RESUMO
Sepsis, a frequently fatal condition, emerges from an exaggerated inflammatory response to infection, resulting in multi-organ dysfunction and alarmingly high mortality rates. Despite the urgent need for effective treatments, current therapeutic options remain limited to antibiotics, with no other efficacious alternatives available. Echinatin (Ecn), a potent bioactive compound extracted from the roots and rhizomes of licorice, has gained significant attention for its broad pharmacological properties, particularly its ability to combat oxidative stress. Recent research highlights the crucial role that oxidative stress plays in the onset and progression of sepsis further emphasizing the potential therapeutic value of Ecn in this context. In this study, we explored the protective effects of Ecn in a murine model of sepsis induced by cecal ligation and puncture (CLP). Ecn demonstrated a significant reduction in the levels of inflammatory cytokines and reactive oxygen species (ROS) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Network pharmacology analysis identified 41 targets and top 15 pathways involved in the Ecn-mediated signaling network, revealing that Ecn might exert its effects through key targets including the NF-κB and MAPK signaling pathways. Molecular docking studies suggested a strong affinity between Ecn and MEK, with kinetic simulations and binding energy calculations confirming a stable interaction. Mechanistically, Ecn treatment inhibited NF-κB and the MEK/ERK signaling pathway, as evidenced by decreased phosphorylation of IκBα and nuclear p65, along with reduced phosphorylation of MEK and ERK in both LPS-stimulated RAW 264.7 macrophages and septic mice. Furthermore, the administration of MEK signaling agonists reversed the anti-inflammatory effects of Ecn, indicating the involvement of this signaling pathway in Ecn's protective mechanism. Notably, our investigation revealed that Ecn did not affect bacterial proliferation either in vivo or in vitro, underscoring its specific immunomodulatory effects rather than direct antimicrobial activity. In summation, our findings underscored the potential of Ecn as an innovative therapeutic remedy for sepsis-induced injury, particularly through the regulation of the NF-κB and MEK/ERK signaling pathway. This exploration unveiled a promising therapeutic approach for treating sepsis, supplementing existing interventions and addressing their constraints.
Assuntos
Sistema de Sinalização das MAP Quinases , NF-kappa B , Sepse , Animais , Sepse/tratamento farmacológico , Sepse/metabolismo , NF-kappa B/metabolismo , Camundongos , Células RAW 264.7 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Espécies Reativas de Oxigênio/metabolismo , Simulação de Acoplamento Molecular , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Citocinas/metabolismo , Anti-Inflamatórios/farmacologia , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , ChalconasRESUMO
Chalcones constitute an important group of natural compounds abundant in fruits and comestible plants. They are a subject of increasing interest because of their biological activities, including anti-diabetic and anti-obesity effects. The simple chalcone structural scaffold can be modified at multiple sites with different chemical moieties. Here, we generated an artificial chalcone, i.e., 3,5-dimethyl-2,4,6-trimethoxychalcone (TriMetChalc), derived from 2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC). DMC is a major compound of Cleistocalyx operculatus, a plant widely used in Asia for its anti-hyperglycemic activity. Using ob/ob mice as an obesity model, we report that, after 3 weeks of per os administration, TriMetChalc modified food intake through the specific activation of brain structures dedicated to the regulation of energy balance. TriMetChalc also decreased weight gain, glucose intolerance, and hepatic steatosis. Moreover, through extensive liver lipidomic analysis, we identified TriMetChalc-induced modifications that could contribute to improving the liver status of the animals. Hence, TriMetChalc is a chalcone derivative capable of reducing food intake and the addition of glucose intolerance and hepatic steatosis in a mouse model of obesity. In light of these results, we believe that TriMetChalc action deserves to be more deeply evaluated over longer treatment periods and/or in combination with other chalcones with protective effects on the liver.
Assuntos
Chalconas , Leptina , Camundongos Obesos , Obesidade , Animais , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Chalconas/farmacologia , Chalconas/química , Camundongos , Leptina/metabolismo , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/química , Ingestão de Alimentos/efeitos dos fármacosRESUMO
This study investigated the therapeutic potential of licochalcone D (LicoD), which is derived from Glycyrrhiza uralensis, for improving glucose metabolism in AML12 hepatocytes with high-glucose-induced insulin resistance (IR). Ultra-high-performance liquid chromatography-mass spectrometry revealed that the LicoD content of G. uralensis was 8.61 µg/100 mg in the ethanol extract (GUE) and 0.85 µg/100 mg in the hot water extract. GUE and LicoD enhanced glucose consumption and uptake, as well as Glut2 mRNA expression, in high-glucose-induced IR AML12 cells. These effects were associated with the activation of the insulin receptor substrate/phosphatidylinositol-3 kinase signaling pathway, increased protein kinase B α phosphorylation, and suppression of gluconeogenesis-related genes, such as Pepck and G6pase. Furthermore, GUE and LicoD promoted glycogen synthesis by downregulating glycogen phosphorylase. Furthermore, LicoD and GUE mitigated the downregulated expression of mitochondrial oxidative phosphorylation proteins in IR hepatocytes by activating the PPARα/PGC1α pathway and increasing the mitochondrial DNA content. These findings demonstrate the potential of LicoD and GUE as therapeutic options for alleviating IR-induced metabolic disorders by improving glucose metabolism and mitochondrial function.
Assuntos
Chalconas , Glucose , Glycyrrhiza uralensis , Hepatócitos , Resistência à Insulina , Glycyrrhiza uralensis/química , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Glucose/metabolismo , Animais , Camundongos , Chalconas/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Transdução de Sinais/efeitos dos fármacos , Linhagem CelularRESUMO
Endothelial dysfunction occurs prior to atherosclerosis, which is an independent predictor of cardiovascular diseases (CVDs). Diabetes mellitus impairs endothelial function by triggering oxidative stress and inflammation in vascular tissues. Isoliquiritigenin (ISL), one of the major bioactive ingredients extracted from licorice, has been reported to inhibit inflammation and oxidative stress. However, the therapeutic effects of ISL on ameliorating type 2 diabetes (T2D)-associated endothelial dysfunction remain unknown. In our animal study, db/db male mice were utilized as a model for T2D-associated endothelial dysfunction, while their counterpart, heterozygote db/m+ male mice, served as the control. Mouse brain microvascular endothelial cells (mBMECs) were used for in vitro experiments. Interleukin-1ß (IL-1ß) was used to induce endothelial cell dysfunction. ISL significantly reversed the impairment of endothelium-dependent relaxations (EDRs) in db/db mouse aortas. ISL treatment decreased ROS (reactive oxygen species) levels in db/db mice aortic sections and IL-1ß-treated endothelial cells. Encouragingly, ISL attenuated the overexpression of pro-inflammatory factors MCP-1, TNF-α, and IL-6 in db/db mouse aortas and IL-1ß-impaired endothelial cells. The NOX2 (NADPH oxidase 2) overexpression was inhibited by ISL treatment. Notably, ISL treatment restored the expression levels of IL-10, SOD1, Nrf2, and HO-1 in db/db mouse aortas and IL-1ß-impaired endothelial cells. This study illustrates, for the first time, that ISL attenuates endothelial dysfunction in T2D mice, offering new insights into the pharmacological effects of ISL. Our findings demonstrate the potential of ISL as a promising therapeutic agent for the treatment of vascular diseases, paving the way for the further exploration of novel vascular therapies.
Assuntos
Chalconas , Diabetes Mellitus Tipo 2 , Células Endoteliais , Endotélio Vascular , Glycyrrhiza , Estresse Oxidativo , Extratos Vegetais , Animais , Chalconas/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glycyrrhiza/química , Masculino , Camundongos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Extratos Vegetais/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Aorta/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Camundongos Endogâmicos C57BL , Interleucina-1beta/metabolismoRESUMO
BACKGROUND: Isoliquiritigenin (ISL) is an important pharmacological constituent of Glycyrrhiza glabra, which possesses a range of physiological and pharmacological activities, as well as significant antitumor activity, and can be used as a potential drug for targeted cancer therapy. LINC01503 is an oncogene, which has been closely associated with the malignant biological processes of many cancers. The aim of this study was to investigate the effects of ISL on the proliferation, apoptosis, invasion and migration of lung squamous carcinoma cells by regulating LINC01503. METHODS: Plasma was collected from lung squamous carcinoma patients and healthy individuals treated at Tangshan People's Hospital from January 2021 to December 2022. The expression of LINC01503 in lung squamous carcinoma plasma, tissues and cells was detected by real-time quantitative fluorescence polymerase chain reaction (qRT-PCR). Lung squamous carcinoma cells were treated with different concentrations of ISL for 24 h, and LINC01503 expression was detected by qRT-PCR. The cells were treated in groups: si-NC group, si-LINC01503 group, DMSO (0.1% dimethyl sulfone) group, ISL group, pc DNA3.1(+)-NC group, pc DNA3.1(+)-LINC01503 group, ISL+pc DNA3.1(+)-NC group and ISL+pc DNA3.1(+)- LINC01503 groups. CCK-8 assay, clone formation assay, flow cytometry, Transwell assay and scratch assay were used to explore the effect of LINC01503 on the functional phenotype of lung squamous carcinoma cells. RESULTS: Fluorescence in situ hybridization results showed that the average fluorescence intensity of LINC01503 in tissue microarrays of lung squamous carcinoma patients was higher than that in paracancerous tissues (P<0.05). The expression of LINC01503 in the plasma of patients with lung squamous carcinoma was higher than that in the plasma of healthy individuals (P<0.05). Knockdown of LINC01503 inhibited the proliferation, invasion and migration of lung squamous carcinoma cells and promoted apoptosis (P<0.05). ISL inhibited the proliferation, invasion, migration and promoted apoptosis of lung squamous carcinoma cells (P<0.05). Overexpression of LINC01503 followed by intervention with ISL reversed the promotional effect of overexpression of LINC01503 on the proliferation, invasion and migration of lung squamous carcinoma cells as well as the inhibitory effect on apoptosis (P<0.05). CONCLUSIONS: LINC01503 was highly expressed in lung squamous carcinoma, and LINC01503 could promote the proliferation, invasion and migration of lung squamous carcinoma cells and inhibit the apoptosis, ISL could inhibit the proliferation, invasion and migration of lung squamous carcinoma cells and promote apoptosis of lung squamous carcinoma cells by regulating the expression of LINC01503.
Assuntos
Apoptose , Carcinoma de Células Escamosas , Movimento Celular , Proliferação de Células , Chalconas , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Movimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Saponinas/farmacologia , Feminino , Masculino , Pessoa de Meia-IdadeRESUMO
Porphyromonas gingivalis causes various health issues through oral infections. This study investigates the antibacterial activities of food-derived dihydrochalcone flavonoids against Porphyromonas gingivalis and their mechanisms of antibacterial action through comparative transcriptome profiling. Susceptibility tests showed that two typical dihydrochalcone flavonoids (phloretin and phlorizin) had much lower minimum inhibitory concentrations (12.5 µg mL-1 and 50 µg mL-1, respectively) than the common flavanone naringenin (100 µg mL-1). SEM observations and the LDH activity assay indicated obvious anomalies in cell morphology and increased cell membrane permeability, indicating the destructive effect of those compounds on the cell structure. These compounds might also induce apoptosis in P. gingivalis, as shown by the CLSM fluorescence images. Transcriptomic analysis revealed that the flavonoid treatment impacted DNA function and oxidative damage. These flavonoids may activate antioxidant-related pathways that are lethal to anaerobic bacteria like P. gingivalis. Additionally, the compounds resulted in the silencing of transposition-related genes, potentially inhibiting resistance-gene acquisition and expression. Phloretin regulated fatty acid metabolism pathways, which are related to the construction and maintenance of the cell membrane. This suggests a relationship between the structure and antibacterial activities of the tested compounds that share a flavonoid skeleton but differ in the C-ring and glucose moiety. This is the first report of the antibacterial activities and mechanisms of action of food-derived dihydrochalcone flavonoids at the transcriptome level, offering a promising approach for the development of new antibacterial agents from natural products and enhancing their applicability in treating diseases associated with oral pathogens as a substitute for antibiotics.
Assuntos
Antibacterianos , Chalconas , Flavonoides , Frutas , Testes de Sensibilidade Microbiana , Porphyromonas gingivalis , Porphyromonas gingivalis/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Chalconas/farmacologia , Frutas/química , Flavonoides/farmacologia , Transcriptoma , Perfilação da Expressão Gênica , Extratos Vegetais/farmacologia , Extratos Vegetais/químicaRESUMO
Currently, surgical resection remains the primary approach for treating oral squamous cell carcinoma (OSCC), with limited options for effective drug therapy. Cardamonin, a principal compound derived from Myristica fragrans of the Zingiberaceae family, has garnered attention for its potential to suppress the onset and progression of various malignancies encompassing breast cancer, hepatocellular carcinoma, and ovarian cancers. Nevertheless, the involvement of cardamonin in the treatment of OSCC and its underlying mechanisms are yet to be elucidated. This research explored the possible target of cardamonin in treating OSCC via network pharmacological analysis. Subsequently, this research investigated the impact of cardamonin on OSCC cells via in vitro experiments, revealing its capacity to impede the migration, proliferation, and invasion of OSCC cells. Additionally, western blotting analysis demonstrated that cardamonin facilitates apoptosis by regulating the PI3K/AKT pathway. The findings suggest that MMP9 and the PI3K/AKT signaling pathway may serve as the target and pathway of cardamonin in treating OSCC. To summarize, the research findings suggest that cardamonin may facilitate apoptosis in OSCC cells by inhibition of PI3K/AKT pathway activation. These outcomes offer a theoretical basis for the utilization of cardamonin as a natural drug for treating OSCC.
Assuntos
Apoptose , Carcinoma de Células Escamosas , Movimento Celular , Proliferação de Células , Chalconas , Neoplasias Bucais , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Humanos , Chalconas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Neoplasias Bucais/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Metaloproteinase 9 da Matriz/metabolismoRESUMO
Chalcones have been utilized for centuries as foods and medicines across various cultures and traditions worldwide. This paper concisely overviews their biosynthesis as specialized metabolites in plants and their significance, potential, efficacy, and possibility as future medicines. This is followed by a more in-depth exploration of naturally occurring chalcones and their corresponding mechanisms of action in human bodies. Based on their mechanisms of action, chalcones exhibit many pharmacological properties, including antioxidant, anti-inflammatory, anticancer, antimalarial, antiviral, and antibacterial properties. Novel naturally occurring chalcones are also recognized as potential antidiabetic drugs, and their effect on the GLUT-4 transporter is investigated. In addition, they are examined for their anti-inflammatory effects, focusing on chalcones used for future pharmaceutical utilization. Chalcones also bind to specific receptors and toxins that prevent bacterial and viral infections. Chalcones exhibit physiological protective effects on the biological degradation of different systems, including demyelinating neurodegenerative diseases and preventing hypertension or hyperlipidemia. Chalcones that are/were in clinical trials have been included as a separate section. By revealing the many biological roles of chalcones and their impact on medicine, this paper underlines the significance of naturally occurring chalcones and their extension to patient care, providing the audience with an index of topic-relevant information.
Assuntos
Chalconas , Chalconas/farmacologia , Chalconas/química , Humanos , Ensaios Clínicos como Assunto , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/uso terapêuticoRESUMO
Chalcones, secondary plant metabolites, exhibit various biological properties. The introduction of a chlorine and a glucosyl substituent to the chalcone could enhance its bioactivity and bioavailability. Such compounds can be obtained through a combination of chemical and biotechnological methods. Therefore, 4-chloro-2'-hydroxychalcone and 5'-chloro-2'-hydroxychalcone were obtained by synthesis and then glycosylated in two filamentous fungi strains cultures, i.e., Isaria fumosorosea KCH J2 and Beauveria bassiana KCH J1.5. The main site of the glycosylation of both compounds by I. fumosorosea KCH J2 was C-2' and C-3 when the second strain was utilized. The pharmacokinetics of these compounds were predicted using chemoinformatics tools. Furthermore, antimicrobial activity tests were performed. Compounds significantly inhibited the growth of the bacteria strains Escherichia coli 10536, Staphylococcus aureus DSM 799, and yeast Candida albicans DSM 1386. Nevertheless, the bacterial strain Pseudomonas aeruginosa DSM 939 exhibited significant resistance to their effects. The growth of lactic acid bacteria strain Lactococcus acidophilus KBiMZ 01 bacteria was moderately inhibited, but strains Lactococcus rhamnosus GG and Streptococcus thermophilus KBM-1 were completely inhibited. In summary, chalcones substituted with a chlorine demonstrated greater efficacy in inhibiting the microbial strains under examination compared to 2'-hydroxychalcone, while aglycones and their glycosides exhibited similar effectiveness.
Assuntos
Anti-Infecciosos , Chalconas , Cloro , Glicosídeos , Testes de Sensibilidade Microbiana , Chalconas/química , Chalconas/farmacologia , Glicosídeos/química , Glicosídeos/farmacologia , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Cloro/química , BeauveriaRESUMO
A novel group of indolyl-1,2,4-triazole-chalcone hybrids was designed, synthesized, and assessed for their anticancer activity. The synthesized compounds exhibited significant antiproliferative activity. Compounds 9a and 9e exhibited significant cancer inhibition with GI50 ranging from 3.69 to 20.40 µM and from 0.29 to >100 µM, respectively. Both compounds displayed a broad spectrum of anticancer activity with selectivity ratios ranging between 0.50-2.78 and 0.25-2.81 at the GI50 level, respectively. The synthesized compounds were also screened for their cytotoxicity by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazol (MTT) assay and for inhibition of epidermal growth factor receptor (EGFR) and c-MET (mesenchymal-epithelial transition factor). Some of the tested compounds exhibited significant inhibition against EGFR and/or c-MET. Compound 9b showed the highest c-MET inhibition (IC50 = 4.70 nM) compared to foretinib (IC50 = 2.5 nM). Compound 9d showed equipotent activity compared with erlotinib against EGFR (IC50 = 0.052 µM) and displayed significant c-MET inhibition with an IC50 value of 4.90 nM.
Assuntos
Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Indóis , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Triazóis , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Triazóis/farmacologia , Triazóis/química , Triazóis/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Indóis/farmacologia , Indóis/química , Indóis/síntese química , Relação Dose-Resposta a Droga , Estrutura Molecular , Linhagem Celular Tumoral , Chalconas/farmacologia , Chalconas/síntese química , Chalconas/química , Chalcona/farmacologia , Chalcona/química , Chalcona/síntese químicaRESUMO
SCOPE: Chalcones are widely present in most plants and have various health beneficial functions. This study investigates the suppressive effect of 13 natural and synthetic chalcones on transformation of aryl hydrocarbon receptor (AhR) induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (3-MC) in a cell-free system, Hepa-1c1c7 cells, and liver of ICR mice. METHODS AND RESULTS: In the cell-free system, cardamonin dose-dependently inhibits AhR transformation. Chalcones with substitution on 2' and/or 6' position is important for the suppressive effect, while the substitution on 4' position is negatively for the effect. Moreover, cardamonin and 2'-hydroxychalcone competitively inhibit the binding of [3H]-3-MC to the AhR. In Hepa-1c1c7 cells, cardamonin inhibits AhR transformation and expression of cytochrome P4501A1 (CYP1A1) in a dose-dependent manner through suppressing TCDD-induced phosphorylation of both AhR and AhR nuclear translocator, heterodimerization of them, and nuclear translocation of AhR. In the liver of mice, oral administered cardamonin also inhibits 3-MC-induced AhR translocation and expression of CYP1A1. CONCLUSION: Among used chalcones, a natural chalcone cardamonin competitively binds to AhR and suppresses its transformation. Thus, cardamonin is an effective food factor for suppression of the dioxin-caused biochemical alterations and toxicities.
Assuntos
Chalconas , Citocromo P-450 CYP1A1 , Fígado , Camundongos Endogâmicos ICR , Dibenzodioxinas Policloradas , Receptores de Hidrocarboneto Arílico , Animais , Chalconas/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A1/genética , Fígado/metabolismo , Fígado/efeitos dos fármacos , Camundongos , Metilcolantreno , Masculino , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Fosforilação/efeitos dos fármacos , Ligação CompetitivaRESUMO
In present study, seventeen α-nitrile substituted guaiazulene-based chalcone derivatives including twelve new were designed, synthesized, and assayed for antiviral, cytotoxicity and signal pathway activities. All derivatives showed potential antiviral activity towards influenza virus or herpes simplex virus (HSV), 7 g with the substitution of nitro group showed strong effects towards H1N1 virus at 30 µM with inhibitory rate of 66.0%, 7o with thiophene exhibited potent anti HSV-1 activities with inhibitory rate of 65.8%. Moreover, several compounds exhibited inhibitory effects on tumor cells and hypoxia-inducible factor-1 (HIF1) signaling pathways. These results showed that α-nitrile substituted guaiazulene-based chalcones offered a promising framework for the further development of new highly efficient drugs.
Assuntos
Antivirais , Azulenos , Chalconas , Azulenos/farmacologia , Azulenos/química , Azulenos/síntese química , Humanos , Estrutura Molecular , Antivirais/farmacologia , Antivirais/síntese química , Chalconas/farmacologia , Chalconas/síntese química , Linhagem Celular Tumoral , Sesquiterpenos de Guaiano/farmacologia , Sesquiterpenos de Guaiano/síntese química , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Chalcona/farmacologia , Chalcona/química , Chalcona/análogos & derivados , Chalcona/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Herpesvirus Humano 1/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Desenho de Fármacos , AnimaisRESUMO
Flavivirus infection capitalizes on cellular lipid metabolism to remodel the cellular intima, creating a specialized lipid environment conducive to viral replication, assembly, and release. The Japanese encephalitis virus (JEV), a member of the Flavivirus genus, is responsible for significant morbidity and mortality in both humans and animals. Currently, there are no effective antiviral drugs available to combat JEV infection. In this study, we embarked on a quest to identify anti-JEV compounds within a lipid compound library. Our research led to the discovery of two novel compounds, isobavachalcone (IBC) and corosolic acid (CA), which exhibit dose-dependent inhibition of JEV proliferation. Time-of-addition assays indicated that IBC and CA predominantly target the late stage of the viral replication cycle. Mechanistically, JEV nonstructural proteins 1 and 2A (NS1 and NS2A) impede 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation by obstructing the liver kinase B1 (LKB1)-AMPK interaction, resulting in decreased p-AMPK expression and a consequent upsurge in lipid synthesis. In contrast, IBC and CA may stimulate AMPK by binding to its active allosteric site, thereby inhibiting lipid synthesis essential for JEV replication and ultimately curtailing viral infection. Most importantly, in vivo experiments demonstrated that IBC and CA protected mice from JEV-induced mortality, significantly reducing viral loads in the brain and mitigating histopathological alterations. Overall, IBC and CA demonstrate significant potential as effective anti-JEV agents by precisely targeting AMPK-associated signaling pathways. These findings open new therapeutic avenues for addressing infections caused by Flaviviruses. IMPORTANCE: This study is the inaugural utilization of a lipid compound library in antiviral drug screening. Two lipid compounds, isobavachalcone (IBC) and corosolic acid (CA), emerged from the screening, exhibiting substantial inhibitory effects on the Japanese encephalitis virus (JEV) proliferation in vitro. In vivo experiments underscored their efficacy, with IBC and CA reducing viral loads in the brain and mitigating JEV-induced histopathological changes, effectively shielding mice from fatal JEV infection. Intriguingly, IBC and CA may activate 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) by binding to its active site, curtailing the synthesis of lipid substances, and thus suppressing JEV proliferation. This indicates AMPK as a potential antiviral target. Remarkably, IBC and CA demonstrated suppression of multiple viruses, including Flaviviruses (JEV and Zika virus), porcine herpesvirus (pseudorabies virus), and coronaviruses (porcine deltacoronavirus and porcine epidemic diarrhea virus), suggesting their potential as broad-spectrum antiviral agents. These findings shed new light on the potential applications of these compounds in antiviral research.
Assuntos
Proteínas Quinases Ativadas por AMP , Antivirais , Vírus da Encefalite Japonesa (Espécie) , Encefalite Japonesa , Metabolismo dos Lipídeos , Replicação Viral , Animais , Metabolismo dos Lipídeos/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Vírus da Encefalite Japonesa (Espécie)/efeitos dos fármacos , Vírus da Encefalite Japonesa (Espécie)/fisiologia , Camundongos , Antivirais/farmacologia , Humanos , Encefalite Japonesa/tratamento farmacológico , Encefalite Japonesa/virologia , Proteínas Quinases Ativadas por AMP/metabolismo , Chalconas/farmacologia , Triterpenos/farmacologia , Proteínas não Estruturais Virais/metabolismo , Infecções por Flavivirus/tratamento farmacológico , Infecções por Flavivirus/virologia , Infecções por Flavivirus/metabolismo , Flavivirus/efeitos dos fármacos , Linhagem CelularRESUMO
BACKGROUND: Myocardial hypertrophy is a chronic cardiac condition that often occurs from long-term pressure or volumetric load on the heart. Propranolol hydrochloride has been employed in research on hypertension, pheochromocytoma, myocardial infarction, arrhythmias, angina pectoris, and hypertrophic cardiomyopathy. Current treatments for this condition have side effects, such as arrhythmias and myocardial cell death, thus necessitating safer and more effective alternatives. Recently, natural products have gained attention in drug development because of their low toxicity and high efficacy. Cardamonin, a compound derived from Chinese herbal materials, has shown potential in inhibiting oxidative stress and inflammation, which is beneficial for cardiovascular health. Nevertheless, the impact on myocardial hypertrophy and cardiac remodeling is still uncertain METHODS: Approach We employed a transverse aortic constriction (TAC)model to simulate the pathological conditions of myocardial hypertrophy. Mice were administered varying doses of CAR (10 and 40 mg kg-1/d), and cardiac function was assessed using techniques such as echocardiography, qPCR, Masson staining, DHE staining, immunofluorescence, and immunohistochemistry. Propranolol hydrochloride was the positive control for observing the anti-myocardial hypertrophic effects of CAR. RESULTS: Cardamonin significantly reduced TAC-induced myocardial hypertrophy, fibrosis, inflammation, and oxidative stress. High CAR concentrations showed better anti-myocardial remodeling effects. The anti-hypertrophic effect of cardamonin was similar to that of propranolol hydrochloride. Further investigating the mechanism of action revealed that ubiquitin-specific peptidase (USP)18, a deubiquitnating enzyme that regulates various cellular signaling pathways, was a key downstream regulator affected by cardamonin. To confirm this, AAV9-cTNT-Usp18 and Usp18 myocardial-specific knockout mice were generated and treated with TAC. Usp18 downregulation was found to interfere with the protective effects of CAR against myocardial remodeling, whereas its overexpression enhanced these effects. CONCLUSION: This study used propranolol as a positive control and provided the first in-depth exploration of the concentration-dependent effects of cardamonin on myocardial hypertrophy and cardiac remodeling. CAR is a new candidate drug for cardiovascular disease treatment. This comparative study provides evidence for assessing the clinical application potential of new drugs and delves into its mechanisms of action, particularly the interaction with Usp18. Comprehending these mechanisms is beneficial for formulating more targeted future treatment approaches.
Assuntos
Cardiomegalia , Chalconas , Estresse Oxidativo , Animais , Chalconas/farmacologia , Camundongos , Cardiomegalia/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Miocárdio/patologiaRESUMO
Elafibranor (IQIRVO®) is a first-in-class peroxisome proliferator-activated receptor (PPAR) agonist being developed by Ipsen, under license from Genfit, for the treatment of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). On 10 June 2024, elafibranor received accelerated approval based on reduction of alkaline phosphatase (ALP) in the USA for the treatment of PBC in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. Elafibranor has also received a positive opinion in the EU. This article summarizes the milestones in the development of elafibranor leading to this first approval for PBC.
Assuntos
Aprovação de Drogas , Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Ácido Ursodesoxicólico/farmacologia , Colangite Esclerosante/tratamento farmacológico , Fosfatase Alcalina/metabolismo , Estados Unidos , Nitrilas/uso terapêutico , Nitrilas/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Quimioterapia Combinada , Propionatos , ChalconasRESUMO
In this study, heterocyclic compounds containing a benzothiophene scaffold were designed and synthetized, and their inhibitory activity against cholinesterases (ChE) and the viability of SH-SY5Y cells have been evaluated. Benzothiophenes 4a-4i and benzothiophene-chalcone hybrids 5a-5i were tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing interesting structure-activity relationships. In general, benzothiophene-chalcone hybrids from series 5 proved to be better inhibitors of both enzymes, with compound 5f being the best AChE inhibitor (IC50 = 62.10 µM) and compound 5h being the best BChE inhibitor (IC50 = 24.35 µM), the last one having an IC50 similar to that of galantamine (IC50 = 28.08 µM), the reference compound. The in silico ADME profile of the compounds was also studied. Molecular docking calculations were carried out to analyze the best binding scores and to elucidate enzyme-inhibitors' interactions.
Assuntos
Acetilcolinesterase , Butirilcolinesterase , Chalconas , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Tiofenos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Humanos , Tiofenos/química , Tiofenos/farmacologia , Tiofenos/síntese química , Chalconas/química , Chalconas/síntese química , Chalconas/farmacologia , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Relação Estrutura-Atividade , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Estrutura Molecular , Linhagem Celular TumoralRESUMO
Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 µΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.
Assuntos
Cumarínicos , Glutationa S-Transferase pi , Simulação de Acoplamento Molecular , Sulfonamidas , Humanos , Cumarínicos/química , Cumarínicos/farmacologia , Glutationa S-Transferase pi/antagonistas & inibidores , Glutationa S-Transferase pi/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Linhagem Celular Tumoral , Chalcona/química , Chalcona/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Chalconas/química , Chalconas/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Células MCF-7RESUMO
In this experiment, a rapid and highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technology was established and validated for the quantitation and pharmacokinetic analysis of eupafolin in rat plasma, utilizing licochalcone B as internal standard (IS). After liquid-liquid extraction of the analyte samples by ethyl acetate, chromatographic separation was achieved using a UPLC HSS T3 column under gradient elution conditions, with the mobile phase consisting of acetonitrile and water (with 0.1 % formic acid). Eupafolin was quantified by multiple reaction monitoring (MRM) in electrospray positive-ion mode (ESI+), employing the mass transition m/z 315.2 â 300.3 for eupafolin and m/z 285.4 â 270.3 for IS. Eupafolin demonstrated excellent linear relationship (r > 0.99) over the concentration range of 1.25-1250 ng/mL, with the lower limit of quantification (LLOQ) of the UPLC-MS/MS assay determined as 1.25 ng/mL. Method validation followed the bioanalytical method validation criteria outlined by the FDA. The accuracy of eupafolin ranged from 86.7 % to 111.2 %, and the precision was less than 12 %. The matrix effect was observed at 92.8 %-98.6 %, while the recoveries exceeded 83.2 %. The established UPLC-MS/MS assay was successfully employed for the pharmacokinetic evaluation of eupafolin in rats. The half-lives (t1/2z) were determined to be 1.4 ± 0.4 h and 2.5 ± 1.4 h for intravenous and oral administration, respectively. Notably, the bioavailability of eupafolin was relatively low (8.3 %). The optimized UPLC-MS/MS technology showed highly sensitive, selective, and effective, rendering it suitable for the pharmacokinetics of eupafolin in preclinical practice.
Assuntos
Limite de Detecção , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Animais , Espectrometria de Massas em Tandem/métodos , Ratos , Cromatografia Líquida de Alta Pressão/métodos , Reprodutibilidade dos Testes , Masculino , Modelos Lineares , Chalconas/farmacocinética , Chalconas/sangue , Chalconas/química , Sensibilidade e Especificidade , Espectrometria de Massa com Cromatografia LíquidaRESUMO
Phenol soluble modulins (PSMs) are small amphipathic peptides involved in a series of biological functions governing staphylococcal pathogenesis, primarily by facilitating the formation of an extracellular fibril structure with amyloid-like properties. This fibrillar architecture stabilizes the staphylococcal biofilm making it resilient to antibiotic treatment. Our study aims to abrogate the amyloid fibrillation of PSM α1 with novel insights on the amyloid modulatory potential of a prenylated chalcone, Isobavachalcone (IBC). A combination of biophysical and computational assays to address the amyloid modulatory effect of IBC has been undertaken to arrive at a model for the inhibition of PSM α1 fibrillation. ThT kinetics studies indicated that IBC must be stably interacting with the amyloidogenic core of PSM α1 monomers or it may be inhibiting the pre-fibrillar aggregates populated at the early stages of amyloid transformation kinetics. This heteromolecular association further inhibits the amyloid transformation corroborated by a â¼ 94% and â¼ 91% reduction in the ThT maxima, even at sub-stoichiometric concentrations. Transmission electron microscopy (TEM) of end-stage aggregates (â¼ 55 h) depict mature, inter-twined, laterally stacked amyloid fibrils in untreated PSM α1 samples while this fibrillar load is remarkably reduced in the presence of IBC. The inhibitory effect of IBC on the ß-sheet transitions of PSM α1 were also validated using far-UV CD spectra. Molecular dynamics simulation studies with PSM aggregates (PSM-A) have also suggested that IBC disrupts the hydrogen bonding interactions and corroborates the inhibition of alpha to beta transitions of PSM-A. Collectively, our data proposes a novel structural motif for the rational discovery of non-toxic therapeutic agents targeting the functional amyloids which have slowly emerged as potent factors, consolidating the antibiotic resistant staphylococcal biofilm assembly.
Assuntos
Amiloide , Chalconas , Staphylococcus aureus , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Chalconas/farmacologia , Chalconas/química , Chalconas/metabolismo , Amiloide/metabolismo , Amiloide/química , Simulação de Dinâmica Molecular , Cinética , Prenilação , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Biofilmes/efeitos dos fármacos , Toxinas BacterianasRESUMO
Phloretin is a natural dihydrochalcone (DHC) that exhibits various pharmacological and therapeutic activities. Malus hupehensis Rehd. (M. hupehensis) is widely planted in the middle of China and its leaves contain an extremely high content of phloridzin, a glycosylated derivative of phloretin. In the present study, we observed a significant increase in phloretin content in the leaves of M. hupehensis planted at high altitudes. To investigate the mechanisms of phloretin accumulation, we explored changes in the proteome profiles of M. hupehensis plants grown at various altitudes. The results showed that at high altitudes, photosynthesis- and DHC biosynthesis-related proteins were downregulated and upregulated, respectively, leading to reduced chlorophyll content and DHC accumulation in the leaves. Moreover, we identified a novel phloridzin-catalyzing glucosidase whose expression level was significantly increased in high-altitude-cultivated plants. This work provided a better understanding of the mechanism of phloretin accumulation and effective and economic strategies for phloretin production.