Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 267
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Genomics ; 116(5): 110883, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38857813

RESUMO

Pigmented potato tubers are abundant in chlorogenic acids (CGAs), a metabolite with pharmacological activity. This article comprehensively analyzed the transcriptome and metabolome of pigmented potato Huaxingyangyu and Jianchuanhong at four altitudes of 1800 m, 2300 m, 2800 m, and 3300 m. A total of 20 CGAs and intermediate CGA compounds were identified, including 3-o-caffeoylquinic acid, 4-o-caffeoylquinic acid, and 5-o-caffeoylquinic acid. CGA contents in Huaxinyangyu and Jianchuanhong reached its maximum at an altitude of 2800 m and slightly decreased at 3300 m. 48 candidate genes related to the biosynthesis pathway of CGAs were screened through transcriptome analysis. Weighted gene co-expression network analysis (WGCNA) identified that the structural genes of phenylalanine deaminase (PAL), coumarate-3 hydroxylase (C3H), cinnamic acid 4-hydroxylase (C4H) and the transcription factors of MYB and bHLH co-regulate CGA biosynthesis. The results of this study provide valuable information to reveal the changes in CGA components in pigmented potato at different altitudes.

2.
BMC Genomics ; 25(1): 283, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38500027

RESUMO

MYB transcription factors play an extremely important regulatory role in plant responses to stress and anthocyanin synthesis. Cloning of potato StMYB-related genes can provide a theoretical basis for the genetic improvement of pigmented potatoes. In this study, two MYB transcription factors, StMYB113 and StMYB308, possibly related to anthocyanin synthesis, were screened under low-temperature conditions based on the low-temperature-responsive potato StMYB genes family analysis obtained by transcriptome sequencing. By analyzed the protein properties and promoters of StMYB113 and StMYB308 and their relative expression levels at different low-temperature treatment periods, it is speculated that StMYB113 and StMYB308 can be expressed in response to low temperature and can promote anthocyanin synthesis. The overexpression vectors of StMYB113 and StMYB308 were constructed for transient transformation tobacco. Color changes were observed, and the expression levels of the structural genes of tobacco anthocyanin synthesis were determined. The results showed that StMYB113 lacking the complete MYB domain could not promote the accumulation of tobacco anthocyanins, while StMYB308 could significantly promote the accumulation involved in tobacco anthocyanins. This study provides a theoretical reference for further study of the mechanism of StMYB113 and StMYB308 transcription factors in potato anthocyanin synthesis.


Assuntos
Solanum tuberosum , Fatores de Transcrição , Fatores de Transcrição/metabolismo , Solanum tuberosum/genética , Solanum tuberosum/metabolismo , Antocianinas , Temperatura , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , Plantas Geneticamente Modificadas/genética
3.
J Am Chem Soc ; 146(10): 6753-6762, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38412236

RESUMO

High-temperature rechargeable batteries are essential for energy storage in elevated-temperature situations. Due to the resource abundance of potassium, high-temperature K-ion batteries are drawing increasing research interest. However, raising the working temperature would aggravate the chemical and mechanical instability of the KIB anode, resulting in very fast capacity fading, especially when high capacity is pursued. Here, we demonstrated that a porous conductive metal-organic framework (MOF), which is constructed by N-rich aromatic molecules and CuO4 units via π-d conjugation, could provide multiple accessible redox-active sites and promised robust structure stability for efficient potassium storage at high temperatures. Even working at 60 °C, this MOF anode could deliver high initial capacity (455 mAh g-1), impressive rate, and extraordinary cyclability (96.7% capacity retention for 1600 cycles), which is much better than those of reported high-temperature KIB anodes. The mechanistic study revealed that C═N groups and CuO4 units contributed abundant redox-active sites; the synergistic effect of π-d conjugated character and reticular porous architecture facilitated the K+/e- transport and ensured an insoluble electrode with small volume deformation, thus achieving stable high-capacity potassium storage.

4.
BMC Plant Biol ; 24(1): 274, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605295

RESUMO

Temperature is one of the important environmental factors affecting plant growth, yield and quality. Moreover, appropriately low temperature is also beneficial for tuber coloration. The red potato variety Jianchuanhong, whose tuber color is susceptible to temperature, and the purple potato variety Huaxinyangyu, whose tuber color is stable, were used as experimental materials and subjected to 20 °C (control check), 15 °C and 10 °C treatments during the whole growth period. The effects of temperature treatment on the phenotype, the expression levels of structural genes related to anthocyanins and the correlations of each indicator were analyzed. The results showed that treatment at 10 °C significantly inhibited the potato plant height, and the chlorophyll content and photosynthetic parameters in the leaves were reduced, and the enzyme activities of SOD and POD were significantly increased, all indicating that the leaves were damaged. Treatment at 10 °C also affected the tuberization of Huaxinyangyu and reduced the tuberization and coloring of Jianchuanhong, while treatment at 15 °C significantly increased the stem diameter, root-to-shoot ratio, yield and content of secondary metabolites, especially anthocyanins. Similarly, the expression of structural genes were enhanced in two pigmented potatoes under low-temperature treatment conditions. In short, proper low temperature can not only increase yield but also enhance secondary metabolites production. Previous studies have not focused on the effects of appropriate low-temperature treatment during the whole growth period of potato on the changes in metabolites during tuber growth and development, these results can provide a theoretical basis and technical guidance for the selection of pigmented potatoes with better nutritional quality planting environment and the formulation of cultivation measures.


Assuntos
Solanum tuberosum , Temperatura , Solanum tuberosum/metabolismo , Antocianinas/metabolismo , Temperatura Baixa , Fotossíntese , Tubérculos/genética
5.
Angew Chem Int Ed Engl ; 63(27): e202402497, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38679571

RESUMO

The large size of K-ion makes the pursuit of stable high-capacity anodes for K-ion batteries (KIBs) a formidable challenge, particularly for high temperature KIBs as the electrode instability becomes more aggravated with temperature climbing. Herein, we demonstrate that a hollow ZnS@C nanocomposite (h-ZnS@C) with a precise shell modulation can resist electrode disintegration to enable stable high-capacity potassium storage at room and high temperature. Based on a model electrode, we identify an interesting structure-function correlation of the h-ZnS@C: with an increase in the shell thickness, the cyclability increases while the rate and capacity decrease, shedding light on the design of high-performance h-ZnS@C anodes via engineering the shell thickness. Typically, the h-ZnS@C anode with a shell thickness of 60 nm can deliver an impressive comprehensive performance at room temperature; the h-ZnS@C with shell thickness increasing to 75 nm can achieve an extraordinary stability (88.6 % capacity retention over 450 cycles) with a high capacity (450 mAh g-1) and a superb rate even at an extreme temperature of 60 °C, which is much superior than those reported anodes. This contribution envisions new perspectives on rational design of functional metal sulfides composite toward high-performance KIBs with insights into the significant structure-function correlation.

6.
J Transl Med ; 21(1): 293, 2023 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-37121999

RESUMO

BACKGROUND: Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. METHODS: A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. RESULTS: PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. CONCLUSION: This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI.


Assuntos
Lesão Pulmonar Aguda , Ferroptose , Sepse , Animais , Camundongos , Antígenos CD59 , Ciclo-Oxigenase 2 , Lipopolissacarídeos/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Sepse/complicações , Fator 2 Ativador da Transcrição
7.
Virol J ; 20(1): 8, 2023 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647143

RESUMO

Herpes simplex virus type 1 (HSV-1) is a widely disseminated virus that establishes latency in the brain and causes occasional but fatal herpes simplex encephalitis. Currently, acyclovir (ACV) is the main clinical drug used in the treatment of HSV-1 infection, and the failure of therapy in immunocompromised patients caused by ACV-resistant HSV-1 strains necessitates the requirement to develop novel anti-HSV-1 drugs. Artemisia argyi, a Traditional Chinese Medicine, has been historically used to treat inflammation, bacterial infection, and cancer. In this study, we demonstrated the antiviral effect and mechanism of ethanol extract of A. argyi leaves (hereafter referred to as 'AEE'). We showed that AEE at 10 µg/ml exhibits potent antiviral effects on both normal and ACV-resistant HSV-1 strains. AEE also inhibited the infection of HSV-2, rotavirus, and influenza virus. Transmission electron microscopy revealed that AEE destroys the membrane integrity of HSV-1 viral particles, resulting in impaired viral attachment and penetration. Furthermore, mass spectrometry assay identified 12 major components of AEE, among which two new flavones, deoxysappanone B 7,3'-dimethyl ether, and 3,7-dihydroxy-3',4'-dimethoxyflavone, exhibited the highest binding affinity to HSV-1 glycoprotein gB at the surface site critical for gB-gH-gL interaction and gB-mediated membrane fusion, suggesting their involvement in inactivating virions. Therefore, A. argyi is an important source of antiviral drugs, and the AEE may be a potential novel antiviral agent against HSV-1 infection.


Assuntos
Antivirais , Artemisia , Herpesvirus Humano 1 , Extratos Vegetais , Aciclovir/farmacologia , Antivirais/química , Antivirais/farmacologia , Etanol , Herpesvirus Humano 1/efeitos dos fármacos , Envelope Viral , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Artemisia/química , Folhas de Planta/química
8.
Am J Obstet Gynecol ; 228(5): 535-546, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36283479

RESUMO

OBJECTIVE: Preeclampsia is a common disease during pregnancy that leads to fetal and maternal adverse events. Few head-to-head clinical trials are currently comparing the effectiveness of prophylactic strategies for preeclampsia. In this network meta-analysis, we aimed to compare the efficacy of prophylactic strategies for preventing preeclampsia in pregnant women at risk. DATA SOURCES: Articles published in or before September 2021 from PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov, references of key articles, and previous meta-analyses were manually searched. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing prophylactic strategies preventing preeclampsia with each other or with negative controls were included. METHODS: Two reviewers independently extracted data, assessed the risk of bias, and assessed evidence certainty. The efficacy of prophylactic strategies was estimated by frequentist and Bayesian network meta-analysis models. The primary composite outcome was preeclampsia/ pregnancy-induced hypertension. RESULTS: In total, 130 trials with a total of 112,916 patients were included to assess 13 prophylactic strategies. Low-molecular-weight heparin (0.60; 95% confidence interval, 0.42-0.87), vitamin D supplementation (0.65; 95% confidence interval, 0.45-0.95), and exercise (0.68; 95% confidence interval, 0.50-0.92) were as efficacious as calcium supplementation (0.71; 95% confidence interval, 0.62-0.82) and aspirin (0.79; 95% confidence interval, 0.72-0.86) in preventing preeclampsia/pregnancy-induced hypertension, with a P score ranking of 85%, 79%, 76%, 74%, and 61%, respectively. In the head-to-head comparison, no differences were found between these effective prophylactic strategies for preventing preeclampsia and pregnancy-induced hypertension, except with regard to exercise, which tended to be superior to aspirin and calcium supplementation in preventing pregnancy-induced hypertension. Furthermore, the prophylactic effects of aspirin and calcium supplementation were robust across subgroups. However, the prophylactic effects of low-molecular-weight heparin, exercise, and vitamin D supplementation on preeclampsia and pregnancy-induced hypertension varied with different risk populations, dosages, areas, etc. The certainty of the evidence was moderate to very low. CONCLUSION: Low-molecular-weight heparin, vitamin D supplementation, exercise, calcium supplementation, and aspirin reduce the risk of preeclampsia/pregnancy-induced hypertension. No significant differences between effective prophylactic strategies were found in preventing preeclampsia. These findings raise the necessity to reevaluate the prophylactic effects of low-molecular-weight heparin, vitamin D supplementation, and exercise on preeclampsia.


Assuntos
Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Gravidez , Humanos , Feminino , Pré-Eclâmpsia/prevenção & controle , Pré-Eclâmpsia/tratamento farmacológico , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Cálcio , Metanálise em Rede , Teorema de Bayes , Ensaios Clínicos Controlados Aleatórios como Assunto , Aspirina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Vitamina D/uso terapêutico
9.
J Org Chem ; 88(5): 3346-3352, 2023 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-36763542

RESUMO

Described herein is the convenient synthesis of an efficient trifluoromethoxylation reagent, nC4F9SO3CF3, by using cheap and widely available reagents and without the need of any tedious column chromatography purification procedure.

10.
J Org Chem ; 88(7): 4818-4828, 2023 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-36913713

RESUMO

Described here is the R3P/ICH2CH2I-promoted dehydroxylative sulfonylation of alcohols with a variety of sulfinates. In contrast to previous dehydroxylative sulfonylation methods, which are usually limited to active alcohols, such as benzyl, allyl, and propargyl alcohols, our protocol can be extended to both active and inactive alcohols (alkyl alcohols). Various sulfonyl groups can be incorporated, such as CF3SO2 and HCF2SO2, which are fluorinated groups of interest in pharmaceutical chemistry and the installation of which has received increasing attention. Notably, all reagents are cheap and widely available, and moderate to high yields were obtained within 15 min of reaction time.

11.
Org Biomol Chem ; 21(45): 8989-8992, 2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-37937947

RESUMO

Owing to the ubiquity of the hydroxyl group, reductive deoxygenation of alcohols has become an active research area. The classic Barton-McCombie reaction suffers from a tedious two-step procedure. New efficient methods have been developed, but they have some limitations, such as a narrow substrate scope and the use of moisture-sensitive Lewis acids. In this work, we describe the Ph3P/ICH2CH2I-promoted reductive deoxygenation of alcohols with NaBH4. The process is applicable to benzyl, allyl and propargyl alcohols, and also to primary and secondary alcohols, demonstrating a wide substrate scope and a good level of functional group tolerance. This protocol features convenient operation and low cost of all reagents.

12.
Nicotine Tob Res ; 25(12): 1856-1864, 2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-37455648

RESUMO

INTRODUCTION: The kappa-opioid receptor (KOR) has been implicated in mediating the behavioral and biochemical effects associated with nicotine reward and withdrawal; however, its underlying mechanisms remain to be further explored. METHODS: Adult male Sprague-Dawley rats were used to establish a nicotine dependence and withdrawal model by injecting nicotine (3 mg/kg/day, s.c.) or vehicle for 14 days, followed by the termination of nicotine for 7 days. Body weight gain, pain behaviors, and withdrawal scores were assessed in succession. MicroRNA (miRNA) sequencing was performed, and quantitative real-time PCR was used to detect the expression of candidate miRNAs and Oprk1. Western blotting was performed to examine KOR protein expression of KOR. Luciferase assay was conducted to validate the relationship of certain miRNAs/Oprk1. RESULTS: The behavioral results showed that nicotine dependence and withdrawal induced behavioral changes. Biochemical analyses demonstrated that miR-144-3p expression decreased and Oprk1/KOR expression increased in the prefrontal cortex, nucleus accumben, and hippocampus. Further investigation suggested that miR-144-3p exerted an inhibitory effect on Oprk1 expression in PC12 cells. CONCLUSIONS: This study revealed that miR-144-3p/Oprk1/KOR might be a potential pathway underlying the adverse effects induced by nicotine dependence and withdrawal, and might provide a novel therapeutic target for smoking cessation. IMPLICATIONS: This study demonstrates an impact of nicotine dependence and nicotine withdrawal on behavioral outcomes and the expressions of miR-144-3p/Oprk1/KOR in male rats. These findings have important translational implications given the continued use of nicotine and the difficulty in smoking cessation worldwide, which can be applied to alleviated the adverse effects induced by nicotine dependence and withdrawal, thus assist smokers to quit smoking.


Assuntos
MicroRNAs , Receptores Opioides kappa , Síndrome de Abstinência a Substâncias , Tabagismo , Animais , Masculino , Ratos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Nicotina/farmacologia , Ratos Sprague-Dawley , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Tabagismo/genética , Tabagismo/tratamento farmacológico
13.
Acta Biochim Biophys Sin (Shanghai) ; 55(9): 1487-1495, 2023 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-37162264

RESUMO

Angiopoietin-1 (ANG1) is a pro-angiogenic regulator that contributes to the progression of solid tumors by stimulating the proliferation, migration and tube formation of vascular endothelial cells, as well as the renewal and stability of blood vessels. However, the functions and mechanisms of ANG1 in triple-negative breast cancer (TNBC) are unclear. The clinical sample database shows that a higher level of ANG1 in TNBC is associated with poor prognosis compared to non-TNBC. In addition, knockdown of ANG1 inhibits TNBC cell proliferation and induces cell cycle G1 phase arrest and apoptosis. Overexpression of ANG1 promotes tumor growth in nude mice. Mechanistically, ANG1 promotes TNBC by upregulating carboxypeptidase A4 (CPA4) expression. Overall, the ANG1-CPA4 axis can be a therapeutic target for TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Neoplasias de Mama Triplo Negativas/metabolismo , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Camundongos Nus , Células Endoteliais/metabolismo , Proliferação de Células/genética , Carboxipeptidases/genética , Carboxipeptidases/metabolismo , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética
14.
Heart Surg Forum ; 26(6): E770-E779, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38178357

RESUMO

PURPOSE: Global longitudinal strain (GLS) seems accurate for detecting subclinical myocardial dysfunction. This study aimed to determine the association between GLS and postoperative intensity of inotropic support in the patients undergoing heart valve surgery with preserved left ventricular ejection fraction. METHODS: 74 patients with preserved left ventricular ejection fraction who underwent valve surgery during the period between March 2021 and June 2022 were included in this prospective observational study. Transthoracic echocardiography including strain analysis with speckle tracking was performed before surgery. Patients were stratified according to the left ventricle (LV) GLS: LV-GLS ≥-16% (Impaired GLS group) and LV-GLS <-16% (Normal GLS group). The primary endpoint was postoperative vasoactive inotropic score. A high vasoactive inotropic score (VIS) was defined as a maximum VIS of ≥15 within 24 hours postoperatively. Postoperative adverse events, baseline clinical and echocardiographic data were also recorded. We invested the ability of preoperative GLS in predicting adverse postoperative outcomes, such as prolonged mechanical ventilation and the need for pharmacologic hemodynamic support after cardiac surgery. RESULTS: Seventy-four patients were included and analyzed in this study, including thirty-three in impaired GLS group and forty-one in normal GLS group. In-hospital mortality was 1.27% (1/74). Patients in impaired GLS group were more likely to have prolonged mechanical ventilation (p = 0.041). Multivariable logistic regression analysis revealed that the apical four-chamber view of the left ventricle (A4C)-GLS was significantly associated with high VIS (OR 1.373, p = 0.007). A4C-GLS had a sensitivity of 62.5% and a specificity of 89.66% for predicting high VIS (area under the curve, 0.78). The relationships between GLS and other secondary outcome measures were not statistically significant. The optimal cutoff of A4C-GLS for postoperative high vasoactive inotropic score was -10.85%. CONCLUSION: Preoperative LV dysfunction is an independent risk factor for postoperative high VIS. A4C-GLS may be a reliable tool in predicting high VIS after cardiac surgery. Those patients with impaired contractility were at high risk for elevated inotropic support and prolonged mechanical ventilation after cardiac surgery. These findings suggest an important role for echocardiographic GLS in perioperative assessment of cardiac function in the patients undergoing cardiac surgery.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Disfunção Ventricular Esquerda , Humanos , Função Ventricular Esquerda , Volume Sistólico , Ventrículos do Coração/diagnóstico por imagem , Deformação Longitudinal Global , Prognóstico , Valvas Cardíacas
15.
J Biochem Mol Toxicol ; 36(6): e23044, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35499365

RESUMO

Inhibition of histone deacetylase (HDAC) may be a useful approach in the treatment of disorders characterized by cognitive dysfunction. Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has demonstrated neuroprotective effects. Here, we attempted to investigate the protective effects of DEX on postoperative cognitive dysfunction (POCD) involving HDAC2. Male C57BL/6 mice were selected to develop a POCD model, where HDAC2, HIF-1α, and PFKFB3 expression was quantified. DEX was administered before POCD modeling. Then the cognitive function of POCD mice was evaluated with the open field and Y-maze tests. Meanwhile, lipopolysaccharide (LPS) was employed to induce BV-2 microglial cells to simulate the inflammatory response. The contents of TNF-α, IL-6, and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA) in mouse serum and BV-2 cell supernatant. Abundant expression of HDAC2, HIF-1α, and PFKFB3 was confirmed in POCD mice (p < 0.05). Cognitive dysfunction in POCD mice could be alleviated following pharmacological inhibition of HDAC2 by FK228 (p < 0.05). Mechanistically, HDAC2 upregulated HIF-1α and PFKFB3 and promoted the secretion of inflammatory factors in LPS-exposed BV-2 cells (p < 0.05). DEX attenuated neuroinflammation and the resulting cognitive dysfunction by decreasing HDAC2 expression and HIF-1α-dependent PFKFB3 upregulation in POCD mice (p < 0.05). In conclusion, DEX-regulated HDAC2 may play an inhibitory role in mice with POCD through regulation of the HIF-1α/PFKFB3 axis.


Assuntos
Disfunção Cognitiva , Dexmedetomidina , Complicações Cognitivas Pós-Operatórias , Animais , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Modelos Animais de Doenças , Hipocampo/metabolismo , Histona Desacetilase 2/metabolismo , Histona Desacetilase 2/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Fosfofrutoquinase-2/metabolismo
16.
Int J Mol Sci ; 23(24)2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36555725

RESUMO

HSV-1 is a typical neurotropic virus that infects the brain and causes keratitis, cold sores, and occasionally, acute herpes simplex encephalitis (HSE). The large amount of proinflammatory cytokines induced by HSV-1 infection is an important cause of neurotoxicity in the central nervous system (CNS). Microglia, as resident macrophages in CNS, are the first line of defense against neurotropic virus infection. Inhibiting the excessive production of inflammatory cytokines in overactivated microglia is a crucial strategy for the treatment of HSE. In the present study, we investigated the effect of nicotinamide n-oxide (NAMO), a metabolite mainly produced by gut microbe, on HSV-1-induced microglial inflammation and HSE. We found that NAMO significantly inhibits the production of cytokines induced by HSV-1 infection of microglia, such as IL-1ß, IL-6, and TNF-α. In addition, NAMO promotes the transition of microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type. More detailed studies revealed that NAMO enhances the expression of Sirtuin-1 and its deacetylase enzymatic activity, which in turn deacetylates the p65 subunit to inhibit NF-κB signaling, resulting in reduced inflammatory response and ameliorated HSE pathology. Therefore, Sirtuin-1/NF-κB axis may be promising therapeutic targets against HSV-1 infection-related diseases including HSE.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Humanos , NF-kappa B/metabolismo , Microglia/metabolismo , Herpesvirus Humano 1/metabolismo , Sirtuína 1/metabolismo , Inflamação/metabolismo , Citocinas/metabolismo , Herpes Simples/patologia
17.
Molecules ; 27(11)2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35684303

RESUMO

The iridoid compounds in traditional Chinese medicine play a prominent role in their antiviral effects. We previously reported the anti-inflammatory effect of new iridoids from the aerial parts of Morinda officinalis. Nevertheless, several open questions remain to explore the other biological functions of these new iridoid compounds. Herpes simplex virus-1 (HSV-1) is one of the most prevalent pathogens in human beings worldwide and due to limited therapies, mainly with the guanosine analog aciclovir (ACV) and other analogs, the search for new drugs with different modes of action and low toxicity becomes particularly urgent for public health. This study aimed to explore the anti-HSV-1 effects of iridoids from the aerial parts of Morinda officinalis. The dried aerial parts of Morinda officinalis were extracted with 95% ethanol and systematic separation and purification were then carried out by modern column chromatography methods such as silica gel column, RP-ODS column, Sephadex LH-20 gel column, and semi-preparative liquid phase, and the structure of these compounds were identified through the physical and chemical properties and a variety of spectral techniques. The obtained seven new iridoid compounds were screened for antiviral activity on HSV-1 through CCK8 and the cytopathic effect, and then the plaque reduction assay, the anti-fluorescence reporter virus strain replication, and RT-qPCR experiments were carried out to further evaluate the antiviral effect. Seven new iridoid compounds (officinaloside A-G) were identified from the aerial parts of Morinda officinalis, and officinaloside C showed anti-HSV-1 activity. Further functional experiments confirmed that officinaloside C has a significant inhibiting effect on HSV-1 virus plaque formation, viral gene, and protein expression, and fluorescent virus replication. Our findings suggest that officinaloside C has significant inhibitory effects on viral plaque formation, genome replication, and viral protein expression of HSV-1 which implies that officinaloside C exhibits viral activity and may be a promising treatment for HSV-1 infection.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Chlorocebus aethiops , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 2 , Humanos , Iridoides/farmacologia , Iridoides/uso terapêutico , Células Vero , Replicação Viral
18.
Molecules ; 27(6)2022 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-35335337

RESUMO

DNA methylation, as one of the major means of epigenesis change, makes a large difference in the spatial structure of chromatin, transposable element activity and, fundamentally, gene transcription. It has been confirmed that DNA methylation is closely related to innate immune responses. Decitabine, the most efficient available DNA methyltransferase inhibitor, has demonstrated exhilarating immune activation and antiviral effects on multiple viruses, including HIV, HBV, HCV, HPV and EHV1. This review considers the role of decitabine in regulating innate immune responses and antiviral ability. Understanding the complex transcriptional and immune regulation of decitabine could help to identify and validate therapeutic methods to reduce pathogen infection-associated morbidity, especially virus infection-induced morbidity and mortality.


Assuntos
Antivirais , Imunomodulação , Antivirais/farmacologia , Antivirais/uso terapêutico , Cognição , Decitabina/farmacologia , Imunidade Inata
19.
Mol Med ; 27(1): 110, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530730

RESUMO

Posttranslational modification (PTM) and regulation of protein stability are crucial to various biological processes. Histone deacetylase 6 (HDAC6), a unique histone deacetylase with two functional catalytic domains (DD1 and DD2) and a ZnF-UBP domain (ubiquitin binding domain, BUZ), regulates a number of biological processes, including gene expression, cell motility, immune response, and the degradation of misfolded proteins. In addition to the deacetylation of histones, other nonhistone proteins have been identified as substrates for HDAC6. Hsp90, a molecular chaperone that is a critical modulator of cell signaling, is one of the lysine deacetylase substrates of HDAC6. Intriguingly, as one of the best-characterized regulators of Hsp90 acetylation, HDAC6 is the client protein of Hsp90. In addition to regulating Hsp90 at the post-translational modification level, HDAC6 also regulates Hsp90 at the gene transcription level. HDAC6 mainly regulates the Hsp90-HSF1 complex through the ZnF-UBP domain, thereby promoting the HSF1 entry into the nucleus and activating gene transcription. The mutual interaction between HDAC6 and Hsp90 plays an important role in the regulation of protein stability, cell migration, apoptosis and other functions. Plenty of of studies have indicated that blocking HDAC6/Hsp90 has a vital regulatory role in multifarious diseases, mainly in cancers. Therefore, developing inhibitors or drugs against HDAC6/Hsp90 becomes a promising development direction. Herein, we review the current knowledge on molecular regulatory mechanisms based on the interaction of HDAC6 and Hsp90 and inhibition of HDAC6 and/or Hsp90 in oncogenesis and progression, antiviral and immune-related diseases and other vital biological processes.


Assuntos
Proteínas de Choque Térmico HSP90/metabolismo , Desacetilase 6 de Histona/metabolismo , Processamento de Proteína Pós-Traducional , Acetilação , Animais , Desenvolvimento de Medicamentos , Descoberta de Drogas , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/genética , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/genética , Histonas/metabolismo , Humanos , Isoenzimas , Ligação Proteica , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
20.
Acc Chem Res ; 53(8): 1498-1510, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32786338

RESUMO

Owing to the special effects of the fluorine element, including high electronegativity and small atomic radius, the incorporation of a fluorinated group into organic molecules may modify their physical, chemical, and biological properties. Fluorine-containing compounds have found widespread application in a variety of areas, and thus, the development of efficient reagents and methods for the incorporation of fluorinated groups has become a subject of significant interest.Described in this Account are our recent discoveries in the chemistry of fluorinated ylides/carbenes and related intermediates generated from phosphonium/sulfonium salts. Initially, we obtained the (triphenylphosphonio) difluoroacetate, Ph3P+CF2CO2- (PDFA), which was proposed as a reactive intermediate but had never been successfully synthesized. PDFA, shelf-stable and easy to prepare, is not only a mild ylide (Ph3P+CF2-) reagent, but also an efficient difluorocarbene source. It can directly generate difluorocarbene, via the first generation of ylide Ph3P+CF2-, simply under warming conditions without the need for any additive. Interestingly, difluorocarbene chemistry was then discovered by using PDFA as a reagent. Difluorocarbene can be oxidized to CF2═O, can react with elemental sulfur to afford CF2═S, and can be trapped by NaNH2 or NH3 to give CN-. The development of these processes into synthetic tools allowed us to achieve various reactions, including the challenging 18F-trifluoromethylthiolation and cyanodifluoromethylation. It was found that a substituent on the cation of a phosphonium salt can be directly transferred as a nucleophile despite the cation's high electrophilicity. This transfer process is like an "umpolung" of the cation, which may provide more opportunities for the synthetic utilities of phosphonium salts. The investigation of this transfer process led us to find that iodophosphonium salts, active intermediates which can be easily generated, may efficiently promote deoxygenative functionalizations of aldehydes and alcohols. Dehydroxylative substitution of alcohols by this protocol permits the use of unprotected amines with higher pKa values as nucleophiles, which is an attractive feature compared with the Mitsunobu reaction. On the basis of the ylide-to-carbene process (Ph3P+CF2- → :CF2), we further developed sulfonium salts as precursors of fluorinated ylides and fluorinated methyl carbenes. In particular, the studies on difluoromethylcarbene, remaining largely unexplored, may deserve more attention. The discoveries may find utility in the synthesis of biologically active fluorine-containing molecules.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA