RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Triptolide is a major bioactive and toxic ingredient isolated from the traditional Chinese herb Tripterygium wilfordii (T. wilfordii) Hook F. It exhibits potent antitumor, immunosuppressive, and anti-inflammatory biological activities; however, its clinical application is hindered by severe systemic toxicity. Two preparations of T. wilfordii, including T. wilfordii glycoside tablets and T. wilfordii tablets, containing triptolide, are commonly used in clinical practice. However, their adverse side effects, particularly hepatotoxicity, limit their safe use. Therefore, it is crucial to discover potent and specific detoxification medicines for triptolide. AIM OF THE STUDY: This study aimed to investigate the detoxification effects and potential mechanism of action of spironolactone on triptolide-induced hepatotoxicity to provide a potential detoxifying strategy for triptolide, thereby promoting the safe applications of T. wilfordii preparations in clinical settings. MATERIALS AND METHODS: Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and crystal violet staining. Nuclear fragmentation was visualized using 4',6-diamidino-2-phenylindole (DAPI) staining, and protein expression was analyzed by Western blotting. The inhibitory effect of spironolactone on triptolide-induced hepatotoxicity was evaluated by examining the effects of spironolactone on serum alanine aminotransferase and aspartate aminotransferase levels, as well as liver pathology in a mouse model of triptolide-induced acute hepatotoxicity. Furthermore, a survival assay was performed to investigate the effects of spironolactone on the survival rate of mice exposed to a lethal dose of triptolide. The effect of spironolactone on triptolide-induced global transcriptional repression was assessed through 5-ethynyl uridine staining. RESULTS: Triptolide treatment decreased the cell viability, increased the nuclear fragmentation and the cleaved caspase-3 levels in both hepatoma cells and hepatocytes. It also increased the alanine aminotransferase and aspartate aminotransferase levels, induced the hepatocyte swelling and necrosis, and led to seven deaths out of 11 mice. The above effects could be mitigated by pretreatment with spironolactone. Additionally, molecular mechanism exploration unveiled that spironolactone inhibited triptolide-induced DNA-directed RNA polymerase II subunit RPB1 degradation, consequently increased the fluorescence intensity of 5-ethynyl uridine staining for nascent RNA. CONCLUSIONS: This study shows that spironolactone exhibits a potent detoxification role against triptolide hepatotoxicity, through inhibition of RPB1 degradation induced by triptolide and, in turn, retardation of global transcriptional inhibition in affected cells. These findings suggest a potential detoxification strategy for triptolide that may contribute to the safe use of T. wilfordii preparations.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Diterpenos , Compostos de Epóxi , Fenantrenos , Espironolactona , Compostos de Epóxi/toxicidade , Fenantrenos/toxicidade , Fenantrenos/farmacologia , Diterpenos/farmacologia , Diterpenos/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Camundongos , Espironolactona/farmacologia , Masculino , Humanos , Sobrevivência Celular/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Células Hep G2RESUMO
Alzheimer's disease is associated with the misfolding and aggregation of two distinct proteins, beta-amyloid and tau. Previously, it has been shown that activation of the cytoprotective heat shock response (HSR) pathway reduces beta-amyloid toxicity. Here, we show that activation of the HSR is also protective against tau toxicity in a cell-autonomous manner. Overexpression of HSF-1, the master regulator of the HSR, ameliorates the motility defect and increases the lifespan of transgenic C. elegans expressing human tau. By contrast, RNA interference of HSF-1 exacerbates the motility defect and shortens lifespan. Targeting regulators of the HSR also affects tau toxicity. Additionally, two small-molecule activators of the HSR, Geranylgeranylacetone (GGA) and Arimoclomol (AC), have substantial beneficial effects. Taken together, this research expands the therapeutic potential of HSR manipulation to tauopathies and reveals that the HSR can impact both beta-amyloid and tau proteotoxicity in Alzheimer's disease.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Diterpenos , Resposta ao Choque Térmico , Proteínas tau , Proteínas tau/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Humanos , Diterpenos/farmacologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Animais Geneticamente Modificados , Longevidade/efeitos dos fármacos , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Fatores de TranscriçãoRESUMO
Colistin is one of the last-resort antibiotics in treating infections caused by multidrug-resistant (MDR) pathogens. Unfortunately, the emergence of colistin-resistant gram-negative strains limit its clinical application. Here, we identify an FDA-approved drug, valnemulin (Val), exhibit a synergistic effect with colistin in eradicating both colistin-resistant and colistin-susceptible gram-negative pathogens both in vitro and in the mouse infection model. Furthermore, Val acts synergistically with colistin in eliminating intracellular bacteria in vitro. Functional studies and transcriptional analysis confirm that the combinational use of Val and colistin could cause membrane permeabilization, proton motive force dissipation, reduction in intracellular ATP level, and suppression in bacterial motility, which result in bacterial membrane disruption and finally cell death. Our findings reveal the potential of Val as a colistin adjuvant to combat MDR bacterial pathogens and treat recalcitrant infections.
Assuntos
Antibacterianos , Colistina , Diterpenos , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas , Testes de Sensibilidade Microbiana , Colistina/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Camundongos , Diterpenos/farmacologia , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Bactérias Gram-Negativas/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , HumanosRESUMO
Tumor proliferation and metastasis are intricately linked to blood vessel formation, with vascular endothelial growth factor (VEGF) playing a pivotal role in orchestrating angiogenesis throughout tumor progression. Pseudolaric acid B (PAB) has emerged as a potent inhibitor of tumor cell proliferation, migration, and angiogenesis. In efforts to enhance its efficacy, 37 derivatives of PAB were synthesized and assessed for their capacity to suppress VEGF secretion in SiHa cells under hypoxic conditions. Notably, majority of these derivatives exhibited significant inhibition of VEGF protein secretion without inducing cytotoxicity. Among them, compound M2 displayed the most potent inhibitory activity, with an IC50 value of 0.68 µM, outperforming the lead compound PAB (IC50 = 5.44 µM). Compound M2 not only curbed the migration and angiogenesis of HUVECs under hypoxic conditions but also hindered the invasion of SiHa cells. Mechanistic investigations unveiled that compound M2 may impede the accumulation and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) in SiHa cells, thereby downregulating VEGF expression. This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis. Furthermore, compound M2 was observed to modulate the PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells, thereby regulating HIF-1α translation and synthesis. In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis.
Assuntos
Inibidores da Angiogênese , Antineoplásicos , Proliferação de Células , Diterpenos , Desenho de Fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Fator A de Crescimento do Endotélio Vascular , Humanos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Diterpenos/farmacologia , Diterpenos/síntese química , Diterpenos/química , Transdução de Sinais/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Animais , Movimento Celular/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismoRESUMO
C_(20)-diterpenoid alkaloids are mainly distributed in plants of genus Aconitum, Delphinium, and Consolida in the Ranunculaceae. Their chemical structures are mainly categorized into nine types such as atisines, denudatines, hetidines, and hetisines. Bioactivity studies have shown that C_(20)-diterpenoid alkaloids have exhibited superior anti-tumor, analgesic, antiarrhythmic, and anti-inflammatory effects. In this review, the chemical structures and biological activities of 190 C_(20)-diterpenoid alkaloids reported in the Ranunculaceae from 2002 to the present were summarized, so as to provide a reference for the subsequent research on C_(20)-diterpenoid alkaloids in plants of Ranunculaceae.
Assuntos
Alcaloides , Diterpenos , Ranunculaceae , Alcaloides/química , Alcaloides/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Animais , Humanos , Ranunculaceae/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Estrutura Molecular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/químicaRESUMO
In search for new molecules of diterpene origin with promising anticancer activity, two amino-derivatives (methyl maleopimarate aminoimide and methyl 1ß,13-epoxydihydroquinopimarate C4-hydrazone) were involved in the 4-component Ugi reaction (Ugi-4CR) and pseudo-7-component azido-Ugi condensation (azido-Ugi-7CR) to afford a series of adducts holding α-aminoacylamide and bis-1,5-disubstituted tetrazole substituents. The NCI-60 cancer cell panel screening revealed diterpene-type Ugi adducts 2, 5, and 6 with strong antiproliferative potency with GI50 in range of 1.2-15.4 µM. The high positive correlations with standard anticancer drugs suggest microtubules or progesterone and androgen receptors as possible targets of the synthesized compounds.
Assuntos
Antineoplásicos , Diterpenos , Tetrazóis , Humanos , Tetrazóis/química , Tetrazóis/síntese química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Amidas/químicaRESUMO
The prevalence of infections by methicillin-resistant Staphylococcus aureus (MRSA) has led to dramatically increased mortality and threated the public health worldwide. Pleuromutilin compound 14-O-[(4-(pyrrolidine-1-yl)-6-methylpyrimidine-2-yl) thioacetyl] mutilin (PMTM) is a new antibacterial agent with excellent antibacterial efficacy against Gram positive bacteria. For further developing PMTM as a potential drug against MRSA infections, the in vitro antibacterial efficacy and preclinical safety were explored in this study. The results revealed that PMTM presented the higher anti-MRSA activity, increasing post-antibiotic effect (PAE) and limited potential to develop resistance. In safety evaluation, PMTM demonstrated low cytotoxicity, poor hemolytic activity, tolerable oral acute toxic effects in rats, devoid of mutagenic response and weak inhibitory potential on CYP3A4, but displayed moderate potential hERG K+ channel inhibition. Furthermore, two salts of PMTM with sulfuric acid and hydrochloric acid were prepared and confirmed. The sulfate salt of PMTM exhibited the highest solubility based on powder dissolution experiments and was chosen to evaluate pharmacokinetics properties, in which it displayed improved mouse pharmacokinetics parameters and oral bioavailability. The present study successfully provides a good foundation of PMTM for new antibacterial drug development.
Assuntos
Antibacterianos , Diterpenos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Pleuromutilinas , Compostos Policíclicos , Ratos Sprague-Dawley , Animais , Compostos Policíclicos/farmacocinética , Compostos Policíclicos/farmacologia , Diterpenos/farmacocinética , Diterpenos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Masculino , Camundongos , Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Antibacterianos/toxicidade , Antibacterianos/administração & dosagem , Humanos , Ratos , FemininoRESUMO
Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer-associated death globally with a lack of efficient therapy. The pathogenesis of HCC is a complex and multistep process, highly reliant on de novo lipogenesis, from which tumor cells can incorporate fatty acids to satisfy the necessary energy demands of rapid proliferation and provide survival advantages. Triptolide (TP) is a bioactive ingredient exhibiting potent abilities of anti-proliferation and lipid metabolism regulation, but its clinical application is constrained because of its toxicity and non-specific distribution. The present study has developed galactosylated bovine serum albumin nanoparticles loaded with TP (Gal-BSA-TP NPs) to alleviate systemic toxicity and increase tumor-targeting and antitumor efficacy. Furthermore, Gal-BSA-TP NPs could inhibit de novo lipogenesis via the p53-SREBP1C-FASN pathway to deprive the fuel supply of HCC, offering a specific strategy for HCC treatment. In general, this study provided a biocompatible delivery platform for targeted therapy for HCC from the perspective of de novo lipogenesis.
Assuntos
Carcinoma Hepatocelular , Diterpenos , Compostos de Epóxi , Lipogênese , Neoplasias Hepáticas , Fenantrenos , Soroalbumina Bovina , Compostos de Epóxi/farmacologia , Compostos de Epóxi/administração & dosagem , Diterpenos/farmacologia , Diterpenos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Lipogênese/efeitos dos fármacos , Fenantrenos/farmacologia , Fenantrenos/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Animais , Humanos , Soroalbumina Bovina/química , Galactose , Camundongos , Células Hep G2 , Camundongos Nus , Progressão da Doença , Camundongos Endogâmicos BALB C , Nanopartículas , Linhagem Celular Tumoral , Masculino , Sistemas de Liberação de Medicamentos/métodos , Proliferação de Células/efeitos dos fármacosRESUMO
Apple ring rot, caused by the pathogenic fungus Botryosphaeria dothidea, has inflicted substantial economic losses and caused significant food safety concerns. In this study, a pimarane-type diterpenoid, diaporthein B (DTB), isolated from a marine-derived fungus, exhibited significant antifungal activity against B. dothidea, with an EC50 value of 8.8 µg/mL. Transcriptome, metabolome, and physiological assays revealed that DTB may target mitochondria and disrupt the tricarboxylic acid (TCA) cycle and oxidative phosphorylation processes. This interference led to increased accumulation of reactive oxygen species and subsequent lipid peroxidation, ultimately inhibiting fungal growth. Furthermore, DTB exhibited an inhibitory potency against apple ring rot at a concentration of 31.2 µg/mL, achieving rates ranging from 67.7 to 81.6% across four distinct apple cultivars. These results indicated that DTB could serve as a novel fungicide for controlling apple ring rot in apple cultivation, transportation, and storage.
Assuntos
Ascomicetos , Fungicidas Industriais , Malus , Doenças das Plantas , Malus/microbiologia , Malus/química , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Ascomicetos/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Diterpenos/farmacologia , Diterpenos/química , Frutas/microbiologia , Frutas/químicaRESUMO
Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge. Minnelide, a prodrug of triptolide currently being tested in clinical trials, has shown anti-tumorigenic activity in multiple malignancies via targeting super enhancers, Myc and anti-apoptotic pathways such as HSP70. Distinct super-enhancer landscape drives cancer stem cells (CSC) in TNBC subtype while inducing immune suppressive TME. We show that Minnelide selectively targets CSCs in human and murine TNBC cell lines compared to cell lines of luminal subtype by targeting Myc and HSP70. Minnelide in combination with cyclophosphamide significantly reduces the tumor growth and eliminates metastasis by reprogramming the tumor microenvironment and enhancing cytotoxic T cell infiltration in 4T1 tumor-bearing mice. Resection of residual tumors following the combination treatment leads to complete eradication of disseminated tumor cells as all mice are free of local and distant recurrences. All control mice showed recurrences within 3 weeks of post-resection while single Minnelide treatment delayed recurrence and one mouse was free of tumor. We provide evidence that Minnelide targets tumor intrinsic pathways and reprograms the immune suppressive microenvironment. Our studies also suggest that Minnelide in combination with cyclophosphamide may lead to durable responses in patients with basal/TNBC subtype warranting its clinical investigation.
Assuntos
Diterpenos , Compostos de Epóxi , Células-Tronco Neoplásicas , Fenantrenos , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Humanos , Animais , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/imunologia , Feminino , Camundongos , Linhagem Celular Tumoral , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Fenantrenos/farmacologia , Fenantrenos/uso terapêutico , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Camundongos Endogâmicos BALB C , OrganofosfatosRESUMO
We report the discovery of MED6-189, an analog of the kalihinol family of isocyanoterpene natural products that is effective against drug-sensitive and drug-resistant Plasmodium falciparum strains, blocking both asexual replication and sexual differentiation. In vivo studies using a humanized mouse model of malaria confirm strong efficacy of the compound in animals with no apparent hemolytic activity or toxicity. Complementary chemical, molecular, and genomics analyses revealed that MED6-189 targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. Its high potency, excellent therapeutic profile, and distinctive mode of action make MED6-189 an excellent addition to the antimalarial drug pipeline.
Assuntos
Antimaláricos , Apicoplastos , Diterpenos , Malária Falciparum , Plasmodium falciparum , Animais , Humanos , Camundongos , Antimaláricos/química , Antimaláricos/farmacologia , Apicoplastos/efeitos dos fármacos , Apicoplastos/metabolismo , Modelos Animais de Doenças , Resistência a Medicamentos/genética , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Mutação , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/genética , Diterpenos/química , Diterpenos/farmacologiaRESUMO
There has been no specific review on the secondary metabolites from soft corals of the genus Capnella till now. In this work, all secondary metabolites from different species of the title genus were described. It covered the first work from 1974 to May 2024, spanning five decades. In the viewpoint of the general structural features, these chemical constituents were classified into four groups: sesquiterpenes, diterpenes, steroids, and lipids. Additionally, the 1H and 13C NMR data of these metabolites were provided when available in the literature. Among them, sesquiterpenes were the most abundant chemical compositions from soft corals of the genus Capnella. A variety of pharmacological activities of these compounds were evaluated, such as cytotoxic, antibacterial, antifungal, and anti-inflammatory activities. In addition, the chemical synthesis works of several representative sesquiterpenes were provided. This review aims to provide an up-to-date knowledge of the chemical structures, pharmacological activities, and chemical synthesis of the chemical constituents from soft corals of the genus Capnella.
Assuntos
Antozoários , Antozoários/química , Animais , Espectroscopia de Ressonância Magnética , Metabolismo Secundário , Humanos , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Diterpenos/farmacologia , Diterpenos/química , Estrutura Molecular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Esteroides/química , Esteroides/farmacologiaRESUMO
Sphaerococcenol A is a cytotoxic bromoditerpene biosynthesized by the red alga Sphaerococcus coronopifolius. A series of its analogues (1-6) was designed and semi-synthesized using thiol-Michael additions and enone reduction, and the structures of these analogues were characterized by spectroscopic methods. Cytotoxic analyses (1-100 µM; 24 h) were accomplished on A549, DU-145, and MCF-7 cells. The six novel sphaerococcenol A analogues displayed an IC50 range between 14.31 and 70.11 µM on A549, DU-145, and MCF-7 malignant cells. Compound 1, resulting from the chemical addition of 4-methoxybenzenethiol, exhibited the smallest IC50 values on the A549 (18.70 µM) and DU-145 (15.82 µM) cell lines, and compound 3, resulting from the chemical addition of propanethiol, exhibited the smallest IC50 value (14.31 µM) on MCF-7 cells. The highest IC50 values were exhibited by compound 4, suggesting that the chemical addition of benzylthiol led to a loss of cytotoxic activity. The remaining chemical modifications were not able to potentiate the cytotoxicity of the original compounds. Regarding A549 cell viability, analogue 1 exhibited a marked effect on mitochondrial function, which was accompanied by an increase in ROS levels, Caspase-3 activation, and DNA fragmentation and condensation. This study opens new avenues for research by exploring sphaerococcenol A as a scaffold for the synthesis of novel bioactive molecules.
Assuntos
Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Células MCF-7 , Apoptose/efeitos dos fármacos , Desenho de Fármacos , Rodófitas/química , Sobrevivência Celular/efeitos dos fármacos , Células A549 , Relação Estrutura-Atividade , Diterpenos/farmacologia , Diterpenos/síntese química , Diterpenos/química , Espécies Reativas de Oxigênio/metabolismo , Concentração Inibidora 50RESUMO
Euphorbia kansui, a toxic Chinese medicine used for more than 2000 years, has the effect of "purging water to promote drinking" and "reducing swelling and dispersing modules". Diterpenes and triterpenes are the main bioactive components of E. kansui. Among them, ingenane-type diterpenes have multiple biological activities as a protein kinase C δ (PKC-δ) activator, which have previously been shown to promote anti-proliferative and pro-apoptotic effects in several human cancer cell lines. However, the activation of PKC subsequently promoted the survival of macrophages. Recently, we found that 13-hydroxyingenol-3-(2,3-dimethylbutanoate)-13-dodecanoate (compound A) from E. kansui showed dual bioactivity, including the inhibition of tumor-cell-line proliferation and regulation of macrophage polarization. This study identifies the possible mechanism of compound A in regulating the polarization state of macrophages, by regulating PKC-δ-extracellular signal regulated kinases (ERK) signaling pathways to exert anti-tumor immunity effects in vitro, which might provide a new treatment method from the perspective of immune cell regulation.
Assuntos
Apoptose , Diterpenos , Euphorbia , Macrófagos , Transdução de Sinais , Euphorbia/química , Diterpenos/farmacologia , Diterpenos/química , Apoptose/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Animais , Camundongos , Transdução de Sinais/efeitos dos fármacos , Humanos , Proteína Quinase C/metabolismo , Células RAW 264.7 , Proliferação de Células/efeitos dos fármacos , Proteína Quinase C-delta/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacosRESUMO
The enmein-type diterpenoids are a class of anticancer ent-Kaurane diterpnoids that have received much attention in recent years. Herein, a novel 1,14-epoxy enmein-type diterpenoid 4, was reported in this project for the first time. A series of novel enmein-type diterpenoid derivatives were also synthesized and tested for anticancer activities. Among all the derivatives, compound 7h exhibited the most significant inhibitory effect against A549 cells (IC50 = 2.16 µM), being 11.03-folds better than its parental compound 4. Additionally, 7h exhibited relatively weak anti-proliferative activity (IC50 > 100 µM) against human normal L-02 cells, suggesting that it had excellent anti-proliferative selectivity for cancer cells. Mechanism studies suggested that 7h induced G0/G1 arrest and apoptosis in A549 cells by inhibiting the PI3K/AKT/mTOR pathway. This process was associated with elevated intracellular ROS levels and collapsed MMP. In summary, these data identified 7h as a promising lead compound that warrants further investigation of its anticancer properties.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Diterpenos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Humanos , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/síntese química , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células A549 , Desenho de Fármacos , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Espécies Reativas de Oxigênio/metabolismoRESUMO
OBJECTIVE: The aim of this study was to optimize the formulation of a C60-modified self-microemulsifying drug delivery system loaded with triptolide (C60-SMEDDS/TP) and evaluate the cytoprotective effect of the C60-SMEDDS/TP on normal human cells. RESULTS: The C60-SMEDDS/TP exhibited rapid emulsification, an optimal particle size distribution of 50 ± 0.19 nm (PDI 0.211 ± 0.049), and a near-neutral zeta potential of -1.60 mV. The release kinetics of TP from the C60-SMEDDS/TP exhibited a sustained release profile and followed pseudo-first-order release kinetics. Cellular proliferation and apoptosis analysis indicated that the C60-SMEDDS/TP (with a mass ratio of TP: DSPE-PEG-C60 = 1:10) exhibited lower toxicity towards L02 and GES-1 cells. This was demonstrated by a higher IC50 (40.88 nM on L02 cells and 17.22 nM on GES-1 cells) compared to free TP (21.3 nM and 11.1 nM), and a lower apoptosis rate (20.8% on L02 cells and 26.3% on GES-1 cells, respectively) compared to free TP (50.5% and 47.0%) at a concentration of 50 nM. In comparison to the free TP group, L02 cells and GES-1 cells exposed to the C60-SMEDDS/TP exhibited a significant decrease in intracellular ROS and an increase in mitochondrial membrane potential (ΔψM). On the other hand, the C60-SMEDDS/TP demonstrated a similar inhibitory effect on BEL-7402 cells (IC50 = 28.9 nM) and HepG2 cells (IC50 = 107.6 nM), comparable to that of the free TP (27.2 nM and 90.4 nM). The C60-SMEDDS/TP group also exhibited a similar intracellular level of ROS and mitochondrial membrane potential compared to the SMEDDS/TP and free TP groups. METHOD: Fullerenol-Grafted Distearoyl Phosphatidylethanolamine-Polyethylene Glycol (DSPE-PEG-C60) was synthesized and applied in the self-microemulsifying drug delivery system. The C60-SMEDDS/TP was formulated using Cremophor EL, medium-chain triglycerides (MCT), PEG-400, and DSPE-PEG-C60, and loaded with triptolide (TP). The toxicity and bioactivity of the C60-SMEDDS/TP were assessed using normal human liver cell lines (L02 cells), normal human gastric mucosal epithelial cell lines (GES-1 cells), and liver cancer cell lines (BEL-7402 cells and HepG2 cells). The production of reactive oxygen species (ROS) after the C60-SMEDDS/TP treatment was assessed using 2',7'-dichlorofluorescein diacetate (DCFDA) staining. The alterations in mitochondrial membrane potential (ΔψM) were assessed by measuring JC-1 fluorescence. CONCLUSIONS: The cytoprotection provided by the C60-SMEDDS/TP favored normal cells (L02 and GES-1) over tumor cells (BEL-7402 and HepG2 cells) in vitro. This suggests a promising approach for the safe and effective treatment of TP.
Assuntos
Apoptose , Diterpenos , Sistemas de Liberação de Medicamentos , Emulsões , Compostos de Epóxi , Fulerenos , Fenantrenos , Humanos , Diterpenos/farmacologia , Diterpenos/química , Fenantrenos/química , Fenantrenos/farmacologia , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Fulerenos/química , Fulerenos/farmacologia , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Tamanho da Partícula , Proliferação de Células/efeitos dos fármacosRESUMO
Cholestatic liver injury results from the accumulation of toxic bile acids in the liver, presenting a therapeutic challenge with no effective treatment available to date. Andrographolide (AP) has exhibited potential as a treatment for cholestatic liver disease. However, its limited oral bioavailability poses a significant obstacle to harnessing its potent therapeutic properties and restricts its clinical utility. This limitation is potentially attributed to the involvement of gut microbiota in AP metabolism. In our study, employing pseudo-germ-free, germ-free and strain colonization animal models, along with 16S rRNA and shotgun metagenomic sequencing analysis, we elucidate the pivotal role played by gut microbiota in the C-sulfonate metabolism of AP, a process profoundly affecting its bioavailability and anti-cholestatic efficacy. Subsequent investigations pinpoint a specific enzyme, adenosine-5'-phosphosulfate (APS) reductase, predominantly produced by Desulfovibrio piger, which catalyzes the reduction of SO42- to HSO3-. HSO3- subsequently interacts with AP, targeting its C=C unsaturated double bond, resulting in the formation of the C-sulfonate metabolite, 14-deoxy-12(R)-sulfo andrographolide (APM). Inhibition of APS reductase leads to a notable enhancement in AP bioavailability and anti-cholestatic efficacy. Furthermore, employing RNA sequencing analysis and farnesoid X receptor (FXR) knockout mice, our findings suggest that AP may exert its anti-cholestatic effects by activating the FXR pathway to promote bile acid efflux. In summary, our study unveils the significant involvement of gut microbiota in the C-sulfonate metabolism of AP and highlights the potential benefits of inhibiting APS reductase to enhance its therapeutic effects. These discoveries provide valuable insights into enhancing the clinical applicability of AP as a promising treatment for cholestatic liver injury.
Assuntos
Disponibilidade Biológica , Diterpenos , Microbioma Gastrointestinal , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Diterpenos/metabolismo , Diterpenos/farmacologia , Camundongos , Colestase/metabolismo , Colestase/tratamento farmacológico , Colestase/microbiologia , Masculino , RNA Ribossômico 16S/genética , Ácidos e Sais Biliares/metabolismo , Bactérias/metabolismo , Bactérias/classificação , Bactérias/genética , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Humanos , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Fígado/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Modelos Animais de DoençasRESUMO
BACKGROUND: In recent decades, natural compounds have been considered a significant source of new antitumor medicines due to their unique advantages. Several in vitro and in vivo studies have focused on the effect of terpenoids on apoptosis mediated by mitochondria in malignant cells. RECENT FINDINGS: In this review article, we focused on six extensively studied terpenoids, including sesquiterpenes (dihydroartemisinin and parthenolide), diterpenes (oridonin and triptolide), and triterpenes (betulinic acid and oleanolic acid), and their efficacy in targeting mitochondria to induce cell death. Terpenoid-induced mitochondria-related cell death includes apoptosis, pyroptosis, necroptosis, ferroptosis, autophagy, and necrosis caused by mitochondrial permeability transition. Apoptosis and autophagy interact in meaningful ways. In addition, in view of several disadvantages of terpenoids, such as low stability and bioavailability, advances in research on combination chemotherapy and chemical modification were surveyed. CONCLUSION: This article deepens our understanding of the association between terpenoids and mitochondrial cell death, presenting a hypothetical basis for the use of terpenoids in anticancer management.
Assuntos
Mitocôndrias , Neoplasias , Terpenos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Terpenos/farmacologia , Terpenos/uso terapêutico , Apoptose/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Diterpenos/farmacologia , Diterpenos/uso terapêuticoRESUMO
Psoriasis, an immune-mediated inflammatory skin disorder, seriously affects the quality of life of nearly four percent of the world population. Euphorbia helioscopia L. is the monarch constituent of Chinese ZeQi powder preparation for psoriasis, so it is necessary to illustrate its active ingredients. Thus, twenty-three diterpenoids, including seven new ones, were isolated from the whole herb of E. helioscopia L. Compounds 1 and 2, each featuring a 2,3-dicarboxylic functionality, are the first examples in the ent-2,3-sceo-atisane or the ent-2,3-sceo-abietane family. Extensive spectroscopic analysis (1D, 2D NMR, and HRMS data) and computational methods were used to confirm their structures and absolute configurations. According to the previous study and NMR data from the jatropha diterpenes obtained in this study, some efficient 1H NMR spectroscopic rules for assigning the relative configurations of 3α-benzyloxy-jatroph-11E-ene and 7,8-seco-3α-benzyloxy-jatropha-11E-ene were summarized. Moreover, the hyperproliferation of T cells and keratinocytes is considered a key pathophysiology of psoriasis. Anti-proliferative activities against induced T/B lymphocytes and HaCaT cells were tested, and IC50 values of some compounds ranged from 6.7 to 31.5 µM. Compounds 7 and 11 reduced the secretions of IFN-γ and IL-2 significantly. Further immunofluorescence experiments and a docking study with NF-κB P65 showed that compound 13 interfered with the proliferation of HaCaT cells by inhibiting the NF-κB P65 phosphorylation at the protein level.
Assuntos
Diterpenos , Euphorbia , Psoríase , Euphorbia/química , Humanos , Psoríase/tratamento farmacológico , Psoríase/patologia , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Queratinócitos/efeitos dos fármacosRESUMO
Eight novel clerodane diterpenoids (1-8) were isolated from the twigs of Casearia graveolens. Their structures were elucidated through comprehensive nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), and electronic circular dichroism (ECD) analyses. In addition to structural determination, surface plasmon resonance (SPR) assays were conducted to investigate molecular interactions, revealing that compound 8 exhibited high affinity for vascular endothelial growth factor receptor 2 (VEGFR2), a key regulator of tumor angiogenesis. Subsequent in vivo experiments demonstrated that compound 8 effectively inhibited angiogenesis and displayed significant antitumor activity by suppressing tumor proliferation and metastasis in zebrafish xenograft models. These findings suggest that compound 8 holds promise as an anticancer lead compound targeting VEGFR-2 to obstruct tumor angiogenesis.