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1.
J Pharm Biomed Anal ; 207: 114404, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34700199

RESUMO

Ulotaront (SEP-363856) is a novel non-D2-receptor-binding agent under development for the treatment of patients with schizophrenia. A highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with lower limit of quantitation of 0.0200 ng/mL (i.e. 20.0 pg/mL) was successfully developed and validated for the simultaneous quantitation of ulotaront and its N-desmethyl metabolite (M11A) in human plasma. Plasma samples were extracted by solid phase extraction with Oasis MCX 96-well plate, followed by a reversed phase LC separation coupled with MS/MS detection in positive mode (m/z 184.1 → 135.0 for ulotaront and 170.1 → 135.0 for M11A). Stable isotope-labeled compounds SEP-363856-d3 and M11A-d4 were used as internal standards (IS) for corresponding analytes. The validated calibration curve range was 0.0200-20.0 ng/mL for both analytes using a 0.200 mL plasma. Extraction recoveries were found to be 75.7% and 75.1% for ulotaront and IS1, and 82.7% and 83.9% for M11A and IS2, respectively. Frozen plasma samples were confirmed to be stable for up to 730 days at both -20 °C and -70 °C. The validated method has been successfully used to evaluate the pharmacokinetics (PK) of ulotaront and M11A in clinical studies. The application to the first-in-human PK study (single ascending dose) presented in this work demonstrated that ulotaront exhibited near dose proportionality for both Cmax (maximum concentration) and AUC (area under the curve) over the dose range from 5 to 125 mg. M11A was found as a minor metabolite with an exposure of about 2-3% of the parent compound.


Assuntos
Plasma , Espectrometria de Massas em Tandem , Cromatografia Líquida , Humanos , Piranos , Reprodutibilidade dos Testes
2.
Biomaterials ; 278: 121138, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34634662

RESUMO

Chemoresistance and inadequate therapeutics transport across the blood brain barrier (BBB) remain the major barriers to treating medulloblastoma (MB). Hedgehog (Hh) and IGF/PI3K pathways regulate tumor cell proliferation and resistance in MB. Current Hh inhibitors are effective initially to treat SHH-MB but acquire resistance. Herein, we showed that Hh inhibitor MDB5 and BRD4/PI3K dual inhibitor SF2523 synergistically inhibited the proliferation of DAOY and HD-MB03 cells when used in combination. Treatment of these MB cells with the combination of MDB5 and SF2523 significantly decreased colony formation and expression of MYCN, p-AKT, and cyclin D1 but significantly increased in Bax expression, compared to individual drugs. We used our previously reported copolymer mPEG-b-PCC-g-DC copolymer, which showed 8.7 ± 1.0 and 6.5 ± 0.1% loading for MDB5 and SF2523 when formulated into nanoparticles (NPs). There was sustained drug release from NPs, wherein 100% of MDB5 was released in 50 h, but only 60% of SF2523 was released in 80 h. Targeted NPs prepared by mixing 30:70 ratio of COG-133-PEG-b-PBC and mPEG-b-PCC-g-DC copolymer delivered a significantly higher drug concentration in the cerebellum at 6 and 24h after intravenous injection into orthotopic SHH-MB tumor-bearing NSG mice. Moreover, systemic administration of COG-133-NPs loaded with MDB5 and SF2523 resulted in decreased tumor burden compared to non-targeted drug-loaded NPs, without any hepatic toxicity. In conclusion, our nanomedicine of MDB5 and SF2523 offers a novel therapeutic strategy to treat chemoresistant MB.


Assuntos
Neoplasias Cerebelares , Meduloblastoma , Animais , Derivados de Benzeno , Linhagem Celular Tumoral , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/genética , Proteínas Hedgehog , Meduloblastoma/tratamento farmacológico , Meduloblastoma/genética , Camundongos , Morfolinas , Nanomedicina , Proteínas Nucleares , Fosfatidilinositol 3-Quinases , Piranos , Piridinas , Fatores de Transcrição
3.
Photochem Photobiol Sci ; 20(10): 1309-1321, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34562236

RESUMO

The initial objective of our work was to synthesize a series of 2-amino-4H-pyran-3-carbonitriles to be tested for their antifungal activities against economically relevant phytopathogenic fungi. Fourteen compounds were prepared in up to 94% yield and shown percentages of Botrytis cinerea inhibition above 70%. Despite the promising biological results, we observed that stock solutions prepared for biological tests showed color changing when kept for a few days on the laboratory bench, under room conditions, illuminated by common LED daylight tubes (4500-6000 k). This prompted us to investigate the possible photo-induced degradation of our compounds. FT-IR ATR experiments evidenced variations in the expected bands for functional of -amino-4H-pyran-3-carbonitriles stored under LED daylight. Following, HPLC-UV analysis showed reductions in the intensity of chromatographic peaks of 2-amino-4H-pyran-3-carbonitriles, and but not for solutions kept in the dark. A solution of (E)-2-amino-8-(4-nitrobenzylidene)-4-(4-nitrophenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile underwent 84.4% of conversion after 72 h of exposure to continuous LED daylight in a BOD chamber, and the reaction product was isolated in 36% yield and characterized as (E)-7-cyano-5-(4-nitrobenzylidene)-8-(4-nitrophenyl)bicyclo[4.2.0]oct-1(6)-ene-7-carboxamide (7*). Despite freshly prepared solutions of 2-amino-4H-pyran-3-carbonitriles produced antifungal activities, these solutions lost biological activity when left on the bench for a week. Besides, compound 7* formed from photo-induced degradation of 7 also showed no antifungal activity. With this, we hope to bring two contributions: (1) production of cyclobutenes through photochemical reactions of 2-amino-4H-pyran-3-carbonitriles can be carried out through exposure to simple white LED daylight; (2) biological applications of such 2-amino-4H-pyran-3-carbonitriles may be impaired by their poor photostability.


Assuntos
Antifúngicos/farmacologia , Botrytis/efeitos dos fármacos , Luz , Piranos/química , Antifúngicos/síntese química , Antifúngicos/química , Cromatografia Líquida de Alta Pressão , Conformação Molecular , Fotólise/efeitos da radiação , Piranos/síntese química , Piranos/farmacologia , Espectrofotometria Ultravioleta
4.
Chem Biol Interact ; 348: 109653, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34516974

RESUMO

Angiotensin II, the effector peptide of the renin-angiotensin system, is not only a pivotal peptide implicated in the regulation of blood pressure but also a key mediator of the inflammatory processes that play an important role in the pathology of hypertension-related cSVD. Harpagide is the major bioactive constituent of Scrophulariae Radix widely used in traditional Chinese medicine for numerous diseases including hypertension. The present study aimed to investigate the effect of harpagide on Ang II-induced neuroinflammation and the potential mechanism. Pretreated with harpagide or resatorvid (the TLR4 pathway inhibitor), BV2 cells were treated with Ang II or LPS (the TLR4 activator). NO, pro-inflammatory cytokines, the proteins on TLR4/MyD88/NF-κB signaling pathway and the expression of CD86, CD206, TREM2 in BV2 cells were detected respectively. Subsequently, the effects of harpagide on neurotoxicity and BBB destruction triggered by Ang II-induced neuroinflammation were investigated in the co-cultures of BV2 microglia/HT22 hippocampal neurons, BV2 microglia/bEnd.3 endotheliocyte and BV2 microglia/BBB monolayer model. We found that Ang II converted microglia into M1 state and resulted in neuroinflammation through activating TLR4/MyD88/NF-κB signaling pathway. It also triggered the imbalance of TLR4/TREM2 in microglia. Ang II-mediated inflammation microglia further led to neuronal apoptosis and BBB damage. Harpagide showed the effect of alleviating Ang II-mediated neuroinflammation as well as the resulting neurotoxicity and BBB destruction through inhibiting the TLR4/MyD88/NF-κB pathway. The anti-inflammatory and neuroprotective effect of harpagide suggested that it might be a potential therapeutic strategy in hypertensive cSVD.


Assuntos
Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Glicosídeos Iridoides/farmacologia , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Piranos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular , Humanos , Microglia/citologia , Microglia/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Receptor 4 Toll-Like/metabolismo
5.
Phytomedicine ; 92: 153720, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34481340

RESUMO

BACKGROUND: Bladder cancer (BC) is a very common type of malignant cancer in men and new therapeutic strategies are urgently needed to reduce mortality. Several studies have demonstrated that Rhopaloic acid A (RA), a compound isolated from marine sponges, fights cancer but its potential anti-tumor effect on BC is still unknown. PURPOSE: The present study was aimed to explore the potential anti-tumor effects of RA against human BC cells and the underlying molecular mechanism. METHODS: Cell cytotoxicity was determined using the MTT and colony formation assays. Cell cycle distribution, apoptosis induction and generation of mitochondrial reactive oxygen species (ROS) were analyzed by flow cytometry. Mitochondrial membrane potential, acridine orange staining and intracellular ROS levels were observed using fluorescence microscopy. Levels of various signaling proteins were assessed using Western blotting. Furthermore, a zebrafish BC xenotransplantation model was used to confirm the anti-tumor effect of RA in vivo. RESULTS: Treatment with RA significantly suppressed the proliferation of BC cells that resulted from G2/M cycle arrest. Additionally, RA induced mitochondrial-mediated apoptosis and autophagy in BC cells. The death of BC cells induced by RA was rescued by treatment with inhibitors of apoptosis (Z-VAD-FMA) or autophagy (3-MA). RA activated the MAPK pathway and increased the production of cellular and mitochondrial ROS. Treatment with the ROS scavenger N-acetyl cysteine, effectively reversed the induction of apoptosis, autophagy, JNK activation and DNA damage elicited by RA. Finally, RA significantly inhibited tumor growth in a zebrafish BC xenotransplantation model. CONCLUSION: Taken together, our findings indicate that RA induces apoptosis and autophagy and activates the MAPK pathway through ROS-mediated signaling in human BC cells. This RA-induced pathway offers insights into the molecular mechanism of its antitumor effect and shows that RA is a promising candidate for the treatment of BC.


Assuntos
Neoplasias da Bexiga Urinária , Animais , Apoptose , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Piranos , Espécies Reativas de Oxigênio , Neoplasias da Bexiga Urinária/tratamento farmacológico , Peixe-Zebra
6.
Inorg Chem ; 60(19): 15010-15023, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34533947

RESUMO

A novel catalyst has been afforded by attaching of a Cu(proline)2 complex to magnetic nanoparticles through cheap, simple, and readily available chemicals. This catalyst was characterized by Fourier transform infrared, energy-dispersive X-ray, X-ray diffraction, vibrating-sample magnetometry, transmission electron microscopy, scanning electron microscopy, and inductively coupled plasma analyses. The catalytic activity of the Fe3O4@NH2@TCT@HProCu nanocatalyst was investigated in a green and effective synthesis of pyran derivatives in high yields by applying three-component reactions of malononitrile, dimedone, and aldehydes in ethanol. Conversion was high under optimal conditions. The obtained nanocatalyst could be easily separated from the mixture of the reaction and was recyclable nine times via a simple magnet without considerable reduction of its catalytic efficiency. Operational simplicity, high product yields, environmental friendliness, ecofriendliness, economical processing, and easy workup are the features of this methodology.


Assuntos
Complexos de Coordenação/química , Cobre/química , Hidroxiprolina/química , Nanopartículas de Magnetita/química , Piranos/síntese química , Catálise , Complexos de Coordenação/síntese química , Ciclização , Estrutura Molecular , Piranos/química
7.
Plant Physiol Biochem ; 167: 921-933, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34555666

RESUMO

Karrikinolide (KAR1), identified in biochars, has gained research attention because of its significant role in seed germination, seedling development, root development, and abiotic stresses. However, KAR1 regulation of salt stress in wheat is elusive. This study investigated the physiological mechanism involved in KAR1 alleviation of salt stress in wheat. The results showed KAR1 boosted seed germination percentage under salinity stress via stimulating the relative expression of genes regulating gibberellins biosynthesis and decreasing the expression levels of abscisic acid biosynthesis and signaling genes. As seen in seed germination, exogenous supplementation of KAR1 dramatically mitigated the salt stress also in wheat seedling, resulting in increased root and shoot growth as measured in biomass as compared to salt stress alone. Salt stress significantly induced the endogenous hydrogen peroxide and malondialdehyde levels, whereas KAR1 strictly counterbalanced them. Under salt stress, KAR1 supplementation showed significant induction in reduced glutathione (GSH) and reduction in oxidized glutathione (GSSG) content, which improved GSH/GSSG ratio in wheat seedlings. Exogenous supplementation of KAR1 significantly promoted the activities of enzymatic antioxidants in wheat seedlings exposed to salt stress. KAR1 induced the relative expression of genes regulating the biosynthesis of antioxidants in wheat seedlings under salinity. Moreover, KAR1 induced the expression level of K+/Na+ homeostasis genes, reduced Na+ concentration, and induced K+ concentration in wheat seedling under salt stress. The results suggest that KAR1 supplementation maintained the redox and K+/Na+ homeostasis in wheat seedling under salinity, which might be a crucial part of physiological mechanisms in KAR1 induced tolerance to salt stress. In conclusion, we exposed the protective role of KAR1 against salt stress in wheat.


Assuntos
Germinação , Triticum , Antioxidantes , Furanos , Homeostase , Oxirredução , Piranos , Estresse Salino , Plântula , Estresse Fisiológico , Triticum/genética
8.
Int J Nanomedicine ; 16: 6367-6382, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34584409

RESUMO

Background: Cervical cancer stem cells (CCSCs), a small part of tumor population, are one of the important reasons for metastasis and recurrence of cervical cancer. Targeting CCSCs may be an effective way to eliminate tumors. Salinomycin (Sal) has been proved to be an effective anticancer drug in many studies, especially for cancer stem cells (CSCs). However, the cytotoxicity of salinomycin limits its further research as an anticancer drug. High-density lipoprotein (HDL) nanoparticles are an excellent drug carrier, which can reduce the toxicity of Sal, have a certain targeting effect and improve the clinical benefit of Sal. Methods: Salinomycin-loaded high-density lipoprotein (S-HDL) was synthesized and characterized by various analytical techniques. CD44highCD24low CCSCs were isolated from HeLa cells by magnetic separation. The uptake of HDL nanoparticles was observed by laser confocal microscopy, and the effect of S-HDL on the proliferation of CCCs and CCSCs was detected by cell viability analysis. Genome-wide analysis was used to analyze the effects of S-HDL on the biological processes of CCCs and then cell apoptosis, cell cycle and cell migration were selected for verification. Results: S-HDL had a particle size of 38.98 ± 1.78 nm and an encapsulation efficiency of 50.73 ± 4.29%. Cell uptake analysis showed that HDL nanoparticles could enhance the drug uptake of CCCs and CCSCs and may target CCCs and CCSCs. In cell viability analysis, CCCs and CCSCs showed high sensitivity to S-HDL. S-HDL can more efficiently prevent CCSCs from developing tumorspheres than Sal in tumorsphere formation study. S-HDL had stronger ability to induce cell cycle arrest, promote cell apoptosis and inhibit cell migration compared with free Sal, which was consistent with the results of Genome Wide analysis. Conclusion: S-HDL can effectively target and eliminate CCCs and CCSCs, which is a potential drug for the treatment of cervical cancer.


Assuntos
Neoplasias do Colo do Útero , Linhagem Celular Tumoral , Feminino , Células HeLa , Humanos , Lipoproteínas HDL , Células-Tronco Neoplásicas , Piranos/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico
9.
Phytother Res ; 35(11): 6241-6254, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34486189

RESUMO

Hypertension and its associated dysfunction of the blood-brain barrier (BBB) contribute to cerebral small vessel disease (cSVD). Angiotensin II (Ang II), a vasoactive peptide of the renin-angiotensin system (RAS), is not only a pivotal molecular signal in hypertension but also causes BBB leakage, cSVD, and cognitive impair. Harpagoside, the major bioactive constituent of Scrophulariae Radix, has been commonly used for the treatment of multiple diseases including hypertension in China. The effect of harpagoside on Ang II-induced BBB damage is unclear. We employed an immortalized endothelial cell line (bEnd.3) to mimic a BBB monolayer model in vitro and investigated the effect of harpagoside on BBB and found that harpagoside alleviated Ang II-induced BBB destruction, inhibited Ang II-associated cytotoxicity in a concentration-dependent manner and attenuated Ang II-induced reactive oxygen species (ROS) impair by downregulation of Nox2, Nox4, and COX-2. Harpagoside prevented Ang II-induced apoptosis via keeping Bax/Bcl-2 balance, decreasing cytochrome c release, and inactivation of caspase-8, caspase-9, and caspase-3 (the mitochondria-dependent and death receptor-mediated apoptosis pathways). Moreover, harpagoside can alleviate Ang II-induced BBB damage through upregulation of tight junction proteins and decrease of caveolae-mediated endocytosis. Thus, harpagoside might be a potential drug to treat Ang II-induced cSVD.


Assuntos
Angiotensina II , Barreira Hematoencefálica , Angiotensina II/toxicidade , Glicosídeos/farmacologia , Piranos , Espécies Reativas de Oxigênio
10.
Diabetes Res Clin Pract ; 179: 108999, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34390762

RESUMO

AIMS: To date, no clinical studies have compared once-weekly dipeptidyl peptidase 4 (DPP-4) inhibitors with once-daily DPP-4 inhibitors in terms of glucose variability (GV) and oxidative stress (OS). METHODS: Thirty-six patients with type 2 diabetes mellitus (T2DM) treated with once-daily DPP-4 inhibitors for at least 12 weeks were randomized to either continue once-daily DPP-4 inhibitors or receive omarigliptin, a once-weekly DPP-4 inhibitor, for 24 weeks. The primary end points were changes in the diacron-reactive oxygen metabolite (d-ROMs) test, a marker of OS, and GV using flash glucose monitoring. The secondary end point was changes in the diabetes treatment satisfaction questionnaire (DTSQ) scores. RESULTS: There were no significant group differences in d-ROMs and DTSQ scores after 24 weeks of treatments. However, omarigliptin was superior to once-daily DPP-4 inhibitors in controlling fasting plasma glucose (FPG) and time in range (TIR). Although FPG and TIR were unchanged at 24 weeks after switching to omarigliptin, these parameters increased in the group receiving maintenance therapy with once-daily DPP-4 inhibitors. No statistically significant changes in hemoglobin A1c were observed between the two groups. CONCLUSIONS: Our findings suggest that switching from once-daily DPP-4 inhibitors to omarigliptin may be efficacious for maintaining FPG and TIR in T2DM patients.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Glicemia , Automonitorização da Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose , Hemoglobina A Glicada/análise , Compostos Heterocíclicos com 2 Anéis , Humanos , Hipoglicemiantes , Estresse Oxidativo , Estudos Prospectivos , Piranos , Resultado do Tratamento
11.
Arch Biochem Biophys ; 711: 109021, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34464591

RESUMO

BACKGROUND: Apelin and its receptor angiotensin receptor - like 1 (APJ) are closely related to renal fibrosis, but their specific roles in renal fibrosis are still controversial. In this article, we discussed the role of Apelin/APJ system in renal fibrosis and its mechanism. METHODS: Chronic intermittent hypoxia (CIH) rat model was established to induce the environment of renal fibrosis and a competitive antagonist of the APJ receptor ML221 was administered to CIH rats. The rats were divided into Control, CIH and ML221 groups. HE staining was used to detect the inflammatory injury and fibrosis of renal tissue. The expressions of renal fibrosis-related indicators transforming growth factor-ß (TGF-ß), α-smooth muscle actin (α-SMA) and Human type I collagen (Col-Ⅰ) were detected by immunohistochemistry. The levels of oxidative stress indexes reactive oxygen species (ROS), Malondialdehyde (MDA), Superoxide Dismutase (SOD) and inflammation-related indexes Interleukin (IL) -6, tumor necrosis factor-α (TNF-α) and IL-1ß were detected by ELISA. At the same time, the levels of Apelin-13 and AngiotensinII (AngⅡ) were also measured by ELISA. Finally, western blot was used to detect the expression of Apelin pathway and renal fibrosis-related proteins. In addition, at the cellular level, we divided the cells into Control, CIH, Apelin-13 and Apelin-13+ML-221 groups to further verify the specific mechanisms at the cellular level. RESULTS: The expression of Apeline-13 and its related pathways was significantly increased after the induction of CIH in rats. However, the degree of renal fibrosis in ML221 group was further significantly increased after inhibiting the expression of Apelin. At the cellular level, CIH model cells treated with Apelin-13 significantly reduced cell proliferation, oxidative stress and inflammatory response, and decreased the expression of fibrosis-related proteins, which can be reversed by ML221 administration. CONCLUSION: The increased reactivity of Apelin may be one of the protective mechanisms against renal fibrosis induced by CIH.


Assuntos
Apelina/metabolismo , Fibrose/metabolismo , Hipóxia/complicações , Nefropatias/metabolismo , Angiotensina II/metabolismo , Animais , Receptores de Apelina/antagonistas & inibidores , Linhagem Celular , Fibrose/etiologia , Fibrose/patologia , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/etiologia , Nefropatias/patologia , Masculino , Nitrobenzoatos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Piranos/farmacologia , Ratos Wistar
12.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201477

RESUMO

Pyranoanthocyanins are anthocyanin-derived pigments with higher stability to pH and storage. However, their slow formation and scarcity in nature hinder their industrial application. Pyranoanthocyanin formation can be accelerated by selecting anthocyanin substitutions, cofactor concentrations, and temperature. Limited information is available on the impacts of the chemical structure of the cofactor and anthocyanin; therefore, we evaluated their impacts on pyranoanthocyanin formation efficiency under conditions reported as favorable for the reaction. Different cofactors were evaluated including pyruvic acid, acetone, and hydroxycinnamic acids (p-coumaric, caffeic, ferulic, and sinapic acid) by incubating them with anthocyanins in a molar ratio of 1:30 (anthocyanin:cofactor), pH 3.1, and 45 °C. The impact of the anthocyanin aglycone was evaluated by incubating delphinidin, cyanidin, petunidin, or malvidin derivatives with the most efficient cofactor (caffeic acid) under identical conditions. Pigments were identified using UHPLC-PDA and tandem mass spectrometry, and pyranoanthocyanin formation was monitored for up to 72 h. Pyranoanthocyanin yields were the highest with caffeic acid (~17% at 72 h, p < 0.05). When comparing anthocyanins, malvidin-3-O-glycosides yielded twice as many pyranoanthocyanins after 24 h (~20%, p < 0.01) as cyanidin-3-O-glycosides. Petunidin- and delphinidin-3-O-glycosides yielded <2% pyranoanthocyanins. This study demonstrated the importance of anthocyanin and cofactor selection in pyranoanthocyanin production.


Assuntos
Antocianinas/química , Ácidos Cumáricos/química , Acetona/química , Berberis/química , Ácidos Cafeicos/química , Glicosídeos/química , Estrutura Molecular , Piranos/química , Ácido Pirúvico/química
13.
J Infect Chemother ; 27(10): 1436-1446, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34226112

RESUMO

INTRODUCTION: We conducted a post-marketing surveillance of laninamivir octanoate hydrate for Inhalation Suspension Set in patients under the age of 5 infected with the influenza virus to evaluate safety and efficacy of the drug. METHODS: Subjects enrolled by the centralized enrollment system were administered laninamivir once using a nebulizer based on the package insert. RESULTS: Safety was evaluated in 1104 patients. The incidence of ADRs was 1.00% (11/1104). Compared to the incidence of ADRs of 2.04% (9/441) in the clinical trials for development, no increase in the frequency of ADRs was noted. Serious ADRs were noted in 3 patients (5 cases): 2 cases of convulsive attack, each 1 case of muscular weakness, a depressed level of consciousness, and pain in extremities. Excluding 2 patients with unknown outcomes, all of the patients recovered or their symptoms were alleviated. To detect risk factors for the occurrence of ADRs, 16 attributes were examined, and none of them were found to be significant. Efficacy was evaluated in 881 patients. The median time (95% CI) to fever resolution was 37.0 (33.0-39.0) h in type A virus (785 patients), 45.0 (34.0-56.0) h in type B virus (95 patients), and 22.0 h (1 patient) in the mixed type. This was similar to the time to fever resolution in the clinical trials. CONCLUSION: The results of this surveillance verified that there are no noticeable problems with the safety or efficacy of laninamivir for children under the age of 5 infected with the influenza A and B viruses.


Assuntos
Influenza Humana , Neuraminidase , Administração por Inalação , Antivirais/efeitos adversos , Pré-Escolar , Guanidinas/uso terapêutico , Humanos , Influenza Humana/tratamento farmacológico , Vigilância de Produtos Comercializados , Piranos/uso terapêutico , Ácidos Siálicos/uso terapêutico , Zanamivir/efeitos adversos
14.
Nat Commun ; 12(1): 4491, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301950

RESUMO

Intron selection during the formation of prespliceosomes is a critical event in pre-mRNA splicing. Chemical modulation of intron selection has emerged as a route for cancer therapy. Splicing modulators alter the splicing patterns in cells by binding to the U2 snRNP (small nuclear ribonucleoprotein)-a complex chaperoning the selection of branch and 3' splice sites. Here we report crystal structures of the SF3B module of the U2 snRNP in complex with spliceostatin and sudemycin FR901464 analogs, and the cryo-electron microscopy structure of a cross-exon prespliceosome-like complex arrested with spliceostatin A. The structures reveal how modulators inactivate the branch site in a sequence-dependent manner and stall an E-to-A prespliceosome intermediate by covalent coupling to a nucleophilic zinc finger belonging to the SF3B subunit PHF5A. These findings support a mechanism of intron recognition by the U2 snRNP as a toehold-mediated strand invasion and advance an unanticipated drug targeting concept.


Assuntos
DNA/genética , Íntrons/genética , Piranos/metabolismo , Ribonucleoproteína Nuclear Pequena U2/metabolismo , Compostos de Espiro/metabolismo , Spliceossomos/metabolismo , Microscopia Crioeletrônica , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Humanos , Lactonas/química , Lactonas/metabolismo , Modelos Moleculares , Conformação de Ácido Nucleico , Ligação Proteica , Conformação Proteica , Piranos/química , Pironas/química , Pironas/metabolismo , Ribonucleoproteína Nuclear Pequena U2/química , Compostos de Espiro/química , Spliceossomos/ultraestrutura
15.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281279

RESUMO

(1) Background: Autophagy, the major cytoplasmic process of substrate turnover, declines with age, contributing to proteostasis decline, accumulation of harmful protein aggregates, damaged mitochondria and to ROS production. Accordingly, abnormalities in the autophagic flux may contribute to many different pathophysiological conditions associated with ageing, including neurodegeneration. Recent data have shown that extra-virgin olive oil (EVOO) polyphenols stimulate cell defenses against plaque-induced neurodegeneration, mainly, through autophagy induction. (2) Methods: We carried out a set of in vitro experiments on SH-SY5Y human neuroblastoma cells exposed to toxic Aß1-42 oligomers to investigate the molecular mechanisms involved in autophagy activation by two olive oil polyphenols, oleuropein aglycone (OleA), arising from the hydrolysis of oleuropein (Ole), the main polyphenol found in olive leaves and drupes and its main metabolite, hydroxytyrosol (HT). (3) Results: Our data show that the mixture of the two polyphenols activates synergistically the autophagic flux preventing cell damage by Aß1-42 oligomers., in terms of ROS production, and impairment of mitochondria. (4) Conclusion: Our results support the idea that EVOO polyphenols act synergistically in autophagy modulation against neurodegeneration. These data confirm and provide the rationale to consider these molecules, alone or in combination, as promising candidates to contrast ageing-associated neurodegeneration.


Assuntos
Doença de Alzheimer/dietoterapia , Azeite de Oliva/farmacologia , Polifenóis/farmacologia , Acetatos/administração & dosagem , Acetatos/química , Acetatos/farmacologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Autofagia/efeitos dos fármacos , Linhagem Celular , Monoterpenos Ciclopentânicos/administração & dosagem , Monoterpenos Ciclopentânicos/química , Monoterpenos Ciclopentânicos/farmacologia , Dieta Mediterrânea , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Neurológicos , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Degeneração Neural/prevenção & controle , Neurônios/efeitos dos fármacos , Neurônios/patologia , Azeite de Oliva/administração & dosagem , Azeite de Oliva/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Polifenóis/administração & dosagem , Polifenóis/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Piranos/administração & dosagem , Piranos/química , Piranos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina/metabolismo
16.
ACS Chem Biol ; 16(8): 1576-1586, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34296611

RESUMO

Cancer cells reprogram their metabolism to survive and grow. Small-molecule inhibitors targeting cancer are useful for studying its metabolic pathways and functions and for developing anticancer drugs. Here, we discovered that glutipyran and its derivatives inhibit glycolytic activity and cell growth in human pancreatic cancer cells. According to proteomic profiling of glutipyran-treated cells using our ChemProteoBase, glutipyran was clustered within the group of endoplasmic reticulum (ER) stress inducers that included glycolysis inhibitors. Glutipyran inhibited glucose uptake and suppressed the growth of various cancer cells, including A431 cells that express glucose transporter class I (GLUT1) and DLD-1 GLUT1 knockout cells. When cotreated with the mitochondrial respiration inhibitor metformin, glutipyran exhibited a synergistic antiproliferative effect. Metabolome analysis revealed that glutipyran markedly decreased most metabolites of the glycolytic pathway and the pentose phosphate pathway. Glutipyran significantly suppressed tumor growth in a xenograft mouse model of pancreatic cancer. These results suggest that glutipyran acts as a broad-spectrum GLUT inhibitor and reduces cancer cell growth.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Piranos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Metabolômica , Metformina/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteômica , Piranos/síntese química , Piranos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Expert Opin Pharmacother ; 22(16): 2095-2103, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34292100

RESUMO

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively novel glucose-lowering drugs (GLDs) which additionally promote weight loss and blood pressure reduction among other beneficial effects.Areas covered: This review reflects on the extra-glycemic effects of SGLT2 inhibitors and their impact on important clinical endpoints, and provides an overview of data relating to a newer member of the SGLT2 inhibitor class, bexagliflozin.Expert opinion: SGLT2 inhibitors, while consolidating glycemic control as adjunctive therapy, indisputably affect cardio-renal benefits in the T2D population which is prevalently afflicted by heightened cardiovascular risk and a disproportionately increased incidence of unfavorable cardiovascular and renal outcomes. The data from landmark trials demonstrate that beneficial effects of SGLT2 inhibitors extend to non-diabetic patients with chronic kidney disease (CKD) and/or heart failure with reduced ejection fraction (HFrEF). Preliminary findings from the BEST trial suggest that Bexagliflozin's effects reflect those of other licensed drugs in its class. Bexagliflozin has also been shown to be safe and effective in patients with diabetes and CKD stage 3b. If and when approved, it presents physicians with the prospect of an additional therapeutic option in managing patients with type 2 diabetes mellitus (T2D), and conceivably also, nondiabetic patients with established CKD and/or HFrEF.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Piranos , Volume Sistólico
18.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071319

RESUMO

A new series of mollugin-1,2,3-triazole derivatives were synthesized using a copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of corresponding O-propargylated mollugin with aryl azides. All the compounds were evaluated for their cytotoxicity on five human cancer cell lines (HL-60, A549, SMMC-7721, SW480, and MCF-7) using MTS assays. Among the synthesized series, most of them showed cytotoxicity and most of all, compounds 14 and 17 exhibited significant cytotoxicity of all five cancer cell lines.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Piranos/química , Células A549 , Azidas/farmacologia , Linhagem Celular Tumoral , Células HL-60 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/química
19.
Arch Oral Biol ; 129: 105199, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34174589

RESUMO

OBJECTIVE: The mechanism underlying lipopolysaccharide (LPS)-induced primary human periodontal ligament (PDLC) cell injury is unclear. In this study, we focused on the therapeutic function of asperuloside (ASP) on LPS-induced cell injury. DESIGN: The study enrolled 41 participants, including 18 healthy controls and 23 CP patients. Western blotting was used to measure the expression of Toll-like receptor 4 (TLR4), phosphorylated p65 (p-p65) and cyclin D1. Enzyme-linked immunosorbent assays (ELISAs) were utilized to evaluate the protein levels of proinflammatory factors interleukin (IL)-1ß, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α). MTT assays and 5-ethynyl-2'-deoxyuridine (EdU) staining were performed to investigate cell proliferation. Immunohistochemistry was used to detect TLR4 and p65 expression in gingival tissues. RESULTS AND CONCLUSIONS: Asperuloside ameliorates lipopolysaccharide-induced PDLC cell injury by decreasing TLR4 expression and NF-κB activation, while this protective effect of ASP was reversed by TLR4 overexpression.


Assuntos
Lipopolissacarídeos , Receptor 4 Toll-Like , Monoterpenos Ciclopentânicos , Glucosídeos , Humanos , NF-kappa B , Ligamento Periodontal , Piranos , Fator de Necrose Tumoral alfa
20.
J Orthop Surg Res ; 16(1): 397, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34154621

RESUMO

BACKGROUND: Osteoporosis is a common disease closely associated with aging. In this study, we aimed to investigate the role of Cornuside I in promoting osteogenic differentiation of bone mesenchymal stem cells (BMSCs) and the potential mechanism. METHODS: BMSCs were isolated and treated with different concentrations of Cornuside I (0, 10, 30, 60 µM). Cell proliferation was analyzed by Cell Counting Kit-8 (CCK-8) assay. RNA sequencing was performed on the isolated BMSCs with control and Cornuside I treatment. Differentially expressed genes were obtained by the R software. Alkaline phosphatase (ALP) staining and Alizarin Red Staining (ARS) were performed to assess the osteogenic capacity of the NEO. qRT-PCR and western blot were used to detect the expression of osteoblast markers. RESULTS: Cornuside I treatment significantly improved BMSC proliferation. The optimal dose of Cornuside I was 30 µM (P < 0.05). Cornuside I dose dependently increased the ALP activity and calcium deposition than control group (P < 0.05). A total of 704 differentially expressed genes were identified between Cornuside I and normal BMSCs. Cornuside I significantly increased the PI3K and Akt expression. Moreover, the promotion effects of Cornuside I on osteogenic differentiation of BMSCs were partially blocked by PI3K/Akt inhibitor, LY294002. CONCLUSION: Cornuside I plays a positive role in promoting osteogenic differentiation of BMSCs, which was related with activation of PI3K/Akt signaling pathway.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Glucosídeos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Piranos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Osteoblastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
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