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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120279, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34438118

RESUMO

A new Schiff base 2-ethoxy-3-{[(6-{[(2-ethoxy-4-hydroxy-2H-chromen-3-yl)methylidene]amino}pyridine-2-yl)imino]methyl}-2H-chromen-4-ol (CD) was synthesized as a result of the condensation of 2,6-diaminopyridine and 3-formyl chromone in 1:2 M ratio and used for cupric ions detection and characterized through FTIR, HRMS and 1H NMR spectral techniques. The sensing capability of Schiff base for cupric ions as compared to other transition metal ions was examined by absorbance and emission studies. A considerable decrease in emission intensity appeared in Schiff base in the case of cupric ions while irrelevant changes were examined for the rest of the ions. The binding stoichiometry was obtained as 1:2 for CD: Cu2+ complex intended from the job's plot which was confirmed through HRMS spectral technique. DFT calculations were carried for the confirmation of structural relationships and absorption-emission data. The Regression coefficient, Limit of detection, and Association constant were obtained as 98.7%, 1.2 × 10-6 M, and 3.26 × 104 M-1 respectively using Benesi-Hildebrand (B-H) equation. The sensing power of Schiff base CD to recognize cupric ions was unaltered by the addition of the rest of metal ions, which was authenticated through interference studies. Schiff base CD and its complex with cupric ions were found stable over an extensive time period as revealed by time-reliant studies. The data collected by pH studies revealed that the preferred pH range for detecting cupric ions by Schiff base CD was 6 to 11. The Schiff base was finally utilized for sensing cupric ions in a variety of spiked samples of water like canal water, tap water, groundwater, distilled water.


Assuntos
Cromonas , Corantes Fluorescentes , Íons , Piridinas , Espectrometria de Fluorescência
2.
Zhongguo Zhong Yao Za Zhi ; 46(21): 5658-5664, 2021 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-34951219

RESUMO

The calibration of chromone reference extract(CRE) was conducted and a quality control method of Saposhnikoviae Radix(SR) was established based on CRE. Meanwhile, the quality control system of SR was improved and the feasibility of using reference extract as a substitute for single reference substance in quality control of Chinese medicine was discussed. In this study, the content of the prepared CRE was calibrated with prim-O-glucosylcimifugin, cimifugin, 4'-O-ß-D-glucosyl-5-O-methylvisamminol, and secO-glucosylhamaudol as indicators. Subsequently, an HPLC analytical method was developed to determine the content of four chromones in 20 batches of SR samples based on the CRE with known content as the standard substance. T-test was used for the comparison of the determination results of the two methods(single chemical component and CRE as reference substances, respectively), and the P values of prim-O-glucosylcimifugin, cimifugin, 4'-O-ß-D-glucosyl-5-O-methylvisamminol, and sec-O-glucosylhamaudol were 0. 16,0. 39, 0. 14, and 0. 42. The results demonstrated that there was no significant difference between the two methods. This study initially verified the feasibility that the CRE could be used as a substitute for single reference substance in quality control of SR. In conclusion,this study is expected to provide a scientific basis and a new research model for the application of reference extract in the quality control of Chinese medicine.


Assuntos
Apiaceae , Medicamentos de Ervas Chinesas , Calibragem , Cromatografia Líquida de Alta Pressão , Cromonas , Controle de Qualidade
3.
Zhongguo Zhong Yao Za Zhi ; 46(20): 5304-5309, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34738433

RESUMO

Perennial herb Hymenocallis littoralis(Amaryllidaceae) boasts anti-tumor, anti-virus, and anti-inflammatory activities. As the representative constituents, alkaloids have attracted much attention, whereas the non-alkaloid constituents have been rarely reported. Therefore, this study investigated the non-alkaloid constituents of H. littoralis and their contribution to the various pharmacological activities of the herb. Thirteen non-alkaloid compounds were isolated from the 95% ethanol extract of dried whole plant of H. littoralis after a series of chromatographic separation steps and spectral analysis, and they were identified as 5,7-dihydroxy-6,8-dimethoxy-2-hydroxymethyl-4H-chromoen-4-one(1), undulatoside A(2),(2S)-7,4'-dihydroxyflavane(3), naringenin(4), 4',7-hydroxy-8-methylflavanone(5), 8-methylnaringenin(6), 8-demethylfarrerol(7), 6-methyl-aromadendrin(8), 4',5,7-trihydroxy-8-methylflavanone(9), syzalterin(10), 6-methylapigenin(11), isoliquiritigenin(12), and undatuside C(13) based on the spectroscopic data analysis. Among them, compound 1 was a new chromone derivative, and compounds 2 and 4-13 were isolated form this plant for the first time.


Assuntos
Alcaloides , Amaryllidaceae , Liliaceae , Cromonas
4.
Molecules ; 26(21)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34770969

RESUMO

Flavonoids are important secondary plant metabolites that have been studied for a long time for their therapeutic potential in inflammatory diseases because of their cytokine-modulatory effects. Five flavonoid aglycones were isolated and identified from the hydrolyzed aqueous methanol extracts of Anastatica hierochuntica L., Citrus reticulata Blanco, and Kickxia aegyptiaca (L.) Nabelek. They were identified as taxifolin (1), pectolinarigenin (2), tangeretin (3), gardenin B (4), and hispidulin (5). These structures were elucidated based on chromatographic and spectral analysis. In this study, molecular docking studies were carried out for the isolated and identified compounds against SARS-CoV-2 main protease (Mpro) compared to the co-crystallized inhibitor of SARS-CoV-2 Mpro (α-ketoamide inhibitor (KI), IC50 = 66.72 µg/mL) as a reference standard. Moreover, in vitro screening against SARS-CoV-2 was evaluated. Compounds 2 and 3 showed the highest virus inhibition with IC50 12.4 and 2.5 µg/mL, respectively. Our findings recommend further advanced in vitro and in vivo studies of the examined isolated flavonoids, especially pectolinarigenin (2), tangeretin (3), and gardenin B (4), either alone or in combination with each other to identify a promising lead to target SARS-CoV-2 effectively. This is the first report of the activity of these compounds against SARS-CoV-2.


Assuntos
Proteases 3C de Coronavírus/efeitos dos fármacos , Flavonas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/farmacologia , Brassicaceae/metabolismo , COVID-19/tratamento farmacológico , Chlorocebus aethiops , Cromonas/farmacologia , Proteases 3C de Coronavírus/metabolismo , Descoberta de Drogas/métodos , Flavonas/metabolismo , Flavonoides/farmacologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Extratos Vegetais/farmacologia , Inibidores de Proteases/química , Quercetina/análogos & derivados , Quercetina/farmacologia , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Células Vero
5.
J Agric Food Chem ; 69(41): 12126-12134, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34633811

RESUMO

A number of novel chromone derivatives containing sulfonamide moieties were designed and synthesized, and the activity of compounds against tomato chlorosis virus (ToCV) was assessed using the ToCVCP-oriented screening method. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models were established based on the dissociation constant (Kd) values of the target compounds, and compound 35 was designed and synthesized with the aid of CoMFA and CoMSIA models. The study of affinity interaction indicated that compound 35 exhibited excellent affinity with ToCVCP with a Kd value of 0.11 µM, which was better than that of the positive control agents xiangcaoliusuobingmi (0.44 µM) and ningnanmycin (0.79 µM). In addition, the in vivo inhibitory effect of compound 35 on the ToCVCP gene was evaluated by the quantitative real-time polymerase chain reaction. ToCVCP gene expression levels of the compound 35 treatment group were reduced by 67.2%, which was better than that of the positive control agent ningnanmycin (59.5%). Therefore, compound 35 can be used as a potential anti-ToCV drug in the future.


Assuntos
Cromonas , Crinivirus , Antivirais/farmacologia , Sulfonamidas
6.
Int J Pharm Compd ; 25(5): 431-439, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34623970

RESUMO

Hydrocortisone is indicated in the treatment of primary or secondary adrenal insufficiency. The oral dosage regimen of hydrocortisone needs to be individualized in the treatment of congenital adrenal hyperplasia, especially in pediatric patients. A review of the therapeutic uses of hydrocortisone reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of hydrocortisone currently exists. Hydrocortisone is commercially available as 5-mg, 10-mg, and 20-mg tablets. An extemporaneously compounded suspension from pure drug powder would provide a convenient option to meet unique patient needs. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded hydrocortisone suspensions in PCCA Base, SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two hydrocortisone concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating high-performance liquid chromatographic assay for the determination of the chemical stability of hydrocortisone in SuspendIt was developed and validated. Suspensions of hydrocortisone were prepared in SuspendIt at 1-mg/mL and 20-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in plastic amber prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially and on the following days: 7, 15, 28, 45, 60, 91, 120, and 185. Physical data such as pH, viscosity, and appearance were also noted. Microbiological stability was tested. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. The study showed that hydrocortisone concentrations did not go below 94% of the label claim (initial drug concentration) at both temperatures studied. No microbial growth was observed. Viscosity and pH values did not change significantly. This study demonstrates that hydrocortisone is physically, chemically, and microbiologically stable in SuspendIt for 185 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for hydrocortisone in a liquid dosage form, with an extended beyond-use date to meet patient needs.


Assuntos
Hidrocortisona , Criança , Cromonas , Composição de Medicamentos , Estabilidade de Medicamentos , Humanos , Suspensões
7.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638853

RESUMO

DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein involved in DNA damage response (DDR) signaling that may mediate kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD) due to its pleiotropic effects on proliferation and survival. To test this hypothesis, the expression of DNA-PK in human ADPKD and the in vitro effects of DNA-PK inhibition in a three-dimensional model of Madin-Darby Canine Kidney (MDCK) cyst growth and human ADPKD cells were assessed. In human ADPKD, the mRNA expression for all three subunits of the DNA-PK complex was increased, and using immunohistochemistry, the catalytic subunit (DNA-PKcs) was detected in the cyst lining epithelia of human ADPKD, in a focal manner. In vitro, NU7441 (a DNA-PK kinase inhibitor) reduced MDCK cyst growth by up to 52% after long-term treatment over 6-12 days. Although human ADPKD cell lines (WT9-7/WT9-12) did not exhibit synthetic lethality in response to DNA-PK kinase inhibition compared to normal human kidney cells (HK-2), the combination of low-dose NU7441 enhanced the anti-proliferative effects of sirolimus in WT9-7 and WT9-12 cells by 17 ± 10% and 11 ± 7%, respectively. In conclusion, these preliminary data suggest that DNA-PK mediates kidney cyst growth in vivo without a synthetically lethal interaction, conferring cell-specificity in human ADPKD cells. NU7441 enhanced the anti-proliferative effects of rapamycin complex 1 inhibitors, but the effect was modest.


Assuntos
Cistos/genética , Proteína Quinase Ativada por DNA/genética , Perfilação da Expressão Gênica/métodos , Rim/metabolismo , Rim Policístico Autossômico Dominante/genética , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cromonas/farmacologia , Cistos/tratamento farmacológico , Cistos/enzimologia , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/metabolismo , Cães , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Rim/patologia , Células Madin Darby de Rim Canino , Morfolinas/farmacologia , Rim Policístico Autossômico Dominante/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/genética
8.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502316

RESUMO

Farrerol (FA) is a flavanone isolated from the Chinese herbal medicine "Man-shan-hong" (Rhododendron dauricum L.). In the present study, FA decreased the viability of SKOV3 cells in a dose- and time-dependent manner, and it induced G2/M cell cycle arrest and cell apoptosis. Cell cycle distribution analysis via flow cytometry showed that FA decreased G1 populations and increased G2/M populations in SKOV3 cells. Additionally, Western blotting confirmed an increase in the expression level of proteins involved in the cell cycle, e.g., CDK and cyclins. FA-induced apoptosis in SKOV3 cells was also investigated using a TUNEL assay, and increased expression levels of proapoptotic factors, including Caspase-3 and poly ADP ribose polymerase (PARP), through the Extracellular signal-regulated kinase (ERK)/MAPK pathway were investigated. Proinflammatory cytokines (e.g., IL-6, TNF-α, and IL-1) have been identified as a driver of the pathological mechanisms underlying involuntary weight loss and impaired physical function, i.e., cachexia, during cancer; in the present study, we showed that farrerol attenuates TNF-α-induced lipolysis and increases adipogenic differentiation in 3T3-L1 cells. Thus, farrerol could potentially be used as an anticancer agent or anticachetic drug.


Assuntos
Cromonas/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Fator de Necrose Tumoral alfa/farmacologia , Apoptose , Ciclo Celular , Proliferação de Células , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Células Tumorais Cultivadas
9.
Life Sci ; 285: 119995, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34592228

RESUMO

3-Epipachysamine B is a natural steroidal alkaloid isolated from Pachysandra terminalis Sieb. et Zucc. (known locally as Kunxianqi). Kunxianqi contains numerous compounds with demonstrated activity against breast cancer (BRCA). However, it is unknown whether 3-epipachysamine B also has anti-BRCA efficacy. In the present study, we employed network pharmacology technology to search and find potential molecular targets of 3-epipachysamine B. We applied cell proliferation, apoptosis, and western blotting assays to test the predicted key targets and the effects of 3-epipachysamine B against BRCA. Network pharmacology disclosed 80 potential BRCA-related targets of 3-epipachysamine B and assigned them to 75 signaling pathways. Of these, the most highly enriched was the PI3K/AKT signaling pathway. PIK3R1, AKT1, and mTOR had high degrees and betweenness centrality in protein-protein interaction network and are associated with PI3K/AKT signaling. Molecular docking and molecular dynamics simulation indicated strong binding between 3-epipachysamine B and PIK3R1, AKT1, and mTOR. 3-Epipachysamine B repressed the proliferation and induced the apoptosis of BRCA cells, as well as downregulated P-AKT/AKT, P-mTOR/mTOR, and P-PI3K/PI3K in the cells. The PI3K inhibitor LY294002 augmented these changes. Hence, 3-epipachysamine could also prove effective as an anticancer agent in future animal tumor model and human clinical breast cancer trials. Successful validation results could lead to a safe and effective new breast cancer treatment that improves patient prognosis and quality of life.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/enzimologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Feminino , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
10.
J Agric Food Chem ; 69(37): 10819-10829, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34516131

RESUMO

A series of novel chromone derivatives containing dithioacetals were prepared, and their antiviral activity against tomato spotted wilt virus (TSWV) was studied. The results showed that compounds A1-A31 had good inhibitory activity against TSWV. The 3D-QSAR model was built to analyze the structure-activity relationship of the compounds. We further found that compounds A32 and A33 had excellent anti-TSWV activities based on the results of 3D-QSAR, which were better than the control agents ningnanmycin and ribavirin. To study the mode of action of these compounds on TSWV, the nucleocapsid protein of TSWV (TSWV N) was cloned, expressed, and purified in the study. The results of the microscale thermophoresis (MST) experiments indicate that compound A33 can better bind with TSWV N. The molecular docking experiment further indicated that the mode of action of the compound A33 is to inhibit the virus by blocking the combination of TSWV N and viral RNA. Therefore, this study has found that chromone compound A33 is a potential anti-TSWV agent that targets TSWV N.


Assuntos
Tospovirus , Cromonas/farmacologia , Simulação de Acoplamento Molecular , RNA Viral , Tospovirus/genética
11.
Anticancer Res ; 41(9): 4377-4385, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475057

RESUMO

BACKGROUND/AIM: Expression of pleckstrin homology-like domain family A member 2 (PHLDA2) has been reported to be suppressed or activated in several cases of malignant tumors. However, its apoptotic regulatory mechanism and role in gastric cancer are not understood. This study examined the role of PHLDA2 in apoptosis in gastric cancer. MATERIALS AND METHODS: We used cell culture, western blotting, semiquantitative reverse transcription polymerase chain reaction, MTT assays, and PHLDA2 knockdown with short hairpin RNA (shRNA). RESULTS: To identify the pathway associated with HGF-induced PHLDA2 up-regulation, the cells were treated with PI3-kinase inhibitor (LY294002), MEK inhibitor (PD098059), or p38 inhibitor (SB203580) and then analyzed by western blotting. HGF-mediated changes in PHLDA2 protein levels were only decreased by LY294002. PHLDA2-shRNA cells showed decreased levels of p53 and increased levels of pAKT. Furthermore, HGF-induced cell proliferation and in vitro invasion were increased in PHLDA2 knockdown cells and HGF-induced cell apoptosis was increased in PHLDA2 knockdown cells. CONCLUSION: PHLDA2 plays a role in gastric cancer tumorigenesis by inhibiting apoptosis through the PI3K/AKT pathway.


Assuntos
Fator de Crescimento de Hepatócito/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Gástricas/metabolismo , Regulação para Cima , Apoptose , Linhagem Celular Tumoral , Cromonas/farmacologia , Flavonoides/farmacologia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Imidazóis , Morfolinas/farmacologia , Proteínas Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Piridinas
12.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3873-3876, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34472262

RESUMO

Compounds(1-6) were isolated and identified from 90% ethanol extract of the stems and leaves of Cassia occidentalis through column chromatography with silica gel, ODS, and Sephadex LH-20. These compounds were identified as 7-hydroxy-5-(3-hydroxy-2-oxopropyl)-2-methyl-4H-chromen-4-one(1), saccharonol A(2), S-6-hydroxymullein(3), 2-methyl-5-acetonyl-7-hydroxy-chromone(4), 2-(2'-hydroxypropyl)-5-methyl-7-hydroxychromone(5) and 7,4'-dihydroxyflavone(6) based on their physicochemical and spectroscopic data. Among them, compound 1 was a new compound, and all the compounds were isolated from this plant for the first time. DPPH method was employed to determine the antioxidant activities of these compounds in vitro. Six compounds exhibited weak antioxidant activities.


Assuntos
Senna (Planta) , Cromonas , Folhas de Planta , Análise Espectral
13.
Trials ; 22(1): 530, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380536

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve multiple organs or systems. Lupus nephritis (LN) is associated with high mortality and morbidity. However, plenty of patients do not respond to present treatment or relapse. Iguratimod (IGU) is a new small molecular, anti-rheumatic drug and has shown the potential for drug repurposing from rheumatoid arthritis (RA) to LN treatment. It has been approved for treating RA in northeast Asia. Beyond expectation in a recent observational study, over 90% of thirteen refractory LN patients responded to iguratimod monotherapy in 24 weeks, with no steroids dose increasing or any other medication add-on during the entire follow-up. METHODS/DESIGN: This study is a multi-center, randomized, 52-week parallel positive drug-controlled study. The study was designed as a head-to-head comparison between the iguratimod and present first-line therapy on LN patients. A total of 120 patients (60 patients each group) is in the enrolling plan. All enrolled patients are assigned randomly into trial and control groups. The patients will be selected from six study sites in China and will all have biopsy-proven active lupus nephritis. In the first 24 weeks of the trial, IGU is compared with cyclophosphamide as an induction therapy, and in the second 24 weeks, IGU is compared with azathioprine as a maintenance therapy. The primary outcome is renal remission rate including both complete remission and partial remission at week 52, which will be analyzed using a non-inferiority hypothesis test. DISCUSSION: Most patients diagnosed with SLE will develop LN within 5 years and LN remains a major cause of morbidity and death for SLE patients. Although some medications are proven effective for the treatment of this condition, at least 20-35% LN patients have to suffer from relapse or ineffective treatment and medication intolerance is also frequent. This trial is designed to demonstrate whether iguratimod can be used as an alternative induction or maintenance therapy in subjects who have lupus nephritis. Data from this study will provide an evidence on whether or not iguratimod should be recommended to active LN patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02936375 . Registered on October 18, 2016.


Assuntos
Azatioprina , Nefrite Lúpica , Azatioprina/efeitos adversos , Cromonas , Ciclofosfamida/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Sulfonamidas , Resultado do Tratamento
14.
Nat Commun ; 12(1): 4838, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376698

RESUMO

Macropinosomes are formed by shaping actin-rich plasma membrane ruffles into large intracellular organelles in a phosphatidylinositol 3-kinase (PI3K)-coordinated manner. Here, we utilize lattice lightsheet microscopy and image visualization methods to map the three-dimensional structure and dynamics of macropinosome formation relative to PI3K activity. We show that multiple ruffling morphologies produce macropinosomes and that the majority form through collisions of adjacent PI3K-rich ruffles. By combining multiple volumetric representations of the plasma membrane structure and PI3K products, we show that PI3K activity begins early throughout the entire ruffle volume and continues to increase until peak activity concentrates at the base of the ruffle after the macropinosome closes. Additionally, areas of the plasma membrane rich in ruffling had increased PI3K activity and produced many macropinosomes of various sizes. Pharmacologic inhibition of PI3K activity had little effect on the rate and morphology of membrane ruffling, demonstrating that early production of 3'-phosphoinositides within ruffles plays a minor role in regulating their morphology. However, 3'-phosphoinositides are critical for the fusogenic activity that seals ruffles into macropinosomes. Taken together, these data indicate that local PI3K activity is amplified in ruffles and serves as a priming mechanism for closure and sealing of ruffles into macropinosomes.


Assuntos
Membrana Celular/metabolismo , Microscopia de Fluorescência/métodos , Fosfatidilinositol 3-Quinases/metabolismo , Pinocitose/fisiologia , Animais , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Cromonas/farmacologia , Inibidores Enzimáticos/farmacologia , Células HEK293 , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/ultraestrutura , Camundongos , Microscopia Eletrônica de Varredura , Morfolinas/farmacologia , Fosfatidilinositóis/metabolismo , Pinocitose/efeitos dos fármacos , Células RAW 264.7
15.
Nat Commun ; 12(1): 4736, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354056

RESUMO

Chromones represent a privileged scaffold in medicinal chemistry and are an omnipresent structural motif in natural products. Chemically encoded non-natural peptidomimetics feature improved stability towards enzymatic degradation, cell permeability and binding affinity, translating into a considerable impact on pharmaceutical industry. Herein, a strategy for the sustainable assembly of chromones via electro-formyl C-H activation is presented. The rational design of the rhodaelectro-catalysis is guided by detailed mechanistic insights and provides versatile access to tyrosine-based fluorogenic peptidomimetics.


Assuntos
Cromonas/química , Peptidomiméticos/química , Benzaldeídos/síntese química , Benzaldeídos/química , Biomimética/métodos , Catálise , Cromonas/síntese química , Técnicas Eletroquímicas , Estrutura Molecular , Oxirredução , Peptidomiméticos/síntese química
16.
Fitoterapia ; 154: 105004, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34339802

RESUMO

Chemical investigation for the secondary metabolite of marine-derived fungus Aspergillus sp. LS57 resulted in the isolation of one new chromone named aspergilluone A (1) containing a chromone skeleton fused with an unusual hydrogenation cyclopentanoid ring, along with three known compounds 2-4. The structure of 1 was elucidated by 1D and 2D nuclear magnetic resonance (NMR) spectroscopic and mass spectrometric analyses. Its absolute configuration was established by combining NMR quantum chemical calculations and comparison between the experimental and calculated circular dichroism (CD) curves. Additionally, the antibacterial assay of compound 1 was performed. As a result, compound 1 showed in vitro anti-Mycobacterium tuberculosis with MIC value of 32 µg/mL, together with moderate antibacterial activity against Staphylococcus aureus (MIC values = 64 µg/mL), and exhibited feeble activity against gram-positive Bacillus subtilis and gram-negative pathogen Escherichia coli (both MICs = 128 µg/mL).


Assuntos
Antibacterianos/farmacologia , Aspergillus/química , Cromonas/farmacologia , Poríferos/microbiologia , Animais , Antibacterianos/isolamento & purificação , China , Cromonas/isolamento & purificação , Testes de Sensibilidade Microbiana , Estrutura Molecular
17.
J Med Chem ; 64(15): 11169-11182, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34269579

RESUMO

Chromone-3-phenylcarboxamides (Crom-1 and Crom-2) were identified as potent, selective, and reversible inhibitors of human monoamine oxidase B (hMAO-B). Since they exhibit some absorption, distribution, metabolism, and excretion (ADME)-toxicity liabilities, new derivatives were synthesized to map the chemical structural features that compose the pharmacophore, a process vital for lead optimization. Structure-activity relationship data, supported by molecular docking studies, provided a rationale for the contribution of the heterocycle's rigidity, the carbonyl group, and the benzopyran heteroatom for hMAO-B inhibitory activity. From the study, N-(3-chlorophenyl)-4H-thiochromone-3-carboxamide (31) (hMAO-B IC50 = 1.52 ± 0.15 nM) emerged as a reversible tight binding inhibitor with an improved pharmacological profile. In in vitro ADME-toxicity studies, compound 31 showed a safe cytotoxicity profile in Caco-2, SH-SY5Y, HUVEC, HEK-293, and MCF-7 cells, did not present cardiotoxic effects, and did not affect P-gp transport activity. Compound 31 also protected SH-SY5Y cells from iron(III)-induced damage. Collectively, these studies highlighted compound 31 as the first-in-class and a suitable candidate for in vivo preclinical investigation.


Assuntos
Cromonas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Linhagem Celular , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade
18.
Biomed Res Int ; 2021: 9941253, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307680

RESUMO

Objective: To investigate the role of PI3K/AKT signaling pathway in nucleus pulposus (NP) cells. Methods: Nucleus pulposus (NP) cells were isolated from SD rat, and thereafter, passage three (P3) NP cells were divided into the following experimental groups: control, PI3K/AKT agonist IGF-1 (25 ng/ml, 50 ng/ml, and 100 ng/ml), and PI3K/AKT inhibitor LY294002 (5 µM, 10 µM, and 20 µM). Flow cytometry and BrdU cell proliferation assays were performed to assess apoptosis and the proliferation rate of NP cells. Western blot analysis was performed to examine the protein expression level of Col II, Col X, Aggrecan, and MMP13. Results: PI3K/AKT inhibitor LY294002 increased the rate of apoptosis in NP cells when compared to the control and decreased the proliferation rate when compared to control. Moreover, LY294002 decreased the protein expression level of Col-II and Aggrecan in NP cells. At the same time, LY294002 increased the protein expression level of MMP13 and Col-X in NP cells. Through activating PI3K/AKT, IGF-1 increased the proliferation rate when compared to control and decreased the rate of apoptosis when compared to control. Additionally, IGF-1 decreased the protein expression level of MMP13 and Col-X and increased Col-II and Aggrecan in NP cells. Conclusion: The inhibition of PI3K/AKT signaling pathway accelerated the apoptosis of NP cells and facilitated the extracellular matrix degradation. However, the activation of PI3K/AKT pathway partly prevented the NP cell from apoptosis and promoted their proliferation. Meanwhile, its activation also delayed the loss of extracellular matrix.


Assuntos
Núcleo Pulposo/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Apoptose , Proliferação de Células/efeitos dos fármacos , Cromonas , Fator de Crescimento Insulin-Like I/metabolismo , Morfolinas , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/agonistas , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ratos Sprague-Dawley
19.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202670

RESUMO

Astragalus membranaceus is a famous herb found among medicinal and food plants in East and Southeastern Asia. The Nrf2-ARE assay-guided separation of an extract from Jing liqueur led to the identification of a nontoxic Nrf2 activator, methylnissolin-3-O-ß-d-glucopyranoside (MNG, a component of A. membranaceus). Nrf2 activation by MNG has not been reported before. Using Western Blot, RT-qPCR and imaging, we investigated the cytoprotective effect of MNG against hydrogen peroxide-induced oxidative stress. MNG induced the expression of Nrf2, HO-1 and NQO1, accelerated the translocation of Nrf2 into nuclei, and enhanced the phosphorylation of AKT. The MNG-induced expression of Nrf2, HO-1, and NQO1 were abolished by Nrf2 siRNA, while the MNG-induced expression of Nrf2 and HO-1 was abated and the AKT phosphorylation was blocked by LY294002 (a PI3K inhibitor). MNG reduced intracellular ROS generation. However, the protection of MNG against the H2O2 insult was reversed by Nrf2 siRNA with decreased cell viability. The enhancement of Nrf2 and HO-1 by MNG upon H2O2 injury was reduced by LY294002. These data showed that MNG protected EA.hy926 cells against oxidative damage through the Nrf2/HO-1 and at least partially the PI3K/Akt pathways.


Assuntos
Astragalus propinquus/química , Citoproteção/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Cromonas , Células Hep G2 , Humanos , Morfolinas , Compostos Fitoquímicos/química
20.
J Org Chem ; 86(15): 10235-10248, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34292727

RESUMO

A domino Michael-aldol double elimination route to indolizines having two different acyl groups at the C5 and C7 positions is described where chromone is employed as a two-carbon unit for the synthesis of a pyridine moiety for the first time. Various analogues were readily accessed in good yields under metal-free and eco-friendly conditions. Further manipulation of the resulting products allowed entry to novel indolizine-heterocycle adducts, which are difficult to access by other methods.


Assuntos
Cromonas , Indolizinas , Aldeídos , Piridinas
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