydrogenation treatment using ZIF-67 as template and hybrid carbon source. The achieved Ni-Co-P@TiO2-x material has several distinct advantages including hollow core-shell structure, flexible conductive carbon matrix, stable electroactive coating layer, and efficient pseudocapacitive behavior, resulting in high reversible capacities, remarkable rate capability and excellent cycle stability. The synergetic battery-capacitor characteristic of Ni-Co-P@TiO2-x material makes it become a promising anode for sodium-ion batteries.

3.
Exp Ther Med ; 25(1): 64, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36605531

RESUMO

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infection and increased incidence of autoimmune disorders and malignancy. WAS is caused by mutations in the was gene, which is expressed exclusively in hematopoietic cells; the spleen serves an important role in hematopoiesis and red blood cell clearance. However, to the best of our knowledge, detailed comparative analysis of the spleen between WASp-knockout (WAS-KO) and wild-type (WT) mice, particularly at the transcriptomic level, have not been reported. The present study investigated the differences in the transcriptomes of spleen tissue of 10-week-old WAS-KO mice. Comparison of the gene expression profiles of WAS-KO and WT mice revealed 1,964 differentially expressed genes (DEGs). Among these genes, 996 DEGs were upregulated and 968 were downregulated in WAS-KO mice. To determine the functions of DEGs, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed for significantly upregulated and downregulated DEGs. The results showed that the levels of cell senescence and apoptosis-associated genes were increased, antigen processing and presentation mechanisms involved in the immune response were damaged and signal transduction processes were impaired in the spleen of WAS-KO mice. Thus, was gene deletion may lead to anemia and hemolysis-associated disease, primarily due to increased osmotic fragility of red blood cells, low hemoglobin and increased bilirubin levels and serum ferritin. These results indicated that senescence and apoptosis of blood cells also play an important role in the occurrence of WAS. Therefore, the present findings provide a theoretical basis for further study to improve the treatment of WAS.

4.
Nanoscale Horiz ; 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36633326

RESUMO

Transition metal sulfides (TMSs) are promising electrocatalysts for hydrogen evolution reaction (HER), while TMSs usually suffer from inevitable surface oxidation in air, and the impact of the surface oxidation on their HER catalytic activity remains unclear. Herein, we demonstrate an effective strategy for reducing the surface oxidation degree of easily oxidized CoS2 by introducing glued vanadium pentoxide (V2O5) nanoclusters, taking advantage of the preferential adsorption and strong interaction between high-valence V and O2. Combining oxidation protection and elaborate oxidation control experiments reveal that reduced surface oxidation degree of CoS2 is conducive to affording promising HER catalytic performance, as the oxidized surface of CoS2 can hinder the dissociation of water and thus is harmful to the HER process. Direct evidence is provided that surface oxidation should be carefully considered for TMS-based HER catalysts. The present work not only develops a new strategy for protecting CoS2 from surface oxidation, but also provides deep insight into the impact of surface oxidation on the HER performance of transition metal compounds.

5.
J Chem Phys ; 158(1): 014702, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36610967

RESUMO

Ion transport in solids is a key topic in solid-state ionics. It is critical but challenging to understand the relationship between material structures and ion transport. Nanochannels in crystals provide ion transport pathways, which are responsible for the fast ion transport in fast lithium (Li)-ion conductors. The controlled synthesis of carbon nanotubes (CNTs) provides a promising approach to artificially regulating nanochannels. Herein, the CNTs with a diameter of 5.5 Å are predicted to exhibit an ultralow Li-ion diffusion barrier of about 10 meV, much lower than those in routine solid electrolyte materials. Such a characteristic is attributed to the similar chemical environment of a Li ion during its diffusion based on atomic and electronic structure analyses. The concerted diffusion of Li ions ensures high ionic conductivities of CNTs. These results not only reveal the immense potential of CNTs for fast Li-ion transport but also provide a new understanding for rationally designing solid materials with high ionic conductivities.

6.
Sensors (Basel) ; 23(2)2023 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-36679509

RESUMO

We propose and implement a terahertz time-of-flight ranging system based on adaptive clock asynchronous optical sampling, where the timing jitter is corrected in real time to recover the depth information in the acquired interferograms after compensating for laser instabilities using electronic signal processing. Consequently, the involved measurement uncertainties caused by the timing jitter during the terahertz sampling process and the noise intensity of the terahertz electric field have been reduced by the utilization of the adaptive clock. The achieved uncertainty range is about 2.5 µm at a 5 cm distance after averaging the acquisition time of 1876 ms 5000 times, showing a significant improvement compared with the asynchronous optical sampling using a constant clock. The implemented terahertz ranging system only uses free-running mode-locked lasers without any phase-locked electronics, and this favors simple and robust operations for subsequent applications that extend beyond the laboratory conditions.


Assuntos
Eletricidade , Eletrônica , Laboratórios , Processamento de Sinais Assistido por Computador , Incerteza
7.
Sensors (Basel) ; 23(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36679832

RESUMO

Accurate state-of-charge (SOC) estimation is essential for maximizing the lifetime of battery-powered wireless sensor networks (WSNs). Lightweight estimation methods are widely used in WSNs due to their low measurement and computation requirements. However, accuracy of existing lightweight methods is not high, and their adaptability to different batteries and working conditions is relatively poor. This paper proposes a lightweight SOC estimation method, which applies Peukert's Law to estimate the effective capacity of the battery and then calculates the SOC by subtracting the cumulative current consumption from the estimated capacity. In order to evaluate the proposed method comprehensively, different primary batteries and working conditions (constant current, constant resistance, and emulated duty-cycle loads) are employed. Experimental results show that the proposed method is superior to existing methods for different batteries and working conditions, which mainly benefits from the ability of Peukert's Law to better model the rate-capacity effect of the batteries.


Assuntos
Fontes de Energia Elétrica , Eletricidade , Registros , Condições de Trabalho
8.
Nature ; 613(7944): 496-502, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36653571

RESUMO

Organic electrochemical transistors (OECTs) and OECT-based circuitry offer great potential in bioelectronics, wearable electronics and artificial neuromorphic electronics because of their exceptionally low driving voltages (<1 V), low power consumption (<1 µW), high transconductances (>10 mS) and biocompatibility1-5. However, the successful realization of critical complementary logic OECTs is currently limited by temporal and/or operational instability, slow redox processes and/or switching, incompatibility with high-density monolithic integration and inferior n-type OECT performance6-8. Here we demonstrate p- and n-type vertical OECTs with balanced and ultra-high performance by blending redox-active semiconducting polymers with a redox-inactive photocurable and/or photopatternable polymer to form an ion-permeable semiconducting channel, implemented in a simple, scalable vertical architecture that has a dense, impermeable top contact. Footprint current densities exceeding 1 kA cm-2 at less than ±0.7 V, transconductances of 0.2-0.4 S, short transient times of less than 1 ms and ultra-stable switching (>50,000 cycles) are achieved in, to our knowledge, the first vertically stacked complementary vertical OECT logic circuits. This architecture opens many possibilities for fundamental studies of organic semiconductor redox chemistry and physics in nanoscopically confined spaces, without macroscopic electrolyte contact, as well as wearable and implantable device applications.

9.
Int J Mol Sci ; 24(2)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36674730

RESUMO

This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor ZA-2 with a fluorosulfate warhead in the structure was found to be a potent inhibitor (EC50 = 11-246 nM) against HIV-1 IIIB and a panel of NNRTIs-resistant strains, being far superior to those of NVP and EFV. Moreover, ZA-2 was demonstrated with lower cytotoxicity (CC50 = 125 µM). In the reverse transcriptase inhibitory assay, ZA-2 exhibited an IC50 value of 0.057 µM with the ELISA method, and the MALDI-TOF MS data demonstrated the covalent binding mode of ZA-2 with the enzyme. Additionally, the molecular simulations have also demonstrated that compounds can form covalent binding to the Tyr318.


Assuntos
Fármacos Anti-HIV , HIV-1 , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , HIV-1/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/metabolismo , Desenho de Fármacos , Relação Estrutura-Atividade
10.
Clin Transplant ; : e14904, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36594638

RESUMO

BACKGROUND: The new United Network for Organ Sharing (UNOS) heart allocation policy prioritizes temporary percutaneous over durable left ventricular assist devices (LVAD) as bridge to transplant. We sought to examine one-year outcomes of heart transplant recipients bridged with Impella versus durable LVADs. METHODS: All primary adult orthotopic heart transplant recipients registered in UNOS between January 2016 to June 2021 were analyzed. Recipients were identified as being bridged with isolated durable or percutaneous LVAD at the time of transplant. Baseline characteristics were compared and one-year survival was examined using the Kaplan Meier method and multivariable Cox proportional hazards regression. RESULTS: During our study period, heart transplant recipients bridged with LVADs were divided between 5,422(94%) durable and 324(6%) percutaneous options. Impella-bridged recipients were more likely to be status 1A under the old allocation system (98% vs 70%, p<0.01) and status 2 or higher under the new allocation system (99% vs 24%, p<0.01). Impella-bridged recipients were less likely to be obese (27% vs 42%, p<0.01), have ischemic cardiomyopathy (27% vs 34%, p<0.01), and were more likely to be on inotropic agents at the time of transplant (68% vs 6%, p<0.01). One-year post-transplant survival was not significantly different between the two groups on univariable (HR 0.87, 95% CI 0.56-1.37) or multivariable analysis (aHR 0.63, 95% CI 0.37-1.07). CONCLUSIONS: Following the UNOS allocation policy change, Impella utilization has increased with no significant difference in one-year survival compared to bridge with durable LVADs. Impella may be a reasonable alternative to durable LVADs in select patients. This article is protected by copyright. All rights reserved.

11.
ACS Appl Mater Interfaces ; 15(4): 5845-5855, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36652453

RESUMO

In the background of air pollution and regular COVID-19 prevention, personal protective masks are necessary for our daily life. However, protective masks with high PM0.3 filtration usually have poor air permeability and are mostly disposable, leading to a heavy burden on the environment. In this work, a reusable membrane based on piezoelectric poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)] nanofibers embedded with BaTiO3 nanoparticles (BTO NPs) was developed. The P(VDF-TrFE)/BTO composite nanofibers not only have enhanced piezoelectricity and surface polarity but also have reduced diameters that could be beneficial for electrostatic adhesion, pole-polar interactions, and mechanical sieving to increase the PM0.3 capture capacity. Moreover, the BTO NPs also improved the charge storage capacity of the composite membrane, which could further enhance the PM0.3 filtration efficiency after corona treatment. The piezoelectric mask based on P(VDF-TrFE)/BTO composite nanofibers has high filtration efficiencies of 96% for PM0.3 and 98% for bacteria, while the pressure drop was only 182 Pa, which is lower than the commercial N95 standard of 343.2 Pa. Furthermore, the piezoelectric mask has a long and stable filtration performance after 5 cycles of 75% alcohol disinfection, demonstrating that the P(VDF-TrFE)/BTO composite membrane has a potential application in personal protective masks with comfortable and reusable properties.

12.
Eur J Pharmacol ; 941: 175502, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36638952

RESUMO

BACKGROUND: Hypoxia is a risk factor of pulmonary hypertension (PH) and may induce pulmonary artery endothelial cells (PAECs) injury and inflammation. Pyroptosis is a form of cell death through maturation and secretion of inflammatory mediators. However, the mechanistic association of pyroptosis, PAECs injury, and inflammation remain unknown. Here, we explored in detail the effects of hypoxia on pyroptosis of PAECs. EXPERIMENTAL APPROACH: Using RNA sequencing, we screened differentially expressed genes in pulmonary artery tissue of a Sugen5416/hypoxia-induced (SuHx) rat PH model. We examined the role of the differentially expressed gene G-protein coupled receptor 146 (GPR146) in PAECs through immunohistochemistry, immunofluorescence, CCK-8 assays, western blotings, real-time PCR, detection of reactive oxygen species, and lactate dehydrogenase release experiments. KEY RESULTS: According to RNA sequencing, GPR146 was 11.64-fold increased in the SuHx-induced PH model, compared to the controls. Further, GPR146 was highly expressed in pulmonary arterial hypertension human lung tissue and SuHx-induced rat PH lung tissues. Our results suggested that the expression of pyroptosis-related proteins was markedly increased under hypoxia, both in vivo and in vitro, which was inhibited by silencing GPR146. Moreover, inhibiting NLRP3 or caspase-1 effectively suppressed cleavage of caspase-1, production of interleukin (IL)-1ß, IL-6, and IL-18 in PAECs by hypoxia and overexpression of GPR146. CONCLUSION: Our results indicated that GPR146 induced pyroptosis and inflammatory responses through the NLRP3/caspase-1 signaling axis, thus triggering endothelial injury and vascular remodeling. Hypoxia may promote PAECs pyroptosis through upregulation of GPR146 and thereby facilitate the progression of PH. Taken together, these insights may help identify a novel target for the treatment of PH.


Assuntos
Hipertensão Pulmonar , Piroptose , Humanos , Ratos , Animais , Artéria Pulmonar/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células Endoteliais , Remodelação Vascular , Hipóxia/complicações , Hipóxia/metabolismo , Hipertensão Pulmonar/metabolismo , Caspase 1/metabolismo , Inflamação/metabolismo
13.
Medicine (Baltimore) ; 102(2): e32659, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36637931

RESUMO

RATIONALE: Lactic acidosis is a disease in which lactic acid accumulates in the blood and causes acidosis in the patient. The criteria for diagnosis are a lactate level of >2 mmol/L in the blood and a blood pH of <7.2. PATIENT CONCERNS: A 72-year-old Asian female with a history of diabetes for 20+ years was admitted to the hospital with the chief complaint of "dry mouth, polydipsia for 20+ years, loss of appetite for 5+ days, vomiting for 1-day." She was admitted with a blood gas pH of 6.795, and a lactate level of >30 mmol/L. DIAGNOSES: Type 2 diabetes mellitus with lactic acidosis, ketoacidosis, chronic renal insufficiency, hypertensive disease, and coronary arteriosclerotic heart disease. INTERVENTIONS: She was treated with symptomatic rehydration and ketone reduction immediately, but then became unconscious and was admitted to the intensive care unit, where she was administered symptomatic support and continuous renal replacement therapy. As the blood culture showed Aeromonas veronii, she was administered a sensitive antibiotic in conjunction. OUTCOMES: However, after achieving a stable internal environment and good infection control, the patient's family decided to discontinue treatment because of persistent heart failure with acute exacerbation of chronic renal insufficiency complicated by gastrointestinal bleeding. LESSONS: Lactic acidosis has low incidence, poor prognosis, and high morbidity and mortality rates. Special attention should be paid to infection-induced acidosis, especially in patients with combined multi-organ insufficiency. Early diagnosis and active management can improve the patient prognosis.


Assuntos
Acidose Láctica , Diabetes Mellitus Tipo 2 , Metformina , Insuficiência Renal Crônica , Humanos , Feminino , Idoso , Metformina/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Acidose Láctica/induzido quimicamente , Acidose Láctica/terapia , Aeromonas veronii , Ácido Láctico , Insuficiência Renal Crônica/complicações
14.
Int J Oncol ; 62(2)2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36601757

RESUMO

With the development of precision medicine, targeted therapy has attracted extensive attention. Poly(ADP­ribose) polymerase inhibitors (PARPi) are critical clinical drugs designed to induce cell death and are major antitumor targeted agents. However, preclinical and clinical data have revealed the limitations of PARPi monotherapy. Therefore, their combination with other targeted drugs has become a research hotspot in tumor treatment. Recent studies have demonstrated the critical role of small molecular inhibitors in multiple haematological cancers and solid tumors via cellular signalling modulation, exhibiting potential as a combined pharmacotherapy. In the present review, studies focused on small molecular inhibitors targeting the homologous recombination pathway were summarized and clinical trials evaluating the safety and efficacy of combined treatment were discussed.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Terapia Combinada , Medicina de Precisão
16.
J Environ Manage ; 329: 117093, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36549064

RESUMO

Aerobic degradation models are important tools for investigating the aerobic degradation behavior of municipal solid waste (MSW). In this paper, a first-order kinetic model for aerobic degradation of MSW was developed. The model comprehensively considers the aerobic degradation of five substrates, i.e., holocellulose, non-cellulosic sugars, proteins, lipids and lignin. The proportion ranges of the five substrates are summarized with the recommended values given. The effects of temperature, moisture content, oxygen concentration and free air space (FAS) on the reaction rates are considered, and the effect of settlement is accounted for in the FAS correction function. The reliability of the model was verified by comparing simulations of the aerobic degradation of low food waste content (LFWC-) and high food waste content (HFWC-) MSWs to the literature. Afterwards, a sensitivity analysis was carried out to establish the relative importance of aeration rate (AR), volumetric moisture content (VMC), and temperature. VMC had the greatest influence on the aerobic degradation of LFWC-MSW, followed by temperature and then AR; for HFWC-MSW, temperature was the most important factor, then VMC and last was AR. The degradation ratio of LFWC-MSW can reach 98.0% after 100 days degradation under its optimal conditions (i.e., temperature: 55 °C, VMC: 40%, AR: 0.16 L min-1 kg-1 DM), while it is slightly higher as 99.5% for HFWC-MSW under its optimal conditions (i.e., temperature: 55 °C, VMC: 40%, AR: 0.20 L min-1 kg-1 DM).


Assuntos
Eliminação de Resíduos , Resíduos Sólidos , Resíduos Sólidos/análise , Alimentos , Reprodutibilidade dos Testes , Instalações de Eliminação de Resíduos
17.
Ecotoxicol Environ Saf ; 249: 114364, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36508806

RESUMO

Ferric citrate (FC) has been used as an iron fortifier and nutritional supplement, which is reported to induce colitis in rats, however the underlying mechanism remains to be elucidated. We performed a 16-week study of FC in male healthy C57BL/6 mice (nine-month-old) with oral administration of Ctr (0.9 % NaCl), 1.25 % FC (71 mg/kg/bw), 2.5 % FC (143 mg/kg/bw) and 5 % FC (286 mg/kg/bw). FC-exposure resulted in colon iron accumulation, histological alteration and reduce antioxidant enzyme activities, such as glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC), together with enhanced lipid peroxidation level, including malondialdehyde (MDA) level and 4-Hydroxynonenal (4-HNE) protein expression. Exposure to FC was associated with upregulated levels of the interleukin (IL)- 6, IL-1ß, IL-18, IL-8 and tumor necrosis factor α (TNF-α), while down-regulated levels of IL-4 and IL-10. Exposure to FC was positively associated with the mRNA and protein expressions of cysteine-aspartic proteases (Caspase)- 9, Caspase-3, Bcl-2-associated X protein (Bax), while negatively associated with B-cell lymphoma 2 (Bcl2) in mitochondrial apoptosis signaling pathway. FC-exposure changed the diversity and composition of gut microbes. Additionally, the serum lipopolysaccharide (LPS) contents increased in FC-exposed groups when compared with the control group, while the expression of colonic tight junction proteins (TJPs), such as Claudin-1 and Occludin were decreased. These findings indicate that the colonic mucosal injury induced by FC-exposure are associated with oxidative stress generation, inflammation response and cell apoptosis, as well as the changes in gut microbes diversity and composition.


Assuntos
Apoptose , Colo , Compostos Férricos , Alimentos Fortificados , Microbioma Gastrointestinal , Inflamação , Estresse Oxidativo , Animais , Masculino , Camundongos , Ratos , Apoptose/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/metabolismo , Compostos Férricos/toxicidade , Alimentos Fortificados/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Glutationa/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Ferro/metabolismo , Camundongos Endogâmicos C57BL , Superóxido Dismutase/metabolismo
18.
Toxicology ; 483: 153393, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36502556

RESUMO

Researches on heroin are more about addiction and some infectious diseases it causes, but liver fibrosis caused by heroin abuse and the mechanism of heroin hepatotoxicity in addicts are ignored. To explore the mechanism of heroin hepatotoxicity, mice in heroin group were intraperitoneally injected by heroin (10 mg/kg) once a day for 14 consecutive days, while mice in heroin withdraw group underwent another 7 days without heroin administration after the same treatment as heroin group. The levels of alanine aminotransferase (ALT)and aspartate aminotransferase (AST) in serum, as biochemical indexes, were applied to evaluate liver damage. H & E staining and oil red O staining were used to observe the pathological changes of liver. Transcriptomics and metabolomics were applied to detect genes and metabolites in livers. The results of biochemical analysis and pathological examination showed that heroin induced liver damage and lipid loss in mice, and these mice did not return to normal completely after a short-term withdrawal. A total of 511 differential genes and 78 differential metabolites were identified by transcriptomics and metabolomics. These differential genes and metabolites were significantly enriched in pathways like lipid metabolism, arachidonic acid metabolism, glutathione metabolism, TCA cycle. And after undergoing 7-day withdrawal of heroin, most of the above differential genes and metabolites did not return to normal. Our study revealed the hepatotoxicity of heroin and that short-term withdrawal of heroin did not fully restore liver function. In addition, transcriptomics and metabolomics revealed that lipid metabolism and arachidonic acid metabolism may be potential therapeutic targets of heroin hepatotoxicity, providing a basis for the treatment of heroin addiction patients in the future.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Heroína , Animais , Camundongos , Heroína/toxicidade , Heroína/metabolismo , Ácido Araquidônico/metabolismo , Transcriptoma , Metabolômica/métodos , Fígado/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo
19.
Angew Chem Int Ed Engl ; 62(6): e202215556, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36478519

RESUMO

Lysophosphatidylcholine acyltransferase-1 (LPCAT1) plays a critical role in the remodeling of phosphatidylcholines (PCs) in cellular lipidome. However, evidence is scarce regarding its sn-selectivity, viz. the preference of assembling acyl-Coenzyme A (CoA) at the C1 or C2-hydroxyl on a glycerol backbone because of difficulty to quantify the thus-formed PC sn-isomers. We have established a multiplexed assay to measure both sn- and acyl-chain selectivity of LPCAT1 toward a mixture of acyl-CoAs by integrating isomer-resolving tandem mass spectrometry. Our findings reveal that LPCAT1 shows exclusive sn-1 specificity regardless of the identity of acyl-CoAs. We further confirm that elevated PC 18 : 1/16:0 relative to its sn-isomer results from an increased expression of LPCAT1 in human hepatocellular carcinoma (HCC) tissue as compared to normal liver tissue. MS imaging via desorption electrospray ionization of PC 18 : 1/16:0 thus enables visualization of HCC margins in human liver tissue at a molecular level.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , 1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Aciltransferases/metabolismo , Fosfatidilcolinas/metabolismo , Espectrometria de Massas em Tandem , Acil Coenzima A/metabolismo , Especificidade por Substrato
20.
Dermatol Ther (Heidelb) ; 13(2): 555-567, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36566344

RESUMO

OBJECTIVES: To evaluate the safety, tolerability, immunogenicity, and induced expression of skin biomarkers of AK111 injection after multiple administrations in subjects with moderate-to-severe plaque psoriasis. METHODS: This study is a randomized, double-blinded, placebo-parallel-controlled study using a dose escalation mode of multiple doses. A total of 48 subjects were sequentially randomized to receive each AK111 dose regimen (75 mg, 150 mg, 300 mg, 450 mg) or the corresponding placebo. All subjects were treated with the study drug at weeks 0, 1, 4, and 8 and were unblinded at week 12, with the placebo group ending and the AK111 group being followed up to 20 weeks. RESULTS: At week 12, compared with placebo, the percentage of subjects achieving Psoriasis Area and Severity Index 75 (PASI75) and static Physician Global Assessment (sPGA) 0/1 in the AK111 75 mg-450 mg dose groups was significantly increased, and higher PASI90 was achieved in the 150 mg, 300 mg, and 450 mg dose groups than in the 75 mg group. All efficacy indicators were maintained at week 20. The incidence of treatment-emergent anti-drug antibodies (ADAs) was 0% (0/48). Neutralizing antibodies (NAbs) were not detected in any subject. The proportion of subjects who reported any treatment-emergent adverse event (TEAE) was 75.0% in the AK111 group, similar to the 66.7% in the placebo group. The most commonly reported adverse events were hyperglycemia, elevated blood pressure, and hypokalemia. The AK111 pharmacokinetics showed approximate dose proportionality with regard to the maximum observed concentration (Cmax) and area under the curve from 0 to the time of the last quantifiable concentration (AUC0-t) following subcutaneous injection doses of 150-450 mg. CONCLUSIONS: After moderate-to-severe plaque psoriasis subjects received multiple subcutaneous AK111 injections of 150-450 mg, AK111 exposure increased in a roughly dose-proportional relationship. AK111 was safe and tolerable. In subjects with moderate-to-severe plaque psoriasis, AK111 demonstrated encouraging preliminary efficacy, which was sustained for a relatively long time after the last dose administration. CLINICAL TRIAL REGISTRATION: The clinical trial identification number is NCT05504317.

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