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1.
Neuroscience ; 551: 177-184, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-38823551

RESUMO

Dopamine D1 receptor agonists improve spatial working memory, but their effects on temporal order memory, particularly prone to the effects of aging, have not been studied. Two D1 agonists, PF6256142 (PF) and 2-methyldihydrexidine (2MDHX), were examined for their effects in a rodent temporal order recognition task. Our results are consistent with the hypothesis that there is an age-related decline in rodent temporal order memory. The data also show that either agonist rescues the poor memory performance with a large effective size. Interestingly, the optimal effective dose varied among individual rats of different age groups. PF showed greater potency for older rats, whereas 2MDHX showed better overall population effectiveness. Both PF and 2MDHX have high intrinsic activity at rodent D1-mediated cAMP synthesis. Conversely, at D1-mediated ß-arrestin recruitment, PF has essentially no intrinsic activity, whereas 2MDHX is a super-agonist. These findings suggest that D1 agonists have potential to treat age-related cognitive decline, and the pattern of functional selectivity may be useful for developing drugs with an improved therapeutic index.


Assuntos
Envelhecimento , Agonistas de Dopamina , Receptores de Dopamina D1 , Animais , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Masculino , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Agonistas de Dopamina/farmacologia , Ratos , Fenantridinas/farmacologia , Relação Dose-Resposta a Droga , Reconhecimento Psicológico/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Endogâmicos F344 , AMP Cíclico/metabolismo
2.
Toxicol Appl Pharmacol ; 489: 117017, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38925513

RESUMO

Liver fibrosis, a progressive process of fibrous scarring, results from the accumulation of extracellular matrix proteins (ECM). If left untreated, it often progresses to diseases such as cirrhosis and hepatocellular carcinoma. Lycorine, a natural alkaloid derived from medicinal plants, has shown diverse bioactivities by targeting JAK2/STAT3 signaling, but its pharmacological effects and potential molecular mechanisms in liver fibrosis remains largely unexplored. The purpose of this study is to elucidate the pharmacological activity and molecular mechanism of lycorine in anti-hepatic fibrosis. Findings indicate that lycorine significantly inhibited hepatic stellate cells (HSCs) activation by reducing the expression of α-SMA and collagen-1. In vivo, lycorine treatment alleviated carbon tetrachloride (CCl4) -induced mice liver fibrosis, improving liver function, decreasing ECM deposition, and inhibiting fibrosis-related markers' expression. Mechanistically, it was found that lycorine exerts protective activity through the JAK2/STAT3 and PI3K/AKT signaling pathways, as evidenced by transcriptome sequencing technology and small molecule inhibitors. These results underscore lycorine's potential as a therapeutic drug for liver fibrosis.


Assuntos
Alcaloides de Amaryllidaceae , Tetracloreto de Carbono , Células Estreladas do Fígado , Janus Quinase 2 , Cirrose Hepática , Fenantridinas , Proteínas Proto-Oncogênicas c-akt , Fator de Transcrição STAT3 , Transdução de Sinais , Animais , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Alcaloides de Amaryllidaceae/farmacologia , Tetracloreto de Carbono/toxicidade , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Masculino , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Fenantridinas/farmacologia , Fenantridinas/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Endogâmicos C57BL , Linhagem Celular
3.
Phytochemistry ; 225: 114198, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38936528

RESUMO

Three previously undescribed and sixteen known alkaloids were bioguidedly isolated from the bulbs of Narcissus tazetta subsp. chinensis (M.Roem.) Masamura & Yanagih. The structures were elucidated by spectroscopic data, including HRESIMS, NMR, and ECD. Eleven of the isolated alkaloids exhibited immunosuppressive activity on the proliferation of human T cells. (+)-Narciclasine (18) showed the most significantly suppressive activity with an IC50 value of 14 ± 5 nM. In vitro, (+)-narciclasine (18) blocked NF-κB signal transduction, but did not affect PI3K/AKT signal transduction. What was more, (+)-narciclasine significantly reduced ALT and AST levels and alleviated liver damage induced by ConA in AIH mouse model.


Assuntos
Alcaloides , Proliferação de Células , Imunossupressores , Narcissus , Narcissus/química , Humanos , Animais , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Imunossupressores/farmacologia , Imunossupressores/química , Imunossupressores/isolamento & purificação , Camundongos , Proliferação de Células/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Estrutura Molecular , NF-kappa B/metabolismo , NF-kappa B/antagonistas & inibidores , Benzofenantridinas/farmacologia , Benzofenantridinas/química , Benzofenantridinas/isolamento & purificação , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Estereoisomerismo , Transdução de Sinais/efeitos dos fármacos , Fenantridinas , Alcaloides de Amaryllidaceae
4.
Free Radic Biol Med ; 221: 23-30, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38740100

RESUMO

The pathogenesis of systemic sclerosis (SSC) fibrosis involves the rapid proliferation of skin fibroblasts, and current anti-fibrotic treatments are limited. This study investigated the relationship between ferroptosis and SSC skin fibroblasts. We observed that erastin-induced ferroptosis was suppressed in SSC fibroblasts. RSL3, a direct inhibitor of Glutathione Peroxidase 4 (GPX4), significantly reduced the viability of the fibroblasts, and upregulation of GPX4 in the SSC fibroblasts contributed to ferroptosis resistance. Furthermore, we demonstrated that transferrin receptor 1 (TfR1) was a crucial transporter for iron deposition in the fibroblasts. Collectively, our results highlight that GPX4 inhibition could enhance the sensitivity to ferroptosis by SSC fibroblasts, which showed distinct characteristics of iron metabolism that were not observed in normal fibroblasts in this study. Taken together, these results suggest that targeting ferroptosis could be a therapeutic strategy for the treatment of SSC.


Assuntos
Ferroptose , Fibroblastos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Escleroderma Sistêmico , Pele , Feminino , Humanos , Antígenos CD/metabolismo , Antígenos CD/genética , Carbolinas , Células Cultivadas , Ferroptose/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/efeitos dos fármacos , Ferro/metabolismo , Fenantridinas/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Piperazinas , Receptores da Transferrina/metabolismo , Receptores da Transferrina/genética , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/genética , Pele/patologia , Pele/metabolismo , Regulação para Cima
5.
Int J Mol Sci ; 25(9)2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38732083

RESUMO

Three new phenanthridine peptide derivatives (19, 22, and 23) were synthesized to explore their potential as spectrophotometric probes for DNA and RNA. UV/Vis and circular dichroism (CD) spectra, mass spectroscopy, and computational analysis confirmed the presence of intramolecular interactions in all three compounds. Computational analysis revealed that compounds alternate between bent and open conformations, highlighting the latter's crucial influence on successful polynucleotide recognition. Substituting one glycine with lysine in two regioisomers (22, 23) resulted in stronger binding interactions with DNA and RNA than for a compound containing two glycines (19), thus emphasizing the importance of lysine. The regioisomer with lysine closer to the phenanthridine ring (23) exhibited a dual and selective fluorimetric response with non-alternating AT and ATT polynucleotides and induction of triplex formation from the AT duplex. The best binding constant (K) with a value of 2.5 × 107 M-1 was obtained for the interaction with AT and ATT polynucleotides. Furthermore, apart from distinguishing between different types of ds-DNA and ds-RNA, the same compound could recognize GC-rich DNA through distinct induced CD signals.


Assuntos
Dicroísmo Circular , DNA , Lisina , Peptídeos , Fenantridinas , Fenantridinas/química , Lisina/química , Peptídeos/química , DNA/química , DNA/metabolismo , RNA/química , Conformação de Ácido Nucleico
6.
J Ethnopharmacol ; 329: 118154, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38614259

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: The plants of Amaryllidaceae family, such as Amaryllis belladonna L., have been used as herbal remedies for thousands of years to address various disorders, including diseases that might today be identified as cancer. AIM OF THE STUDY: The objective of this work was to evaluate the potential of three Amaryllidaceae alkaloids against four cancer cell lines. MATERIAL AND METHODS: The alkaloids lycorine, 1-O-acetylcaranine, and montanine were evaluated in vitro against colon adenocarcinoma cell line (HCT-116) and breast carcinoma cell lines (MCF-7, MDAMB231, and Hs578T). Computational experiments (target prediction and molecular docking) were conducted to gain a deeper comprehension of possible interactions between these alkaloids and potential targets associated with these tumor cells. RESULTS: Montanine presented the best results against HCT-116, MDAMB231, and Hs578T cell lines, while lycorine was the most active against MCF-7. In alignment with the target prediction outcomes and existing literature, four potential targets were chosen for the molecular docking analysis: CDK8, EGFR, ER-alpha, and dCK. The docking scores revealed two potential targets for the alkaloids with scores similar to co-crystallized inhibitors and substrates: CDK8 and dCK. A visual analysis of the optimal docked configurations indicates that the alkaloids may interact with some key residues in contrast to the other docked compounds. This observation implies their potential to bind effectively to both targets. CONCLUSIONS: In vitro and in silico results corroborate with data literature suggesting the Amaryllidaceae alkaloids as interesting molecules with antitumoral properties, especially montanine, which showed the best in vitro results against colorectal and breast carcinoma. More studies are necessary to confirm the targets and pharmaceutical potential of montanine against these cancer cell lines.


Assuntos
Alcaloides de Amaryllidaceae , Antineoplásicos Fitogênicos , Simulação de Acoplamento Molecular , Humanos , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Células MCF-7 , Amaryllidaceae/química , Células HCT116 , Simulação por Computador , Fenantridinas/farmacologia , Fenantridinas/química , Isoquinolinas
7.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 42(2): 163-171, 2024 Apr 01.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38597076

RESUMO

OBJECTIVES: To investigate the mechanism of circadian clock protein Bmal1 (Bmal1) on renal injury with chronic periodontitis, we established an experimental rat periodontitis model. METHODS: Twelve male Wistar rats were randomly divided into control and periodontitis groups (n=6, each group). The first maxillary molars on both sides of the upper jaw of rats with periodontitis were ligated by using orthodontic ligature wires, whereas the control group received no intervention measures. After 8 weeks, clinical periodontal parameters, including probing depth, bleeding index, and tooth mobility, were evaluated in both groups. Micro-CT scanning and three-dimensional image reconstruction were performed on the maxillary bones of the rats for the assessment of alveolar bone resorption. Histopatholo-gical observations of periodontal and renal tissues were conducted using hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining. Renal function indicators, such as creatinine, albumin, and blood urea nitrogen levels, and oxidative stress markers, including superoxide dismutase, glutathione, and malondialdehyde levels, were measured using biochemical assay kits. MitoSOX red staining was used to detect reactive oxygen species (ROS) content in the kidneys. The gene and protein expression levels of Bmal1, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in rat renal tissues were assessed using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical staining. RESULTS: Micro-CT and HE staining results showed significant bone resorption and attachment loss in the maxillary first molar region of the periodontitis group. Histological examination through HE and PAS staining revealed substantial histopathological damage to the renal tissues of the rats in the periodontitis group. The findings of the assessment of renal function and oxidative stress markers indicated that the periodontitis group exhibited abnormal levels of oxidative stress, whereas the renal function levels showed abnormalities without statistical significance. MitoSOX Red staining results showed that the content of ROS in the renal tissue of the periodontitis group was significantly higher than that of the control group, and RT-qPCR and immunohistochemistry results showed that the expression levels of Bmal1, Nrf2, and HO-1 in the renal tissues of the rats in the periodontitis group showed a decreasing trend. CONCLUSIONS: Circadian clock protein Bmal1 plays an important role in the oxidative damage process involved in the renal of rats with periodontitis.


Assuntos
Reabsorção Óssea , Relógios Circadianos , Compostos Organofosforados , Periodontite , Fenantridinas , Animais , Masculino , Ratos , Reabsorção Óssea/metabolismo , Rim/metabolismo , Rim/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Periodontite/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
8.
Phytomedicine ; 129: 155677, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38678951

RESUMO

BACKGROUND: Septic heart failure has been recognized as a puzzle since antiquity and poses a major challenge to modern medicine. Our previous work has demonstrated the potential effects of lycorine (LYC) on sepsis and septic myocardial injury. Nonetheless, further exploration is needed to elucidate the underlying cellular and molecular mechanisms. METHODS: In this study, we conducted transcriptome analysis and weighted gene co-expression network analysis (WGCNA) to identify the key genes and reveal the mechanism of LYC against septic heart failure. PURPOSE: This study aims to apply bioinformatic analysis and experimental validations to explore the protective effects and underlying mechanism of LYC on the cecal ligation and puncture (CLP)-induced sepsis model mice. RESULTS: Transcriptome analysis revealed the differentially expressed genes (DEGs) following LYC treatment. WGCNA analysis identified gene modules associated with LYC-mediated protection, with BCL3 emerging as a core gene within these modules. Notably, BCL3 was an overlapping gene of DEGs and WGCNA core genes induced by LYC treatment, and is highly negatively correlated with cardiac function indicator. In vivo and in vitro study further prove that LYC exerted a protective effect against septic myocardial injury through inhibiting BCL3. BCL3 siRNA ameliorated LPS-induced cardiac injury and inflammation, while BCL3 overexpression reversed the protective effect of LYC against LPS injury. CONCLUSION: In summary, our findings demonstrate the significant attenuation of septic myocardial disorder by LYC, with the identification of BCL3 as a pivotal target gene. This study is the first to report the role of BCL3 in sepsis and septic myocardial injury. Furthermore, the strategy for hub genes screening used in our study facilitates a comprehensive exploration of septic targets and reveals the potential targets for LYC effect. These findings may offer a new therapeutic strategy for the management of septic heart failure, highlighting the cardioprotective effect of LYC as adjunctive therapy for sepsis management.


Assuntos
Alcaloides de Amaryllidaceae , Cardiotônicos , Modelos Animais de Doenças , Insuficiência Cardíaca , Fenantridinas , Sepse , Animais , Sepse/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Fenantridinas/farmacologia , Alcaloides de Amaryllidaceae/farmacologia , Camundongos , Cardiotônicos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Perfilação da Expressão Gênica
9.
ACS Chem Biol ; 19(4): 875-885, 2024 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-38483263

RESUMO

It is well established that oxaliplatin, one of the three Pt(II) anticancer drugs approved worldwide, and phenanthriplatin, an important preclinical monofunctional Pt(II) anticancer drug, possess a different mode of action from that of cisplatin and carboplatin, namely, the induction of nucleolar stress. The exact mechanisms that lead to Pt-induced nucleolar stress are, however, still poorly understood. As such, studies aimed at better understanding the biological targets of both oxaliplatin and phenanthriplatin are urgently needed to expand our understanding of Pt-induced nucleolar stress and guide the future design of Pt chemotherapeutics. One approach that has seen great success in the past is the use of Pt-click complexes to study the biological targets of Pt drugs. Herein, we report the synthesis and characterization of the first examples of click-capable phenanthriplatin complexes. Furthermore, through monitoring the relocalization of nucleolar proteins, RNA transcription levels, and DNA damage repair biomarker γH2AX, and by investigating their in vitro cytotoxicity, we show that these complexes successfully mimic the cellular responses observed for phenanthriplatin treatment in the same experiments. The click-capable phenanthriplatin derivatives described here expand the existing library of Pt-click complexes. Significantly they are suitable for studying nucleolar stress mechanisms and further elucidating the biological targets of Pt complexes.


Assuntos
Antineoplásicos , Nucléolo Celular , Compostos Organoplatínicos , Fenantridinas , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Cisplatino/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Oxaliplatina/farmacologia , Fenantridinas/síntese química , Fenantridinas/química , Fenantridinas/farmacologia , Química Click , Nucléolo Celular/efeitos dos fármacos , Nucléolo Celular/metabolismo
10.
J Plant Physiol ; 296: 154218, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38490054

RESUMO

Jasmonates (JAs) are among the main phytohormones, regulating plant growth and development, stress responses, and secondary metabolism. As the major regulator of the JA signaling pathway, MYC2 also plays an important role in plant secondary metabolite synthesis and accumulation. In this study, we performed a comparative transcriptome analysis of Lycoris aurea seedlings subjected to methyl jasmonate (MeJA) at different treatment times. A total of 31,193 differentially expressed genes (DEGs) were identified by RNA sequencing. Among them, 732 differentially expressed transcription factors (TFs) comprising 51 TF families were characterized. The most abundant TF family was WRKY proteins (80), followed by AP2/ERF-EFR (67), MYB (59), bHLH (52), and NAC protein (49) families. Subsequently, by calculating the Pearson's correlation coefficient (PCC) between the expression level of TF DEGs and the lycorine contents, 41 potential TF genes (|PCC| >0.8) involved in lycorine accumulation were identified, including 36 positive regulators and 5 negative regulators. Moreover, a MeJA-inducible MYC2 gene (namely LaMYC2) was cloned on the basis of transcriptome sequencing. Bioinformatic analyses revealed that LaMYC2 proteins contain the bHLH-MYC_N domain and bHLH-AtAIB_like motif. LaMYC2 protein is localized in the cell nucleus, and can partly rescue the MYC2 mutant in Arabidopsis thaliana. LaMYC2 protein could interact with most LaJAZs (especially LaJAZ3 and LaJAZ4) identified previously. Transient overexpression of LaMYC2 increased lycorine contents in L. aurea petals, which might be associated with the activation of the transcript levels of tyrosine decarboxylase (TYDC) and phenylalanine ammonia lyase (PAL) genes. By isolating the 887-bp-length promoter fragment upstream of the start codon (ATG) of LaTYDC, we found several different types of E-box motifs (CANNTG) in the promoter of LaTYDC. Further study demonstrated that LaMYC2 was indeed able to bind the E-box (CACATG) present in the LaTYDC promoter, verifying that the pathway genes involved in lycorine biosynthesis could be regulated by LaMYC2, and that LaMYC2 has positive roles in the regulation of lycorine biosynthesis. These findings demonstrate that LaMYC2 is a positive regulator of lycorine biosynthesis and may facilitate further functional research of the LaMYC2 gene, especially its potential regulatory roles in Amaryllidaceae alkaloid accumulation in L. aurea.


Assuntos
Acetatos , Alcaloides de Amaryllidaceae , Arabidopsis , Lycoris , Fenantridinas , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Alcaloides de Amaryllidaceae/metabolismo , Lycoris/genética , Lycoris/metabolismo , Ciclopentanos/farmacologia , Ciclopentanos/metabolismo , Oxilipinas/farmacologia , Oxilipinas/metabolismo , Transcriptoma , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas
11.
Z Naturforsch C J Biosci ; 79(3-4): 73-79, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38516999

RESUMO

The Sceletium-type alkaloids, known for their anxiolytic and antidepressant activities, have been recently found to be biosynthesized in Narcissus cv. Hawera, which is largely used as an ornamental plant. An alkaloid fraction enriched with Sceletium-type alkaloids from the plant has shown promising antidepressant and anxiolytic activities. In the present study, qualitative and quantitative analyses of the alkaloids in the plant organs were performed during one vegetation season by GC-MS. The alkaloid pattern and total alkaloid content was found to depend strongly on the stage of development and plant organ. The alkaloid content of bulbs was found to be highest during the dormancy period and lowest in sprouting bulbs. The leaves showed the highest alkaloid content during the intensive vegetative growth and lowest during flowering. In total, 13 alkaloids were detected in the methanol extracts of Narcissus cv. Hawera, six Sceletium-type and seven typical Amaryllidaceae alkaloids. Major alkaloids in the alkaloid pattern were lycorine, 6-epi-mesembrenol, mesembrenone, sanguinine, and galanthamine. The leaves of flowering plants were found to have the highest amount of 6-epi-mesembrenol. Mesembrenone was found to be dominant alkaloid in the leaves of sprouting bulbs and in the flowers. Considering the biomass of the plant, the dormant bulbs are the best source of alkaloid fractions enriched with 6-epi-mesembrenol. The flowers and the young leaves can be used for preparation of alkaloid fractions enriched with mesembrenone. The results indicates that Narcissus cv. Hawera is an emerging source of valuable bioactive compounds and its utilization can be extended as a medicinal plant.


Assuntos
Alcaloides , Alcaloides Indólicos , Narcissus , Fenantridinas , Folhas de Planta , Narcissus/química , Narcissus/metabolismo , Narcissus/crescimento & desenvolvimento , Alcaloides/metabolismo , Alcaloides/química , Folhas de Planta/química , Folhas de Planta/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Flores/química , Flores/metabolismo , Flores/crescimento & desenvolvimento , Extratos Vegetais/química , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Alcaloides de Amaryllidaceae/metabolismo , Alcaloides de Amaryllidaceae/química
12.
Phytomedicine ; 128: 155464, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38484625

RESUMO

BACKGROUND: Ang II induces hypertensive heart failure (HF) via hemodynamic and non-hemodynamic actions. Lycorine (LYC) is an alkaloid derived from Lycoris bulbs, and it possesses anti-cardiovascular disease-related activities. Herein, we explored the potential LYC-mediated regulation of Ang II-induced HF. METHODS: Over 4 weeks, we established a hypertensive HF mouse model by infusing Ang II into C57BL/6 mice using a micro-osmotic pump. For the final two weeks, mice were administered LYC via intraperitoneal injection. The LYC signaling network was then deduced using RNA sequencing. RESULTS: LYC administration strongly suppressed hypertrophy, myocardial fibrosis, and cardiac inflammation. As a result, it minimized heart dysfunction while causing no changes in blood pressure. The Nuclear Factor kappa B (NF-κB) network/phosphoinositol-3-kinase (PI3K)-protein kinase B (AKT) was found to be a major modulator of LYC-based cardioprotection using RNA sequencing study. We further confirmed that in cultured cardiomyocytes and mouse hearts, LYC reduced the inflammatory response and downregulated the Ang II-induced PI3K-AKT/NF-κB network. Moreover, PI3K-AKT or NF-κB axis depletion in cardiomyocytes completely abrogated the anti-inflammatory activities of LYC. CONCLUSION: Herein, we demonstrated that LYC safeguarded hearts in Ang II -stimulated mice by suppressing the PI3K-AKT/NF-κB-induced inflammatory responses. Given the evidence mentioned above, LYC is a robust therapeutic agent for hypertensive HF.


Assuntos
Alcaloides de Amaryllidaceae , Angiotensina II , Camundongos Endogâmicos C57BL , NF-kappa B , Fenantridinas , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Alcaloides de Amaryllidaceae/farmacologia , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fenantridinas/farmacologia , Masculino , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos , Insuficiência Cardíaca/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/induzido quimicamente , Modelos Animais de Doenças , Lycoris/química , Miocárdio
13.
Molecules ; 29(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38474593

RESUMO

Lycorine is a kind of natural active ingredient with a strong antitumor effect. In this study, folate ligand-conjugated polyethylene glycol-block-poly(l-lactide) (PEG-PLLA) nanoparticles (FA-PEG-PLLA NPs) were designed to deliver lycorine to enhance its anti-glioma activity. The successful preparation of the FA-PEG-PLLA polymer was confirmed by 1H-NMR, FT-IR, XRD, TGA, and DSC. The optimal formulation for LYC@FA-PEG-PLLA NPs was determined by response surface analysis as follows: sodium dodecyl sulfate (SDS) of 1%, carrier material of 0.03 g, organic phase volume of 3 mL, and ultrasonic power of 20%. The LYC@FA-PEG-PLLA NPs exhibited an encapsulation efficiency of 83.58% and a particle size of 49.71 nm, demonstrating good stability. Hemolysis experiments, MTT assays, and cell scratch assays revealed excellent biocompatibility of FA-PEG-PLLA and superior anti-glioma activity of LYC@FA-PEG-PLLA NPs compared to the raw drug. Additionally, cell apoptosis assays, ROS experiments, and western blot analysis demonstrated that LYC@FA-PEG-PLLA NPs contributed to cell apoptosis by inducing ROS generation and increasing the expression of NF-κB inhibitory protein IκBα. These results suggested that LYC@FA-PEG-PLLA NPs hold promise for glioma treatment.


Assuntos
Alcaloides de Amaryllidaceae , Glioma , Nanopartículas , Fenantridinas , Humanos , Ácido Fólico/química , Espécies Reativas de Oxigênio , Espectroscopia de Infravermelho com Transformada de Fourier , Nanopartículas/química , Polietilenoglicóis/química , Portadores de Fármacos/química , Tamanho da Partícula , Linhagem Celular Tumoral
14.
Methods Mol Biol ; 2789: 145-151, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38507000

RESUMO

The induction of oxidative stress by engineered nanomaterials has been associated with cytotoxic and inflammatory responses, damaging healthy cells and tissues. In contrast, when directed against cancer and autoinflammatory diseases, some nanomaterials inducing oxidative stress have also been reported as potential therapies for these disorders. Therefore, studying oxidative stress has become a popular tool not only in toxicology and immunotoxicology but in other areas of biology as well, including those related to developing novel therapies. Total oxidative stress may result from multiple cellular organelles. The protocol described herein allows for the analysis of oxidative stress in mitochondria.


Assuntos
Nanopartículas , Compostos Organofosforados , Fenantridinas , Linfócitos T , Estresse Oxidativo , Mitocôndrias/metabolismo , Nanopartículas/toxicidade , Espécies Reativas de Oxigênio/metabolismo
15.
Chem Biodivers ; 21(3): e202302122, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38354224

RESUMO

Griffinia gardneriana Ravenna, Griffinia liboniana Morren and Griffinia nocturna Ravenna (Amarillydaceae) are bulbous plants found in tropical regions of Brazil. Our work aimed to determine the alkaloid profiles of Griffinia spp. and evaluate their anxiolytic potential through in vivo and in silico assays. The plants grown in greenhouses were dried and their ground bulbs were subjected to liquid-liquid partitions, resulting in alkaloid fractions that were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). Anxiolytic activity was evaluated in zebrafish (Danio rerio) through intraperitoneal injection at doses of 40, 100 and 200 mg/kg in light-dark box test. GC-MS analyses revealed 23 alkaloids belonging to different skeleton types: lycorine, homolychorine, galanthamine, crinine, haemanthamine, montanine and narcisclasine. The chemical profiles were relatively similar, presenting 8 alkaloids common to the three species. The major component for G. gardneriana and G. liboniana was lycorine, while G. nocturna consisted mainly of anhydrolycorine. All three alkaloid fractions demonstrated anxiolytic effect. Furthermore, pre-treatment with diazepam and pizotifen drugs was able to reverse the anxiolytic action, indicating involving the GABAergic and serotonergic receptors. Molecular docking showed that the compounds vittatine, lycorine and 11,12-dehydro-2-methoxyassoanine had high affinity with both receptors, suggesting them to be responsible for the anxiolytic effect.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Ansiolíticos , Fenantridinas , Animais , Amaryllidaceae/química , Peixe-Zebra , Ansiolíticos/farmacologia , Simulação de Acoplamento Molecular , Cromatografia Gasosa-Espectrometria de Massas/métodos , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Alcaloides/farmacologia , Alcaloides/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química
16.
Phytomedicine ; 126: 155460, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38394731

RESUMO

BACKGROUND: Multidrug resistance is the major obstacle to cancer chemotherapy. Modulation of P-glycoprotein and drug combination approaches have been considered important strategies to overcome drug resistance. PURPOSE: Aiming at generating a small library of Amaryllidaceae-type alkaloids to overcome drug resistance, two major alkaloids, isolated from Pancratium maritimum, lycorine (1), and 2α-10bα-dihydroxy-9-O-demethylhomolycorine (2), were derivatized, giving rise to nineteen derivatives (3 - 21). METHODS: The main chemical transformation of lycorine resulted from the cleavage of ring E of the diacetylated lycorine derivative (3) to obtain compounds that have carbamate and amine functions (5 - 16), while acylation of compound 2 provided derivatives 17 - 21. Compounds 1 - 21 were evaluated for their effects on cytotoxicity, and drug resistance reversal, using resistant human ovarian carcinoma cells (HOC/ADR), overexpressing P-glycoprotein (P-gp/ABCB1), as model. RESULTS: Excluding lycorine (1) (IC50 values of 1.2- 2.5 µM), the compounds were not cytotoxic or showed moderate/weak cytotoxicity. Chemo-sensitization assays were performed by studying the in vitro interaction between the compounds and the anticancer drug doxorubicin. Most of the compounds have shown synergistic interactions with doxorubicin. Compounds 5, 6, 9 - 14, bearing both carbamate and aromatic amine moieties, were found to have the highest sensitization rate, reducing the dose of doxorubicin 5-35 times, highlighting their potential to reverse drug resistance in combination chemotherapy. Selected compounds (4 - 6, 9 - 14, and 21), able of re-sensitizing resistant cancer cells, were further evaluated as P-gp inhibitors. Compound 11, which has a para­methoxy-N-methylbenzylamine moiety, was the strongest inhibitor. In the ATPase assay, compounds 9-11 and 13 behaved as verapamil, suggesting competitive inhibition of P-gp. At the same time, none of these compounds affected P-gp expression at the mRNA or protein level. CONCLUSIONS: This study provided evidence of the potential of Amaryllidaceae alkaloids as lead candidates for the development of MDR reversal agents.


Assuntos
Adenocarcinoma , Alcaloides , Alcaloides de Amaryllidaceae , Antineoplásicos , Fenantridinas , Humanos , Alcaloides de Amaryllidaceae/farmacologia , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Alcaloides/farmacologia , Carbamatos/farmacologia , Linhagem Celular Tumoral
17.
PLoS One ; 19(1): e0297203, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38215156

RESUMO

BACKGROUND: Breast cancer is one of the most common female malignancies. This study explored the underlying mechanism through which the two plant compounds (Brucaine D and Narclasine) inhibited the proliferation of breast cancer cells. OBJECTIVE: The purpose of this study was to explore the effect of Brucaine D and Narclasine on breast cancer development and their potential drug targets. METHODS: GSE85871 dataset containing 212 samples and the hallmark gene set "h.all.v2023.1.Hs.symbols.gmt" were downloaded from the Gene Expression Omnibus (GEO) database and the Molecular Signatures Database (MSigDB) database, respectively. Principal component analysis (PCA) was applied to classify clusters showing similar gene expression pattern. Single sample gene set enrichment analysis (ssGSEA) was used to calculate the hallmark score for different drug treatment groups. The expressions of genes related to angiogenesis, glycolysis and cell cycle were detected. Protein-protein interaction (PPI) network analysis was performed to study the interaction of the hub genes. Then, HERB database was employed to identify potential target genes for Narclasine and Bruceine D. Finally, in vitro experiments were conducted to validate partial drug-target pair. RESULTS: PCA analysis showed that the significant changes in gene expression patterns took place in 6 drugs treatment groups (Narciclasine, Bruceine D, Japonicone A, 1beta-hydroxyalatolactone, Britanin, and four mixture drugs) in comparison to the remaining drug treatment groups. The ssGSEA pathway enrichment analysis demonstrated that Narciclasine and Bruceine treatments had similar enriched pathways, for instance, suppressed pathways related to angiogenesis, Glycolysis, and cell cycle, etc.. Further gene expression analysis confirmed that Narciclasine and Bruceine had a strong ability to inhibit these cell cycle genes, and that MYC, CHEK2, MELK, CDK4 and EZH2 were closely interacted with each other in the PPI analysis. Drug target prediction revealed that Androgen Receptor (AR) and Estrogen Receptor 1 (ESR1) were the targets for Bruceine D, and Cytochrome P450 3A4 enzyme (CYP3A4) was the target for Narciclasine. Cell experiments also confirmed the connections between Narciclasine and CYP3A4. CONCLUSION: The present study uncovered that Narciclasine and Bruceine D could inhibit the growth of breast cancer and also predicted the potential targets for these two drugs, providing a new therapeutic direction for breast cancer patients.


Assuntos
Alcaloides de Amaryllidaceae , Neoplasias da Mama , Fenantridinas , Quassinas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Citocromo P-450 CYP3A , Proliferação de Células , Proteínas Serina-Treonina Quinases
18.
J Pharm Biomed Anal ; 240: 115935, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38181554

RESUMO

Ligand fishing, also described as affinity-based assay, represents a convenient and efficient approach to separate potential ligands from complex matrixes or chemical libraries. This approach contributes to the identification of lead compounds that can bind to a specific target. In the context of COVID-19, the search for novel therapeutic agents is crucial. Small molecule-based antiviral drugs, such as Amaryllidaceae alkaloids, have been described as potential candidates because they can inhibit RNA viruses. Among various SARS-CoV-2 proteins, Nsp3, Nsp4, and Nsp6 play a crucial role in the pathogenicity of the virus and are attractive targets for developing COVID-19 treatments. These proteins are responsible for the replication/transcription complex (RTC) within double-membrane vesicles (DMVs), and their inhibition disrupts the virus's infectious cycle. Herein, we have successfully expressed and immobilized the SARS-CoV-2 Nsp4 protein on magnetic beads (Nsp4-MBs) and employed a ligand fishing assay to screen a collection of ten Amaryllidaceae-based alkaloids and applied to Hippeastrum aulicum extract. Remarkably, four out of ten alkaloids, namely 2-α-7-dimethoxyhomolycorine (6), haemanthamine (5), albomaculine (8), and tazettine (9), exhibited selective affinities for Nsp4. Albomaculine (8) and haemanthamine (5) were also identified from extract by the affinity assay. These findings highlight the potential of these alkaloids as model compounds for future drug discovery studies aimed at developing therapeutic interventions against SARS-CoV-2 infections.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , COVID-19 , Fenantridinas , Humanos , Alcaloides de Amaryllidaceae/farmacologia , SARS-CoV-2 , Ligantes , Alcaloides/farmacologia , Alcaloides/química , Extratos Vegetais/química , Antivirais/farmacologia
19.
Naunyn Schmiedebergs Arch Pharmacol ; 397(3): 1551-1559, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-37668687

RESUMO

Lycorine is a naturally active alkaloid that has been shown to have inhibitory effects on a variety of cancers. However, the underlying mechanism of lycorine in the treatment of glioblastoma (GBM) is unclear. In this study, we investigated the mechanism of lycorine in the treatment of GBM based on network pharmacology and molecular docking. Lycorine-related targets overlapped with GBM-related targets to obtain intersections that represent potential anti-GBM targets for lycorine. The protein-protein interaction (PPI) network was constructed using the STRING online database and analyzed by Cytoscape software, and 10 key target genes (AKT1, SRC, HSP90AA1, HRAS, MMP9, BCL2L1, IGF1, MAPK14, STAT1, and KDR) were obtained, which played an important role in the therapeutic effect of lycorine on GBM. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that lycorine acts on GBM by multiple pathways, including inducing apoptosis and reactive oxygen species production. The molecular docking results showed that lycorine had strong binding efficiency with the 10 key genes. In addition, we found that the use of lycorine-induced apoptosis in U-87 MG glioblastoma cells. Here, the mechanism of action of lycorine against GBM was elucidated and verified by experiments, which provided evidence support for its clinical application.


Assuntos
Alcaloides de Amaryllidaceae , Glioblastoma , Fenantridinas , Humanos , Simulação de Acoplamento Molecular , Glioblastoma/tratamento farmacológico , Farmacologia em Rede , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/uso terapêutico
20.
Mol Divers ; 28(1): 419-435, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37847467

RESUMO

The development of transition metal-free 2-isocyanobiaryl-based reactions has received much attention due to the widespread presence of phenanthidine frameworks as products in pharmacological chemistry and materials science. This review article focuses on the achievements from 2013 until now in various metal-free catalyzed reactions and discusses challenging mechanisms and features of the transformations.


Assuntos
Metais , Elementos de Transição , Ciclização , Fenantridinas
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