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1.
Bioorg Chem ; 119: 105511, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34847428

RESUMO

Euphoesulatin A (Eup A), a new jatrophane diterpenoid isolated from the Euphorbia esula L. (Euphorbiaceae), was reported to inhibit RANKL-induced osteoclastogenesis. However, the underlying mechanism and the effect in osteoporosis mouse model are still unclear. This study is the first to demonstrate that Eup A inhibits osteoclastogenesis in vitro and in vivo. Mechanistic analysis suggested that Eup A (3, 6, 12 µM) dose-dependently inhibited osteoclastogenesis by down-regulating the activation of NFATc1 and NF-κB and MAPKs signal pathways. Moreover, Eup A (10 mg/kg) significantly prevented bone loss in ovariectomized mice. This work provides in vitro and in vivo evidence that Eup A could be a potential candidate for the development of anti-osteoporosis agents.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34724562

RESUMO

AMP-activated protein kinase (AMPK) is involved in life span maintenance, stress responses, and germ cell cycle arrest upon dauer entry. AMPK is currently considered a promising target for preventing age-related diseases. Rubidium is one of the trace elements in human body. As early as the 1970s, RbCl has been was reported to have neuroprotective effects. In this work, we report the anti-aging effect of RbCl in Caenorhabditis elegans. Specifically, we reveal that (1) RbCl does increase the lifespan and enhance stress resistance in C. elegans without disturbing their fecundity. (2) RbCl induces superoxide dismutase (SOD) expression, which is essential for its anti-aging and anti-stress effect. (3) AAK-2 and DAF-16 are essential to the anti-aging efficacy of RbCl, and RbCl can promote DAF-16 translocating into the nucleus, suggesting that RbCl delays aging through regulating AMPK/FOXO pathway. RbCl can be a promising agent against aging related diseases.

3.
J Nat Prod ; 84(10): 2727-2737, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34596414

RESUMO

Nine new highly oxygenated 3,5-dimethylorsellinic acid-derived meroterpenoids, talaromynoids A-I (1-9), were isolated from the marine-derived fungus Talaromyces purpureogenus SCSIO 41517. Their structures including absolute configurations were elucidated by HRMS, NMR, single-crystal X-ray diffraction analysis, and electronic circular dichroism calculations. Compounds 1 and 7-9 possessed unprecedented 5/7/6/5/6/6, 6/7/6/6/6/5, 6/7/6/5/6/5/4, and 7/6/5/6/5/4 polycyclic systems, respectively. Biologically, compound 5 showed selective inhibitory activity against phosphatase CDC25B with an IC50 value of 13 µM. Moreover, 7-9 and 12 exhibited the activity of reducing triglyceride in 3T3-L1 adipocytes in a dosage-dependent manner.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34354759

RESUMO

Background: Si Jun Zi Tang (SJZ), a four-herb Chinese medicine formula that has been described for approximately one thousand years, is often prescribed for cancer patients as a complementary therapy in China. However, the mechanism by which Si Jun Zi Tang enhances the efficacy of gefitinib is unclear. Methods: We investigated how Si Jun Zi Tang affected the pharmacokinetics of gefitinib in rats. A rapid, specific, and reliable ultra-performance liquid chromatography method with mass spectrometry was established to determine the plasma concentration of gefitinib. Results: The results showed that a single intragastrically administered dose of Si Jun Zi Tang increased the pharmacokinetic parameters of gefitinib (C max, 3156.13 µg/L; A UC, 46281.5 µg/L/h) by 3 folds in rats compared with the administration of gefitinib alone (C max, 1352.07 µg/L; AUC, 11823.7 µg/L/h). Si Jun Zi Tang could also alter the pharmacokinetics of gefitinib by prolonging the time to reach C max. Conclusions: Potential pharmacokinetic interactions between gefitinib and SJZ were evaluated, and SJZ extended T max and T1/2 and increased the C max and AUC of gefitinib. Long-term administration of gefitinib in combination with Si Jun Zi Tang would improve the efficacy of gefitinib.

5.
Front Oncol ; 11: 697247, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34434895

RESUMO

Lung cancer ranks as a leading cause of death. Although targeted therapies usually trigger profound initial patient responses, these effects are transient due to drug resistance and severe side effects. Xihuang Pill (XHW) is a popular Chinese medicine formula that might benefit cancer patients when used as a complementary therapy. However, its underlying mechanism when combined with anticancer drugs is not clearly understood. Here, we used an integrated strategy to reveal the regulatory properties of XHW in increasing the antitumor activity of anlotinib in lung cancer. We evaluated the anti-lung cancer effect of XHW combined with anlotinib in mice bearing Lewis lung carcinoma (LLC). We applied untargeted metabolomics to identify the differences metabolism and found that XHW improved the effects of anlotinib on lung cancer. The components and targets related to the effects of XHW treatment on lung cancer were obtained through network pharmacology. Then, by integrating the biologically active components of XHW and anlotinib as well as the treatment-responsive metabolites and their related targets, an interaction network was constructed to evaluate the combination therapy. Finally, important protein candidates for this response were verified by immunohistochemistry of tumor tissues. The results showed that XHW significantly improved the inhibitory effect of anlotinib on tumor growth in LLC-bearing mice. Additionally, 12 differentially-abundant metabolites were identified by untargeted metabolomics in the XHW/anlotinib group compared with the XHW or anlotinib groups, and they were mainly enriched in fatty acid metabolism, lipid metabolism and amino acid metabolism pathways. Anlotinib, 23 components in Shexiang, 2 components in Niuhuang, 30 components in Ruxiang and 60 components in Moyao work together to act on 30 targets to regulate hexadecanoic acid (also named palmitic acid), linoleic acid, lactosylceramide, adrenaline, arachidonic acid and lysoPC(18:1(9Z)). The results of immunohistochemistry showed that XHW combined with anlotinib reduced the expression of PDGFRA in tumors. Overall, the key metabolites of XHW that enhances the efficacy of anlotinib were regulated by a multicomponent and multitarget interaction network. Our results suggested that anlotinib combined with XHW may be a promising strategy for the treatment of lung cancer.

6.
Nucleic Acids Res ; 49(17): 10106-10119, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34390350

RESUMO

AaRSs (aminoacyl-tRNA synthetases) group into two ten-member classes throughout evolution, with unique active site architectures defining each class. Most are monomers or homodimers but, for no apparent reason, many bacterial GlyRSs are heterotetramers consisting of two catalytic α-subunits and two tRNA-binding ß-subunits. The heterotetrameric GlyRS from Escherichia coli (EcGlyRS) was historically tested whether its α- and ß-polypeptides, which are encoded by a single mRNA with a gap of three in-frame codons, are replaceable by a single chain. Here, an unprecedented X-shaped structure of EcGlyRS shows wide separation of the abutting chain termini seen in the coding sequences, suggesting strong pressure to avoid a single polypeptide format. The structure of the five-domain ß-subunit is unique across all aaRSs in current databases, and structural analyses suggest these domains play different functions on α-subunit binding, ATP coordination and tRNA recognition. Moreover, the X-shaped architecture of EcGlyRS largely fits with a model for how two classes of tRNA synthetases arose, according to whether enzymes from opposite classes can simultaneously co-dock onto separate faces of the same tRNA acceptor stem. While heterotetrameric GlyRS remains the last structurally uncharacterized member of aaRSs, our study contributes to a better understanding of this ancient and essential enzyme family.

7.
ACS Cent Sci ; 7(6): 980-989, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34235259

RESUMO

Ferroptosis is an iron-dependent form of oxidative cell death, and the inhibition of ferroptosis is a promising strategy with which to prevent and treat neurological diseases. Herein we report a new ferroptosis inhibitor 9a with a novel mechanism of action. It is demonstrated that nuclear receptor coactivator 4 (NCOA4), a cargo receptor for ferritinophagy, is the target of 9a. Compound 9a blocks ferroptosis by reducing the amount of bioavailable intracellular ferrous iron through disrupting the NCOA4-FTH1 protein-protein interaction. Further studies indicate that 9a directly binds to recombinant protein NCOA4383-522 and effectively blocks the NCOA4383-522-FTH1 interaction. In a rat model of ischemic stroke, 9a significantly ameliorates the ischemic-refusion injury. With the first ligand 9a, this work reveals that NCOA4 is a promising drug target. Additionally, 9a is the first NCOA4-FTH1 interaction inhibitor. This work paves a new road to the development of ferroptosis inhibitors against neurological diseases.

8.
Fitoterapia ; 153: 104984, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34216691

RESUMO

Ferroptosis is a new type of cell death, which involves central neuronal system. Inhibition of ferroptosis is a promising strategy to prevent and treat neurological diseases. Thirteen phloroglucinols (1-13) were obtained from the whole plants of Hypericum japonicum. Of them, compounds 1-3 are new ones. Their structures were elucidated by extensive analysis of spectroscopic data and X-ray diffraction. All the isolates were evaluated for their inhibitory effect on RSL3-induced ferroptosis. Two new compounds 2-3 showed significant inhibitory effect with EC50 of 0.48 ± 0.14 µM and 0.94 ± 0.14 µM, respectively. DPPH free radical scavenging abilities of all compounds were assessed to evaluate their antioxidant effect. This work first reports the anti-ferroptosis activity of phloroglucinols.


Assuntos
Antioxidantes/farmacologia , Ferroptose/efeitos dos fármacos , Hypericum/química , Floroglucinol/farmacologia , Animais , Antioxidantes/isolamento & purificação , Linhagem Celular , China , Camundongos , Estrutura Molecular , Floroglucinol/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
9.
Bioorg Chem ; 115: 105177, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34303035

RESUMO

Ferroptosis is a new form of cell death, and inhibition of ferroptosis is a promising strategy to treat neurological diseases. In this work, sixteen compounds were isolated from Ajuga nipponensis and assayed for anti-ferroptosis activity in HT22 mouse hippocampal neuronal cells. Ajudecunoid C (1, ADC), a new neoclerodane diterpenoid, showed significant inhibitory activity against erastin and RSL3-induced ferroptosis with EC50 values of 4.1 ± 1.0 and 3.6 ± 0.3 µM, respectively. Experimental results demonstrated that ADC effectively prevented ferroptosis through scavenging free radical and activating NRF2-antioxidant response elements (AREs) pathway. This study reveals that ADC, as a new ferroptosis inhibitor, is a promising lead compound for the development of drugs against ferroptosis-related neurological diseases.

10.
Front Pharmacol ; 12: 657033, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149412

RESUMO

Ferroptosis is a new form of programmed cell death characterized by intracellular iron-dependent accumulation of lipid peroxide and primarily associated with iron metabolism, glutathione-dependent pathway, and coenzyme Q10-dependent pathway. Recent studies demonstrate that ferroptosis is associated with central nervous system (CNS) diseases, such as stroke, Parkinson's disease, Alzheimer's disease, and Huntington's disease. This review summarizes the key regulatory mechanisms of ferroptosis and its role in CNS diseases. These updates may provide novel perspective for the development of therapeutical agents against CNS diseases.

11.
Bioorg Chem ; 114: 105040, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34098257

RESUMO

DNA gyrase is an essential DNA topoisomerase that exists only in bacteria. Since novobiocin was withdrawn from the market, new scaffolds and new mechanistic GyrB inhibitors are urgently needed. In this study, we employed fragment screening and X-ray crystallography to identify new building blocks, as well as their binding mechanisms, to support the discovery of new GyrB inhibitors. In total, 84 of the 618 chemical fragments were shown to either thermally stabilize the ATPase domain of Escherichia coli GyrB or inhibit the ATPase activity of E. coli gyrase. Among them, the IC50 values of fragments 10 and 23 were determined to be 605.3 µM and 446.2 µM, respectively. Cocrystal structures of the GyrB ATPase domain with twelve fragment hits were successfully determined at a high resolution. All twelve fragments were deeply inserted in the pocket and formed H-bonds with Asp73 and Thr165, and six fragments formed an additional H-bond with the backbone oxygen of Val71. Fragment screening further highlighted the capability of Asp73, Thr165 and Val71 to bind chemicals and provided diverse building blocks for the design of GyrB inhibitors.

12.
BMC Ophthalmol ; 21(1): 235, 2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34044792

RESUMO

PURPOSE AND BACKGROUND: Recently, we found that maximal medial rectus recession and lateral rectus resection in patients with complete lateral rectus paralysis resulted in a partial restoration of abduction. In an attempt to understand some of the mechanisms involved with this effect we examined gene expression profiles of lateral recti from these patients, with our focus being directed to genes related to myogenesis. MATERIALS AND METHODS: Lateral recti resected from patients with complete lateral rectus paralysis and those from concomitant esotropia (controls) were collected. Differences in gene expression profiles between these two groups were examined using microarray analysis and quantitative Reverse-transcription PCR (qRT-PCR). RESULTS: A total of 3056 differentially expressed genes (DEGs) were identified between these two groups. Within the paralytic esotropia group, 2081 genes were up-regulated and 975 down-regulated. The results of RT-PCR revealed that PAX7, MYOG, PITX1, SIX1 and SIX4 showed higher levels of expression, while that of MYOD a lower level of expression within the paralytic esotropia group as compared with that in the control group (p < 0.05). CONCLUSION: The decreased expression of MYOD in the paralytic esotropia group suggested that extraocular muscle satellite cell (EOMSCs) differentiation processes were inhibited. Whereas the high expression levels of PAX7, SIX1/4 and MYOG, suggested that the EOMSCs were showing an effective potential for differentiation. The stimulation resulting from muscle surgery may induce EOMSCs to differentiate and thus restore abduction function.


Assuntos
Doenças do Nervo Abducente , Esotropia , Diferenciação Celular , Esotropia/cirurgia , Proteínas de Homeodomínio , Humanos , Músculos Oculomotores/cirurgia , Procedimentos Cirúrgicos Oftalmológicos , Estudos Retrospectivos
13.
FASEB J ; 35(5): e21575, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33826776

RESUMO

Staphylopine (StP) and other nicotianamine-like metallophores are crucial for many pathogens to acquire the transition metals from hosts during invasion. CntL from Staphylococcus aureus (SaCntL) catalyzes the condensation of the 2-aminobutyrate (Ab) moiety of S-adenosylmethionine (SAM) with D-histidine in the biosynthesis of StP. Here, we report the crystal structures of SaCntL in complex with either SAM or two products. The structure of SaCntL consists of an N-terminal four-helix bundle (holding catalytic residue E84) and a C-terminal Rossmann fold (binding the substrates). The sequence connecting the N- and C-terminal domains (N-C linker) in SaCntL was found to undergo conformational alternation between open and closed states. Our structural and biochemical analyses suggested that this intrinsically dynamic interdomain linker forms an additional structural module that plays essential roles in ligand diffusion, recognition, and catalysis. We confirmed that SaCntL stereoselectively carries out the catalysis of D-His but not its enantiomer, L-His, and we found that the N-C linker and active site of SaCntL could accommodate both enantiomers. SaCntL is likely able to bind L-His without catalysis, and as a result, L-His could show inhibitory effects toward SaCntL. These findings provide critical structural and mechanistic insights into CntL, which facilitates a better understanding of the biosynthesis of nicotianamine-like metallophores and the discovery of inhibitors of this process.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Imidazóis/metabolismo , Staphylococcus aureus/enzimologia , Transferases/química , Transferases/metabolismo , Sítios de Ligação , Catálise , Domínio Catalítico , Cristalografia por Raios X , Ligantes , Modelos Moleculares , Conformação Proteica
15.
Nat Commun ; 12(1): 1616, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712620

RESUMO

The polyketide natural product reveromycin A (RM-A) exhibits antifungal, anticancer, anti-bone metastasis, anti-periodontitis and anti-osteoporosis activities by selectively inhibiting eukaryotic cytoplasmic isoleucyl-tRNA synthetase (IleRS). Herein, a co-crystal structure suggests that the RM-A molecule occupies the substrate tRNAIle binding site of Saccharomyces cerevisiae IleRS (ScIleRS), by partially mimicking the binding of tRNAIle. RM-A binding is facilitated by the copurified intermediate product isoleucyl-adenylate (Ile-AMP). The binding assays confirm that RM-A competes with tRNAIle while binding synergistically with L-isoleucine or intermediate analogue Ile-AMS to the aminoacylation pocket of ScIleRS. This study highlights that the vast tRNA binding site of the Rossmann-fold catalytic domain of class I aminoacyl-tRNA synthetases could be targeted by a small molecule. This finding will inform future rational drug design.


Assuntos
Sítios de Ligação/efeitos dos fármacos , Ligases/química , Ligases/efeitos dos fármacos , Piranos/antagonistas & inibidores , RNA de Transferência/efeitos dos fármacos , Compostos de Espiro/antagonistas & inibidores , Aminoacil-tRNA Sintetases/química , Aminoacil-tRNA Sintetases/efeitos dos fármacos , Isoleucina , Isoleucina-tRNA Ligase/química , Isoleucina-tRNA Ligase/efeitos dos fármacos , Ligantes , Modelos Moleculares , Osteoporose/tratamento farmacológico , RNA de Transferência/química , Saccharomyces cerevisiae
16.
J Med Chem ; 64(4): 2010-2023, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33543615

RESUMO

Hsp90 is a new promising target for cancer treatment. Many inhibitors have been discovered as therapeutic agents, and some have passed Phase I and II. However, no one is approved by FDA yet. Novel and druggable Hsp90 inhibitors are still demanding. Here, we report a new way to discover high potent Hsp90 inhibitors as antinasopharyngeal carcinoma agents through assembling fragments. With chemotyping analysis, we extract seven chemotypes from 3482 known Hsp90 inhibitors, screen 500 fragments that are compatible with the chemotypes, and confirm 15 anti-Hsp90 fragments. Click chemistry is employed to construct 172 molecules and synthesize 21 compounds among them. The best inhibitor 3d was further optimized and resulted in more potent 4f (IC50 = 0.16 µM). In vitro and in vivo experiments confirmed that 4f is a promising agent against nasopharyngeal carcinoma. This study may provide a strategy in discovering new ligands against targets without well-understood structures.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Triazóis/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Bases de Dados de Compostos Químicos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Camundongos Nus , Simulação de Dinâmica Molecular , Ligação Proteica , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Triazóis/síntese química , Triazóis/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Eur J Med Chem ; 213: 113185, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33485256

RESUMO

In this work, we found that 14-deoxy-11,12-didehydroandrographolide (2), a derivative of andrographolide (AP, 1), had greatly reduced cytotoxicity compared with AP and exhibited moderate anti-osteoclastogenesis activity. Thirty compounds were synthesized by introducing anti-osteoporosis chemotypes at C-19 of 2. Six of them exhibited stronger inhibition of osteoclastogenesis than AP. Of note, compound 12g displayed the most potent activity with IC50 value of 0.35 µM. The expression levels of osteoclast-specific genes such as TRAcP, CTSK, NFATc1, and MMP-9 were also decreased by 12g treatment. Furthermore, Western blot and immunofluorescence analyses demonstrated that compound 12g inhibited osteoclast differentiation through downregulation of RANKL-induced NF-κB signaling pathway. In an ovariectomized (OVX) female mice model, compound 12g significantly ameliorated bone loss. Therefore, compound 12g exhibited promising in vivo efficacy and low toxicity, indicating its therapeutic potential for the treatment of osteoporosis.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Diterpenos/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Animais , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Diterpenos/síntese química , Diterpenos/química , Relação Dose-Resposta a Droga , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Osteoclastos/metabolismo , Osteoporose/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade
18.
Fitoterapia ; 149: 104829, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33444696

RESUMO

Phytochemical investigation of Ferula seravschanica afforded seven new compounds, including three new bicyclic-type sesquiterpene coumarins (1-3), two new monocyclic-type sesquiterpene coumarins (16-17), two new phenylpropanoids (23-24) as well as twenty-two known compounds (4-15, 18-22, and 25-29). The structures of new compounds were determined by HRESIMS, NMR, ECD calculations, and X-ray single-crystal diffraction analysis. Furthermore, crude EtOAc extract and separated fractions (F1-F12) possessed cytotoxic activity against four human tumor cell lines (HT-29, DU145, HeLa, and Jurkat). Subsequently, we examined Jurkat inhibitory activity of isolated compounds. Compound 12 significantly inhibited the proliferation of the leukemia cells with IC50 value of 2.50 µM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cumarínicos/farmacologia , Ferula/química , Sesquiterpenos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Cumarínicos/isolamento & purificação , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Raízes de Plantas/química , Sesquiterpenos/isolamento & purificação , Tadjiquistão
19.
Eur J Med Chem ; 210: 112982, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33158578

RESUMO

A pre-trained self-attentive message passing neural network (P-SAMPNN) model was developed based on our anti-osteoclastogenesis dataset for virtual screening purpose. Validation processes proved that P-SAMPNN model was significantly superior to the other base line models. A commercially available natural product library was virtually screened by the P-SAMPNN model and resulted in confirmed 5 hits from 10 selected virtual hits. Among the confirmed hits, compounds AP-123/40765213 and AE-562/43462182 are the nanomolar inhibitors against osteoclastogenesis with a new scaffold. Further studies indicate that AP-123/40765213 and AE-562/43462182 significantly suppress the mRNA expression of RANK and downregulate the expressions of osteoclasts-related genes Ctsk, Nfatc1, and Tracp. Our work demonstrated that P-SAMPNN method can guide phenotype-based drug discovery.


Assuntos
Produtos Biológicos/farmacologia , Descoberta de Drogas , Osteoporose/tratamento farmacológico , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Osteogênese/efeitos dos fármacos , Relação Estrutura-Atividade
20.
Ophthalmic Res ; 64(2): 337-344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32344402

RESUMO

INTRODUCTION: Paralytic strabismus involves a functional loss of extraocular muscles resulting from muscular or neuronal disorders. Currently, only a limited number of drugs are available for functional repair of extraocular muscles. Here, we investigated the effects of a novel drug, flavonoids sophoranone, on the differentiation of extraocular muscles as assessed in bothin vivo and in vitro models. MATERIALS AND METHODS: The effect of flavonoids sophoranone on C2C12 cells was examinedin vitro as evaluated with use of apoptosis, reactive oxygen species (ROS), and cell viability assays. Then, both in vivo and in vitro effects of this drug were examined on the differentiation of C2C12 and satellite cells within extraocular muscles in rabbits. For these latter experiments, RT-PCR and Western blot assays were used to determine expression levels of markers for myogenic differentiation. RESULTS: With use of flavonoids sophoranone concentrations ranging from 0 to 10 µM, no effects were observed upon cell apoptosis, ROS, and cell cycle in C2C12 cells. Based on MTT assay results, flavonoids sophoranone was shown to increase C2C12 cell proliferation. Moreover, flavonoids sophoranone promoted the differentiation of C2C12 and satellite cells within extraocular muscles in rabbits, which were verified as based on cell morphology and expression levels of mRNA and protein markers of myogenic differentiation. Finally, flavonoids sophoranone treatment also increased gene expressions of Myh3, Myog, and MCK. CONCLUSION: The capacity for flavonoids sophoranone to upgrade the differentiation of both C2C12 and satellite cells within extraocular muscles in rabbits at concentrations producing no adverse effects suggest that this drug may provide a safe and effective means to promote repair of damaged extraocular muscles.


Assuntos
Apoptose , Flavonoides/farmacologia , Desenvolvimento Muscular/genética , Mioblastos/efeitos dos fármacos , Músculos Oculomotores/citologia , Animais , Ciclo Celular , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais , Mioblastos/citologia , Mioblastos/metabolismo , Músculos Oculomotores/efeitos dos fármacos , Músculos Oculomotores/metabolismo , Coelhos , Espécies Reativas de Oxigênio/metabolismo
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