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1.
J Adv Res ; 40: 249-261, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36100330

RESUMO

INTRODUCTION: Adriamycin (ADR) is an efficient and common broad-spectrum anticancer drug. However, the cumulative and dose-dependent toxicity induced by ADR severely limits its application in the clinic. Previous studies found that psoralidin (PSO) exhibits remarkable therapeutic effects against multiple cancers. OBJECTIVES: The aim of this study was to determine if PSO has beneficial effects on ADR-induced cardiotoxicity and to investigate the underlying mechanisms. METHODS: ADR-induced cardiotoxicity models were established in BALB/c mice and HL-1 cardiomyocytes. A series of experimental methods were used to evaluate the effects of PSO on cardiac function indicators, blood biochemical parameters, histopathology, oxidative stress, apoptosis, mitochondrial function, fibrosis, and SIRT1/PPARγ signaling. RESULTS: PSO significantly improved cardiac function indicators, blood biochemical parameters, and mitochondrial function and reduced the degree of myocardial fibrosis, oxidative stress, and apoptosis in ADR-injured mice. PSO significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in ADR-injured HL-1 cells. Moreover, we also demonstrated there was cross-talk between SIRT1 and PPARγ, as shown by SIRT1 siRNA significantly decreasing the expression of PPARγ and GW9662 (a PPARγ antagonist), which remarkably reduced the expression of SIRT1. CONCLUSION: In summary, this study proved for the first time the beneficial effect of PSO on ADR-induced cardiotoxicity through activation of the SIRT1/PPARγ signaling pathway. Therefore, these findings may favor PSO as a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in the clinic and improve the application of ADR in oncotherapy.


Assuntos
Cardiotoxicidade , Doxorrubicina , Animais , Benzofuranos , Cardiotoxicidade/tratamento farmacológico , Cumarínicos , Doxorrubicina/efeitos adversos , Camundongos , PPAR gama , Sirtuína 1/metabolismo
2.
Sci Rep ; 12(1): 15512, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109625

RESUMO

Hepatitis E Virus (HEV) follows waterborne or zoonotic/foodborne transmission. Genotype 3 HEV infections are worldwide spread, especially in swine populations, representing an emerging threat for human health, both for farm workers and pork meat consumers. Unfortunately, HEV in vitro culture and analysis are still difficult, resulting in a poor understanding of its biology and hampering the implementation of counteracting strategies. Indeed, HEV encodes for only one non-structural multifunctional and multidomain protein (ORF1), which might be a good candidate for anti-HEV drugging strategies. In this context, an in silico molecular modelling approach that consisted in homology modelling to derive the 3D model target, docking study to simulate the binding event, and molecular dynamics to check complex stability over time was used. This workflow succeeded to describe ORF1 RNA Helicase domain from a molecular standpoint allowing the identification of potential inhibitory compounds among natural plant-based flavagline-related molecules such as silvestrol, rocaglamide and derivatives thereof. In the context of scouting potential anti-viral compounds and relying on the outcomes presented, further dedicated investigations on silvestrol, rocaglamide and a promising oxidized derivative have been suggested. For the sake of data reproducibility, the 3D model of HEV RNA Helicase has been made publicly available.


Assuntos
Vírus da Hepatite E , Animais , Benzofuranos , DNA Helicases , Vírus da Hepatite E/genética , Humanos , RNA Helicases , Reprodutibilidade dos Testes , Suínos
3.
Biomed Pharmacother ; 153: 113416, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076484

RESUMO

Glioblastoma (GBM) is the most prevalent type of adult primary brain tumor and chemotherapy of GBM was limited by drug-resistance. Fraxinellone is a tetrahydro-benzofuranone derivative with various pharmacological activities. However, the pharmacological effects of fraxinellone on GBM remains largely unknown. Here, we found that fraxinellone inhibited the proliferation and growth of GBM cells in a dose-dependent manner in vitro. Subsequently, we found that fraxinellone suppressed the migration and induced apoptosis of GBM cells in vitro. Using western blot and immunostaining, we further found that fraxinellone downregulated the expressions of sirtuin 3 (SIRT3), and superoxide dismutase 2 (SOD2), a downstream of SIRT3 in GBM cells. Meanwhile, reactive oxygen species (ROS) were increased in these fraxinellone-treated GBM cells. Interestingly, overexpression of SIRT3 (SIRT3-OE) indeed partially restored the inhibition of both cell proliferation and migration of GBM cells induced by fraxinellone. Finally, we found that fraxinellone could inhibit the growth of GBM in xenograft model through the inactivation of SIRT3 signaling pathway. Taken together, these results suggest that fraxinellone suppressed the growth and migration of GBM cells by downregulating SIRT3 signaling in vitro, and inhibited the tumorigenesis of GBMs in vivo.


Assuntos
Benzofuranos , Neoplasias Encefálicas , Glioblastoma , Sirtuína 3 , Adulto , Animais , Apoptose , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/patologia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sirtuína 3/metabolismo
4.
Neuroreport ; 33(14): 597-603, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36062510

RESUMO

BACKGROUND: Stress is not scarce in peoples' daily life that may result in mental diseases and cognitive impairments. Chronic restraint stress (CRS) is a well-validated animal model used to investigate the mechanism of stress-associated depression and cognitive impairments. Dl-3-n-butylphthalide (NBP) possesses anti-oxidant, anti-inflammatory and anti-apoptotic, promoting neurogenesis and neuroplasticity that exerts neuroprotective effects. However, the effects of NBP on CRS-induced depression and cognitive impairments remain unclear. METHODS: C57BL/6 male mice were randomly divided into the control group, stress group and stress+NBP group. Mice were exposed to CRS for three consecutive weeks and mice in the NBP treatment group were administered with NBP before the CRS procedure. After that, depression and cognition behaviors were evaluated followed by phosphorylation of Ca2+/calmodulin-dependent protein kinase II (p-CaMKII), phosphorylation of cAMP-response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) proteins expression, immunohistochemistry of hippocampal postsynaptic density 95 (PSD95) and synaptophysin, and hippocampal morphology. RESULTS: Our results showed that mice exhibited depression-like behaviors and cognitive deficits after 3 weeks exposure to CRS. Additionally, CRS downregulated CaMKII/CREB/BDNF signaling pathway, reduced PSD95 and synaptophysin expression and induced hippocampal CA1 and dentate gyrus ment significantly reversed the hippocampal pathological and molecular changes induced by CRS. CONCLUSION: In conclusion, these results reveal that NBP exerts a neuroprotective effect on depression and cognitive deficit through activating CaMKII/CREB/BDNF pathway, enhancing PSD95 and synaptophysin expression and protecting hippocampal morphology.


Assuntos
Disfunção Cognitiva , Fármacos Neuroprotetores , Animais , Benzofuranos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/etiologia , Depressão/metabolismo , Depressão/prevenção & controle , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais , Sinaptofisina/metabolismo
5.
Front Endocrinol (Lausanne) ; 13: 932488, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36060953

RESUMO

Background: Glucocorticoids (GCs) induce osteoporosis, which results in fractures in the bond, causing significant morbidity. In the conducted study, we examined the antiosteoporosis effect of dieckol against GC-induced osteoporosis in rats. Methods: Sprague-Dawley (SD) rats were used for the current study and dexamethasone (2.5 mg/kg) induced osteoporosis in the rats that received the dieckol (test) and alendronate (standard) for 20 weeks. Bone turnover parameters, microCT, antioxidant, inflammatory cytokines, nutrient, and hormones parameters. Results: Dieckol noticeably suppressed the body weight and boosted the uterine and vagina weight. Dieckol considerably altered the level of trabecular number (Tb. N), the bone volume to total volume (BV/TV), trabecular separation (Tb.Sp), bone surface to bone volume (BS/BV), and t​r​a​b​e​c​u​l​a​r thickness (Tb.Th). Dieckol noticeably (P < 0.001) elevated the level of osteocalcin (OC) and alleviated the level of bone Gla protein (BGP), acid phosphatase (ACP), alkaline phosphatase (ALP), and ß-CTx. Dieckol markedly boosted the level of malondialdehyde (MDA) and suppressed the level of glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) along with the suppression of inflammatory cytokines like TNF-α, IL-1ß, and IL-6. Dieckol remarkably increased the level of calcium, potassium, magnesium, and 25 (OH) vitamin D. Dieckol substantially (P < 0.001) boosted the level of estradiol and alleviated the level of parathyroid hormone and tartrate-resistant acid phosphatase (TRAP). Dieckol also suppressed the level of receptor activator of nuclear factor κB ligand (RANKL) and boosted the level of osteoprotegerin (OPG). Conclusion: Taken together, our data suggest that dieckol demonstrated the anti-osteoporosis effect against GC-induced osteoporosis in rats.


Assuntos
Benzofuranos , Glucocorticoides , Osteoporose , Animais , Benzofuranos/uso terapêutico , Citocinas , Feminino , Glucocorticoides/efeitos adversos , Osteocalcina , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Osteoporose/prevenção & controle , Ratos , Ratos Sprague-Dawley
6.
Molecules ; 27(17)2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36080338

RESUMO

Bone morphogenetic proteins (BMPs) are growth factors that have a vital role in the production of bone, cartilage, ligaments, and tendons. Tumors' upregulation of bone morphogenetic proteins (BMPs) and their receptors are key features of cancer progression. Regulation of the BMP kinase system is a new promising strategy for the development of anti-cancer drugs. In this work, based on a careful literature study, a library of benzothiophene and benzofuran derivatives was subjected to different computational techniques to study the effect of chemical structure changes on the ability of these two scaffolds to target BMP-2 inducible kinase, and to reach promising candidates with proposed activity against BMP-2 inducible kinase. The results of screening against Lipinski's and Veber's Rules produced twenty-one outside eighty-four compounds having drug-like molecular nature. Computational ADMET studies favored ten compounds (11, 26, 27, 29, 30, 31, 34, 35, 65, and 72) with good pharmacokinetic profile. Computational toxicity studies excluded compound 34 to elect nine compounds for molecular docking studies which displayed eight compounds (26, 27, 29, 30, 31, 35, 65, and 72) as promising BMP-2 inducible kinase inhibitors. The nine fascinating compounds will be subjected to extensive screening against serine/threonine kinases to explore their potential against these critical proteins. These promising candidates based on benzothiophene and benzofuran scaffolds deserve further clinical investigation as BMP-2 kinase inhibitors for the treatment of cancer.


Assuntos
Benzofuranos , Proteína Morfogenética Óssea 2 , Benzofuranos/farmacologia , Proteínas Morfogenéticas Ósseas/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases
7.
Wei Sheng Yan Jiu ; 51(4): 610-616, 2022 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-36047267

RESUMO

OBJECTIVE: To measure polychlorinated biphenyls(PCBs) concentrations in serum of some reproductive aged men in Wuhan and explore the influencing factors of PCBs exposure. METHODS: Based on a cross-sectional study in 2013 on the association between exposure to environmental pollutants and adverse male reproductive health, which was conducted in Wuhan. Levels of dioxins-like PCBs(dl-PCBs) and non-dioxin-like PCBs(ndl-PCBs) in 101 serum samples of men with childbearing age were analyzed via high-resolution gas chromatograph tandem high-resolution mass spectrometer(HRGC-HRMS) method. Multiple linear regression models were used to analyze the associations between PCBs levels and influencing factors. RESULTS: Total concentrations of twelve dl-PCBs(Σdl-PCBs) were in range of 177.85-7271.48 pg/g lipid, the median value was 1530.71 pg/g lipid, and CB-118 was the predominant congener. For six ndl-PCBs, total concentrations(Σndl-PCBs) were in range of 1463.23-40561.47 pg/g lipid, the median value was 5498.37 pg/g lipid, and CB-153 was the predominant congener. The World Health Organization toxicity equivalent(WHO_(2005)-TEQ) of dl-PCBs(ΣTEQ_(dl-PCBs)) were 0.02-162.29 pg TEQ/g lipid, the median value was 1.77 pg TEQ/g lipid. The age was positively correlated with Σmono-ortho PCBs(ß=0.01, 95%CI 0.00-0.02), ΣTEQ_(mono-ortho PCBs)(ß=0.01, 95%CI 0.00-0.02) and Σndl-PCBs(ß=0.02, 95%CI 0.00-0.03). Men who drank alcohol tend to show higher exposure to ΣTEQ_(dl-PCBs)(ß=0.56, 95%CI 0.13-1.00) than those did not drink alcohol. And higher levels of Σndl-PCBs(ß=0.15, 95%CI 0.04-0.26) was found in the men who reside in urban areas as compared to rural one. CONCLUSION: There were PCBs exposure in some reproductive aged men in Wuhan. Age, drink alcohol status, and residence were influencing factors on PCBs.


Assuntos
Benzofuranos , Dioxinas , Poluentes Ambientais , Bifenilos Policlorados , Dibenzodioxinas Policloradas , Adulto , Benzofuranos/análise , Estudos Transversais , Dibenzofuranos Policlorados , Dioxinas/análise , Poluentes Ambientais/análise , Humanos , Lipídeos , Masculino , Bifenilos Policlorados/análise , Dibenzodioxinas Policloradas/análise
8.
Chin J Nat Med ; 20(8): 601-613, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36031232

RESUMO

Vascular endothelial cells and oxidation reduction system play an important role in the pathogenesis of atherosclerosis (AS). If these conditions are disordered, it will inevitably lead to plaque formation and even rupture. Astragaloside IV (AsIV) and salvianolic acid B (Sal B) are the main active ingredients of Astragalus membranaceus and Salvia miltiorrhiza, respectively, and found to ameliorate vascular endothelial dysfunction and protect against oxidative stress in recent studies. However, it is still unknown if the combination of AsIV and Sal B (AsIV + Sal B) can inhibit the development of plaque through amplifying the protective effect of vascular endothelial cells and anti-oxidative stress effect. To clarify the role of AsIV + Sal B in AS, we observed the efficacy of each group (Control, Model, AsIV, Sal B, and AsIV + Sal B) by biomolecular assays, such as observing the pathological morphology of the aorta by oil red O staining, evaluating the level of oxidative stress and endothelial cells in the serum by the Elisa test, and analyzing the changes of all small molecule metabolites in liver tissue by UPLC-QTOF-MS. Results showed that AsIV, Sal B and AsIV + Sal B decreased the deposition of lipid in the arterial wall, so as to exert the effect of anti-oxidant stress and vascular endothelial protection, where the inhibitory effect of AsIV + Sal B was the most obvious. Metabonomics analysis showed that Sal B regulated the metabolic pathways of arginine and proline. AsIV regulated glycerol metabolism and saturated fatty acid biosynthesis metabolism. AsIV + Sal B is mainly related to the regulation of the citrate cycle (TCA cycle), alanine, aspartic acid, and glutamate metabolism, cysteine, and methionine metabolism. Succinic acid and methionine are synergistic metabolites that exert an enhancing effect when AsIV and Sal B were used in combination. In conclusion, we demonstrated that AsIV acompanied with Sal B can be successfully used for anti-oxidative stress and vascular endothelial protection of AS, and succinic acid and methionine are the synergistic metabolites.


Assuntos
Aterosclerose , Saponinas , Triterpenos , Antioxidantes , Benzofuranos , Células Endoteliais , Humanos , Metionina , Ácido Succínico
9.
Chem Commun (Camb) ; 58(70): 9778-9781, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35969016

RESUMO

A metal-free approach to construct indole rings from vinylogous amides derived from o-alkynylanilines involving a cyclization, retro-aza-Michael reaction and amine trapping cascade is reported here. This atom-economical transformation has been extended to synthesize benzofuran derivatives using analogous vinylogous esters derived from o-alkynylphenols. The excellent stereochemical outcome of the double bond geometry in the products makes it attractive.


Assuntos
Benzofuranos , Cetonas , Benzofuranos/química , Ciclização , Indóis/química , Estrutura Molecular
10.
BMC Neurol ; 22(1): 305, 2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-35986234

RESUMO

BACKGROUND: As one of the leading causes of morbidity and mortality, stroke and its recurrence has attracted more and more attention. Dl-3-n-butylphthalidle(NBP) has been widely used for treating acute ischemic stroke in China and shows a great clinical effect. NBP plays a role in different pathophysiological processes in the treatment of ischemic stroke, including antioxidants, anti-inflammatory, anti-apoptotic, anti-thrombosis, and mitochondrial protection. Many randomized, double-blind, placebo-controlled, multicenter clinical trials suggest that NBP is a safe and effective treatment for ischemic stroke. To sum up, the current research is mainly focused on the short-term treatment of stroke patients with RCT (randomized controlled trial). Therefore, we designed this study to confirm the role of butylphthalide in secondary stroke prevention in the real world. METHODS: This study will be a multicenter, prospective real-world trial. We would recruit 8000 patients with ischemic stroke from 78 public hospitals in China. All participants will be allocated to one of two parallel treatment groups according to their own wills: (1) butylphthalide group: 0.2 g of butylphthalide capsules three times daily plus routine treatment (aspirin 50-300 mg/d, clopidogrel 75 mg/d, etc.); (2) control group: routine treatment (aspirin 50-300 mg/d, clopidogrel 75 mg/d, etc.). Treatment duration is 90 consecutive days or more. The primary outcome is recurrence rate of stroke within 1 month, 3 months, 6 months and 1 year in butylphthalide group and control group. The secondary outcomes included NIHSS score, the mRS score, other clinical cardiovascular events within one year (sudden death / myocardial infarction / arrhythmia / heart failure, etc.), and adverse events of patients in groups. NIHSS will be captured in the first month after discharge, and the others will be captured at the same time points as the primary end point. DISCUSSION: This trial will be exploring the efficacy and safety of butylphthalide in secondary prevention of ischemic stroke to expand the scope of application of butylphthalide soft capsules and provide new ideas for enriching the secondary prevention of stroke. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR). TRIAL REGISTRATION NUMBER: ChiCTR2000034481. Registered on 6 July 2020, http://www.chictr.org.cn/showproj.aspx?proj=55800.


Assuntos
Benzofuranos , AVC Isquêmico , Prevenção Secundária , Aspirina/uso terapêutico , Benzofuranos/efeitos adversos , Clopidogrel/uso terapêutico , Método Duplo-Cego , Humanos , Internet , AVC Isquêmico/prevenção & controle , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
11.
ACS Infect Dis ; 8(9): 1869-1882, 2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-35969484

RESUMO

Prion diseases are fatal neurodegenerative disorders caused by the deposition of scrapie prion protein aggregates (PrPSc) in the brain. We previously reported that styrylchromone (SC) and benzofuran (BF) derivatives have potential as imaging probes for PrPSc. To further improve their properties, we designed and synthesized 2-(benzofuran-2-yl)-chromone (BFC) derivatives hybridized with SC and BF backbones as novel single-photon emission computed tomography probes for the detection of cerebral PrPSc deposits. Recombinant mouse prion protein (rMoPrP) aggregates and mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice were used to evaluate the binding properties of BFC derivatives to PrPSc. The BFC derivatives exhibited high binding affinities (equilibrium dissociation constant [Kd] = 22.6-47.7 nM) for rMoPrP aggregates. All BFC derivatives showed remarkable selectivity against amyloid beta aggregates. Fluorescence microscopy confirmed that the fluorescence signals of the BFC derivatives corresponded to the antibody-positive deposits of PrPSc in mBSE-infected mouse brains. Among the BFC derivatives, [125I]BFC-OMe and [125I]BFC-NH2 exhibited high brain uptake and favorable washout from the mouse brain. In vitro autoradiography demonstrated that the distribution of [125I]BFC-OMe in the brain tissues of mBSE-infected mice was colocalized with PrPSc deposits. Taken together, BFC derivatives appear to be promising prion imaging probes.


Assuntos
Benzofuranos , Encefalopatia Espongiforme Bovina , Príons , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Bovinos , Cromonas/metabolismo , Encefalopatia Espongiforme Bovina/metabolismo , Camundongos , Príons/metabolismo
12.
Biomater Adv ; 140: 213046, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35930818

RESUMO

An extracellular matrix-mimicking, biodegradable tissue-engineered skin substitute with improved antibacterial, antibiofilm, and wound healing capabilities is essential in skin tissue regeneration applications. The purpose of this study was to develop a novel biodegradable composite nanofibrous poly(ε-caprolactone) (PCL)/decellularized extracellular matrix (dECM) scaffolds loaded with usnic acid (UA); (PEU), where UA is employed as an antibacterial agent as well as a wound-healing accelerator. The architecture and fiber structure of the scaffolds were examined using scanning electron microscopy, and the results revealed that the average diameters decreased as the dECM content increased. The chemical composition, changes in the crystalline structure, homogeneity, and thermal stability of the nanofiber scaffolds with different material compositions were determined using Fourier-transform infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis, respectively. The composite nanofibrous scaffolds exhibited strong antibacterial activity against various bacterial species, such as Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mutans, and Cutibactrium acnes, and fungal pathogens (such as Candida albicans). Additionally, the composite nanofibrous scaffolds exhibited biofilm inhibition properties against Klebsiella pneumoniae and Pseudomonas aeruginosa. An evaluation of the appearance of in vivo full-thickness excisional wounds treated with the composite nanofiber scaffolds, as well as a histological analysis of the wounds 21 days after surgery, revealed that treatment with nanofibrous PEU scaffolds enhanced wound healing. This study reveals that the proposed composite nanofibrous PEU scaffold has substantial potential for treating infectious full-thickness wounds.


Assuntos
Nanofibras , Infecção dos Ferimentos , Antibacterianos/farmacologia , Benzofuranos , Matriz Extracelular Descelularizada , Humanos , Nanofibras/química , Poliésteres , Tecidos Suporte/química , Cicatrização , Infecção dos Ferimentos/tratamento farmacológico
13.
Int Immunopharmacol ; 111: 109099, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35932615

RESUMO

Non-alcoholic fatty liver disease (NAFLD) has high occurrence in the global world, which poses serious threats to human health. Salvianolic acid B (SalB), an extract of the root of Salvia miltiorrhiza, has the protective effect on metabolic homeostasis. However, the mechanism is still unknown. In this study, we used ob/ob mice, a model of NAFLD, to explore the hepatoprotective effects of SalB. The results showed that SalB significantly reduced the body weights and liver weights, and ameliorated plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), hepatic free fatty acid (FFA), total cholesterol (TC) levels, and hepatic TG and TC levels in ob/ob mice. SalB reduced the number of lipid droplets and inhibited hepatic lipogenesis by regulating peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FASN), stearoyl-Co A desaturase 1 (SCD1), and cluster of differentiation 36 (CD36). Compared to ob/ob mice, the lower expressions of the pro-inflammatory cytokines, such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and F4/80, were observed after SalB treatment. Importantly, SalB treatment inhibited the activation of NLRP3 inflammasome and reduced the severity of liver inflammation. Our findings suggested that SalB improved NAFLD pathology in ob/ob mice by reducing hepatic lipid accumulation and NLRP3 inflammasome activation, which might be the potential hepatoprotective mechanism of SalB.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Benzofuranos , Depsídeos , Humanos , Inflamassomos/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos
14.
J Org Chem ; 87(17): 11852-11856, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-35960255

RESUMO

A PPh3-triggered tandem strategy for the efficient synthesis of valuable 2,3-disubstituted benzofuran derivatives in generally good to high yields from aryl or alkyl acyl chlorides and o-quinone methides has been developed. This method features mild reaction conditions, simple operation, and a broad substrate scope.


Assuntos
Benzofuranos , Indolquinonas , Cloretos , Estrutura Molecular
15.
Oxid Med Cell Longev ; 2022: 9468040, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910845

RESUMO

Osteoarthritis (OA) has been reported as a progressive disease in the elderly, primarily characterized by degenerated articular cartilage. There has been no satisfactory drug for the treatment of OA. DL-3-n-butylphthalide (NBP), a small molecule compound extracted from celery seeds, may have antiapoptotic, antioxidant, and anti-inflammatory activities in numerous studies. However, the effects of NBP on OA and its mechanisms have been rarely reported. In this study, the effect of NBP on OA in vitro and in vivo and its possible mechanism were investigated. The results showed that NBP injection into the knee joint inhibited osteoarthritis development in a rat model of osteoarthritis induced by DMM+ACLT. NBP could increase the expressions of extracellular matrix-related components (such as type II collagen, aggrecan, proteoglycan 4, and SRY-box 9) in human osteoarthritic chondrocytes and cartilage explants. Moreover, NBP promoted the expressions of SOD and CAT. NBP upregulated the expression of FoxO3a by inhibiting the PI3K/AKT pathway, which subsequently inhibited the apoptosis of human OA chondrocytes. In conclusion, NBP promotes cartilage extracellular matrix synthesis and inhibits osteoarthritis development and the underlying mechanism related to the activation of FoxO3a.


Assuntos
Benzofuranos , Cartilagem Articular , Proteína Forkhead Box O3 , Osteoartrite , Idoso , Animais , Benzofuranos/farmacologia , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Matriz Extracelular/metabolismo , Proteína Forkhead Box O3/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Humanos , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos
16.
Environ Int ; 167: 107441, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35926263

RESUMO

Polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) were ubiquitous, persistent chemical compounds attached to particulate matter in the atmosphere. We aimed to study the characteristics of these pollutants in atmospheric PM2.5 of three Asian countries, including Taiwan (Taipei), Thailand (Chiang Mai), and Vietnam (Hanoi). We carried out a source apportionment analysis to determine significant PCDD/F contributors in these areas. Multiple media model was conducted to access the health impact assessment. The PM2.5 concentration in Taipei (n = 7), Chiang Mai (n = 20), and Hanoi (n = 10) were 18.4 ± 6.21 µg/m3, 133 ± 49.5 µg/m3, and 88.1 ± 12.6 µg/m3, respectively. The PCDD/Fs level in Hanoi was 92.4 ± 67.3 fg I-TEQ/m3, and in Taipei and Chiang Mai was 5.01 ± 2.39 fg I-TEQ/m3 and 14.4 ± 13.1 fg I-TEQ/m3, respectively, which showed that the higher PM2.5 concentration was not necessary to follow with higher PCDD/Fs level. In all three cities, the effect of traffic on ambient PCDD/F level was significant (23-25 %). However, we also observed the specific sources of PCDD/Fs in each city during the sampling periods, namely long-range transport (Taipei, 55 %), Biomass/open burning (Chiang Mai, 77 %), and industrial activities (Hanoi, 34 %). In the carcinogenic risk estimation, the highest median total carcinogenic risk was in Hanoi (5.87 × 10-6), followed by Chiang Mai (1.06x10-6), and Taipei (2.95 × 10-7). Although diet was the major absorption pathway, the food contributor of exposure differed among the three areas due to the difference in food consumption composition.


Assuntos
Poluentes Atmosféricos , Benzofuranos , Dibenzodioxinas Policloradas , Poluentes Atmosféricos/análise , Benzofuranos/análise , Benzofuranos/química , Dibenzofuranos/análise , Dibenzofuranos Policlorados/análise , Monitoramento Ambiental , Material Particulado/análise , Dibenzodioxinas Policloradas/análise , Tailândia
17.
Int J Nanomedicine ; 17: 3561-3577, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35974873

RESUMO

Purpose: Ischemic stroke is the second leading cause of death and the third leading cause of disability worldwide. Salvianolic acid B (SAB), a water-soluble phenolic acid derived from the traditional Chinese medicine Salvia miltiorrhiza, exerted protective effects on cerebral ischemia-reperfusion injury. However, the efficacy of SAB is seriously hindered by poor blood brain barrier (BBB) permeability and short biological half-life in plasma. Brain targeted biomimetic nanoparticle delivery systems offer much promise in overcoming these limitations. Methods: A brain targeted biomimetic nanomedicine (RR@SABNPs) was developed, which comprised of SAB loaded bovine serum albumin nanoparticles and functionalized red blood cell membrane (RBCM) with Arg-Gly-Asp (RGD). The characterization parameters, including particle size, zeta potential, morphology, Encapsulation Efficiency (EE), Drug Loading (DL), release behavior, stability, and biocompatibility, were investigated. Moreover, the middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model was used to assess the therapeutic efficacy of RR@SABNPs on ischemic stroke. Finally, the reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were detected by DHE and JC­1 staining in oxygen-glucose deprivation/reperfusion (OGD/R) and H2O2 injured PC12 cells. Results: RR@SABNPs exhibited spheric morphology with core-shell structures and good stability and biocompatibility. Meanwhile, RR@SABNPs can significantly prolong SAB circulation time by overcoming the reticuloendothelial system (RES) and actively targeting ischemic BBB. Moreover, RR@SABNPs had comprehensive protective effects on MCAO/R model mice, manifested as a reduced infarct volume and improved neurological and sensorimotor functions, and significantly scavenged excess ROS and maintained MMP. Conclusion: The designed brain targeted biomimetic nanomedicine RR@SABNPs can significantly prolong the half-time of SAB, deliver SAB into the ischemic brain and exhibit good therapeutic effects on MCAO/R model mice.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Nanopartículas , Traumatismo por Reperfusão , Animais , Benzofuranos , Isquemia Encefálica/tratamento farmacológico , Membrana Eritrocítica/metabolismo , Peróxido de Hidrogênio , Infarto da Artéria Cerebral Média/tratamento farmacológico , Camundongos , Nanopartículas/química , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
18.
Acc Chem Res ; 55(18): 2708-2727, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36043467

RESUMO

ConspectusAsymmetric organocatalysis has been considered to be an efficient and reliable strategy for the stereoselective preparation of optically active chemicals. In particular, chiral tertiary amines as Lewis base organocatalysts bearing core structures including quinuclidine, dimethylaminopyridine (DMAP), N-methylimidazole (NMI), amidine, etc. have provided new and powerful tools for various chemical transformations. However, due to the limitations in structural complexity, synthetic difficulty, low catalytic efficiency, and high cost, the industrial application of such catalysts is still far from being widely adopted. Therefore, the development of new chiral tertiary amine catalysts with higher activity and selectivity is greatly desired.In order to address the contradiction between activity and selectivity caused by the ortho group, a bicyclic imidazole structure bearing a relatively large bond angle ∠θ was designed as the skeleton of our new catalysts. 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole (abbreviated as DPI) and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (abbreviated as TIP) are two of the utilized skeletons. In addition to obtaining satisfactory catalytic activity, excellent enantioselectivity would also be expected because the stereocontrol R group is neither far nor close to the catalytic active site (sp2-N atom) and is adjustable. Based on this skeleton, a family of chiral bicyclic imidazole catalysts were easily prepared and successfully applied in several enantioselective reactions for the synthesis of a variety of valuable chiral compounds.6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole (abbreviated as DPI) is the predominantly utilized skeleton. First, HO-DPI, the key intermediate of the designed chiral bicyclic imidazole catalysts, could be efficiently synthesized from imidazole and acrolein, then separated by kinetic resolution or optical resolution. Second, Alkoxy-DPI, the alkyloxy-substituted chiral bicyclic imidazole catalysts, were synthesized by a one-step alkylation from HO-DPI. This type of catalyst has been successfully applied in asymmetric Steglich rearrangement (C-acylation rearrangement of O-acylated azlactones), asymmetric phosphorylation of lactams, and a sequential four-step acylation reaction. Third, Acyloxy-DPI, the acyloxy-substituted chiral bicyclic imidazole catalysts, were synthesized with a one-step acetylative kinetic resolution from racemic HO-DPI or acylation from enantiopure HO-DPI. The catalyst AcO-DPI has been successfully applied in enantioselective Black rearrangement and in direct enantioselective C-acylation of 3-substituted benzofuran-2(3H)-ones and 2-oxindoles. Fourth, Alkyl-DPI was synthesized via a two-step reaction from racemic HO-DPI and separated easily by resolution. The catalyst Cy-DPI has been successfully applied in dynamic kinetic resolution of 3-hydroxyphthalides through enantioselective O-acylation. Cy-PDPI was synthesized through a Cu-catalyzed amidation from Cy-DPI and successfully applied in the kinetic resolution of secondary alcohols with good to excellent enantioselectivities. Finally, the carbamate type chiral bicyclic imidazole catalysts, Carbamate-DPI, were readily synthesized from HO-DPI, and the catalyst Ad-DPI bearing a bulky adamantyl group was successfully applied in the synthesis of the anti-COVID-19 drug remdesivir via asymmetric phosphorylation. Alongside our initial work, this Account also introduces four elegant studies by other groups concerning asymmetric phosphorylation utilizing chiral bicyclic imidazole catalysts.In summary, this Account focuses on the chiral bicyclic imidazole catalysts developed in our group and provides an overview on their design, synthesis, and application that will serve as inspiration for the exploration of new organocatalysts and related reactions.


Assuntos
Benzofuranos , Bases de Lewis , Acroleína , Amidinas , Aminas , Carbamatos , Catálise , Imidazóis/química , Lactamas/química , Oxindóis , Piridinas , Quinuclidinas , Estereoisomerismo
19.
Drug Des Devel Ther ; 16: 2545-2557, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35959422

RESUMO

Purpose: Chronic myelogenous leukemia (CML) is a hematological malignancy with increased proliferation of cells of the myeloid series. This can disrupt normal hematopoiesis. The 1-(2-(dimethylamino)acetyl)-rocaglaol (MQ-16) is a new synthetic flavagline compound that showed promising activity in chronic myeloid leukemia K562 cells. This study aims to analyze the underlying mechanisms of MQ-16 against CML. Methods: Growth, cell cycle progression, and apoptosis were assessed in K562 cells following MQ-16 exposure by MTT assay and flow cytometry. The effect of MQ-16 on DNA strands between nucleosomes was examined by 1% agarose gel electrophoresis. PI3K/Akt/mTOR, JAK2/STAT3, and mitogen-activated protein kinase (MAPK) pathway-related proteins were detected in MQ-16-treated K562 cells by Western blot. Results: MQ-16 significantly inhibited the proliferation of K562 cells and arrested the cell cycle at the G2/M phase in a time- and concentration-dependent manner. MQ-16 induced mitochondria-dependent apoptosis by downregulating the anti-apoptotic proteins Bcl-2 and Bcl-xL and induced time- and concentration-dependent DNA fragmentation. In addition, MQ-16 affected the expression of PI3K/Akt/mTOR, JAK2/STAT3, and MAPK pathway-related proteins. Conclusion: In summary, MQ-16 appears to be a promising chemotherapeutic drug for treating CML.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Proteínas Proto-Oncogênicas c-akt , Apoptose , Benzofuranos , Proliferação de Células , Humanos , Janus Quinase 2/metabolismo , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Serina-Treonina Quinases TOR/metabolismo
20.
Sci Rep ; 12(1): 13857, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35974091

RESUMO

M1 macrophages secrete a large number of proinflammatory factors and promote the expansion of atherosclerotic plaques and processes. Salvianolic acid B (Sal B) exerts anti-inflammatory, antitumor and other effects, but no study has addressed whether Sal B can regulate the polarization of macrophages to exert these anti-atherosclerotic effects. Therefore, we investigated the inhibition of Sal B in M1 macrophage polarization and the underlying mechanism. The effects of different treatments on cell viability, gene expression and secretion of related proteins, phenotypic markers and cytokines were detected by MTT and western blot assays, RT‒qPCR and ELISAs. Cell viability was not significantly changed when the concentration of Sal B was less than 200 µM, and Lipopolysaccharide (LPS) (100 ng/mL) + interferon-γ (IFN-γ) (2.5 ng/mL) successfully induced M1 polarization. RT‒qPCR and ELISAs indicated that Sal B can downregulate M1 marker (Inducible Nitric Oxide Synthase (iNOS), Tumor Necrosis Factor-α (TNF-α), and Interleukin-6 (IL-6)) and upregulate M2 marker (Arginase-1 (Arg-1) and Interleukin-10 (IL-10)) expression. Western blotting was performed to measure the expression of Nuclear Factor-κB (NF-κB), p-Akt, p-mTOR, LC3-II, Beclin-1, and p62, and the results suggested that Sal B inhibits the M1 polarization of RAW264.7 macrophages by promoting autophagy via the NF-κB signalling pathway. The study indicated that Sal B inhibits M1 macrophage polarization by inhibiting NF-κB signalling pathway activation and downregulating Akt/mTOR activation to promote autophagy.


Assuntos
NF-kappa B , Proteínas Proto-Oncogênicas c-akt , Animais , Benzofuranos , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , Serina-Treonina Quinases TOR/metabolismo
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