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1.
Molecules ; 29(9)2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38731397

RESUMO

A chemical investigation of the arils of Torreya grandis led to the isolation of seven abietane-type diterpenoids (compounds 1-7) including three previously undescribed compounds, one unreported natural product, and three known analogs. The structures of these compounds were determined by means of spectroscopy, single-crystal X-ray diffraction, and ECD spectra. An antibacterial activity assay showed that compounds 5 and 6 had significant inhibitory effects on methicillin-resistant Staphylococcus aureus, with MIC values of 100 µM. Moreover, compounds 1, 3, 4, and 7 exhibited anti-neuroinflammatory activity in LPS-stimulated BV-2 microglia cells, with the IC50 values ranging from 38.4 to 67.9 µM.


Assuntos
Abietanos , Antibacterianos , Abietanos/química , Abietanos/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Testes de Sensibilidade Microbiana , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Animais , Estrutura Molecular , Linhagem Celular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Lipopolissacarídeos/farmacologia
2.
Int J Mol Sci ; 25(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38731894

RESUMO

Triptolide is a natural compound in herbal remedies with anti-inflammatory and anti-proliferative properties. We studied its effects on critical signaling processes within the cell, including Notch1 and STAT3 signaling. Our research showed that triptolide reduces cancer cell proliferation by decreasing the expression of downstream targets of these signals. The levels of each signal-related protein and mRNA were analyzed using Western blot and qPCR methods. Interestingly, inhibiting one signal with a single inhibitor alone did not significantly reduce cancer cell proliferation. Instead, MTT assays showed that the simultaneous inhibition of Notch1 and STAT3 signaling reduced cell proliferation. The effect of triptolide was similar to a combination treatment with inhibitors for both signals. When we conducted a study on the impact of triptolide on zebrafish larvae, we found that it inhibited muscle development and interfered with muscle cell proliferation, as evidenced by differences in the staining of myosin heavy chain and F-actin proteins in confocal fluorescence microscopy. Additionally, we noticed that inhibiting a single type of signaling did not lead to any significant muscle defects. This implies that triptolide obstructs multiple signals simultaneously, including Notch1 and STAT3, during muscle development. Chemotherapy is commonly used to treat cancer, but it may cause muscle loss due to drug-related adverse reactions or other complex mechanisms. Our study suggests that anticancer agents like triptolide, inhibiting essential signaling pathways including Notch1 and STAT3 signaling, may cause muscle atrophy through anti-proliferative activity.


Assuntos
Proliferação de Células , Diterpenos , Compostos de Epóxi , Fenantrenos , Receptor Notch1 , Fator de Transcrição STAT3 , Transdução de Sinais , Peixe-Zebra , Animais , Compostos de Epóxi/farmacologia , Fenantrenos/farmacologia , Diterpenos/farmacologia , Fator de Transcrição STAT3/metabolismo , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Humanos , Receptor Notch1/metabolismo , Receptor Notch1/genética , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Linhagem Celular Tumoral , Receptores Notch/metabolismo
3.
Int Immunopharmacol ; 133: 112170, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38691919

RESUMO

Acute kidney injury (AKI) is characterized by a sudden decline in renal function. Traditional Chinese medicine has employed Fuzi for kidney diseases; however, concerns about neurotoxicity and cardiotoxicity have constrained its clinical use. This study explored mesaconine, derived from processed Fuzi, as a promising low-toxicity alternative for AKI treatment. In this study, we assessed the protective effects of mesaconine in gentamicin (GM)-induced NRK-52E cells and AKI rat models in vitro and in vivo, respectively. Mesaconine promotes the proliferation of damaged NRK-52E cells and down-regulates intracellular transforming growth factor ß1 (TGF-ß1) and kidney injury molecule 1 (KIM-1) to promote renal cell repair. Concurrently, mesaconine restored mitochondrial morphology and permeability transition pores, reversed the decrease in mitochondrial membrane potential, mitigated mitochondrial dysfunction, decreased ATP production, inhibited inflammatory factor release, and reduced early apoptosis rates. In vivo, GM-induced AKI rat models exhibited elevated AKI biomarkers, in which mesaconine was effectively reduced, indicating improved renal function. Mesaconine enhanced superoxide dismutase activity, reduced malondialdehyde content, alleviated inflammatory infiltrate, mitigated tubular and glomerular lesions, and downregulated NF-κB (nuclear factor-κb) p65 expression, leading to decreased tumor necrosis factor-α (TNF-α) and IL-1ß (interleukin-1ß) levels in GM-induced AKI animals. Furthermore, mesaconine inhibited the expression of renal pro-apoptotic proteins (Bax, cytochrome c, cleaved-caspase 9, and cleaved-caspase 3) and induced the release of the anti-apoptotic protein bcl-2, further suppressing apoptosis. This study highlighted the therapeutic potential of mesaconine in GM-induced AKI. Its multifaceted mechanisms, including the restoration of mitochondrial dysfunction, anti-inflammatory and antioxidant effects, and apoptosis mitigation, make mesaconine a promising candidate for further exploration in AKI management.


Assuntos
Aconitum , Injúria Renal Aguda , Apoptose , Rim , Mitocôndrias , Ratos Sprague-Dawley , Animais , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Apoptose/efeitos dos fármacos , Aconitum/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Masculino , Ratos , Linhagem Celular , Rim/efeitos dos fármacos , Rim/patologia , Gentamicinas/toxicidade , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Aconitina/análogos & derivados , Aconitina/farmacologia , Aconitina/uso terapêutico , Modelos Animais de Doenças , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Diterpenos
4.
Reprod Domest Anim ; 59(5): e14595, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38773768

RESUMO

Oocyte maturation involves both nuclear and cytoplasmic maturation. Mogroside V (MV) has been shown to enhance nuclear maturation, mitochondrial content, and developmental potential of porcine oocyte during in vitro maturation (IVM). However, the impact of MV on cytoplasmic maturation and its underlying mechanisms are not understood. This study aimed to assess the effect of MV on cytoplasmic maturation. Germinal vesicle (GV) oocytes treated with MV exhibited a noticeable increase in cortical granules (CGs) formation. Additionally, MV enhanced the expression of NNAT and improved glucose uptake in mature oocytes. Further insights were gained through Smart-seq2 analysis of RNA isolated from 100 oocytes. A total of 11,274 and 11,185 transcripts were identified in oocytes treated with and without MV, respectively. Among quantified genes, 438 differentially expressed genes (DEGs) were identified for further analysis. Gene Ontology (GO) enrichment analysis indicated that these DEGs were primarily involved in DNA repair regulation, cellular response to DNA damage, intracellular components, and organelles. Furthermore, the DEGs were significantly enriched in three KEGG pathways: fatty acid synthesis, pyruvate metabolism, and WNT signalling. To validate the results, lipid droplets (LD) and triglyceride (TG) were examined. MV led to an increase in the accumulation of LD and TG production in mature oocytes. These findings suggest that MV enhances cytoplasmic maturation by promoting lipid droplet synthesis. Overall, this study provides valuable insights into the mechanisms through which MV improves oocyte quality during IVM. The results have significant implications for research in livestock reproduction and offer guidance for future studies in this field.


Assuntos
Técnicas de Maturação in Vitro de Oócitos , Oócitos , Animais , Técnicas de Maturação in Vitro de Oócitos/veterinária , Oócitos/efeitos dos fármacos , Feminino , Suínos , Gotículas Lipídicas/metabolismo , Diterpenos/farmacologia , Triglicerídeos/metabolismo , Triterpenos
5.
Bioorg Chem ; 147: 107417, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38701596

RESUMO

Marine natural products play an important role in biopesticides. Seven new secondary metabolites with different structural classes, including two cycloheptapeptides, scortide A (1) and scortide B (2), two 19-nor-diterpenoids, talascortene H (3) and talascortene I (4), two diterpenoid acids, talascortene J (5) and talascortene K (6), and one triterpenoid, talascortene L (7) were isolated and identified from the sea-anemone-derived endozoic fungus Talaromyces scorteus AS-242. Their structures were comprehensively assigned by spectroscopic data analysis, single-crystal X-ray diffraction, tandem mass spectrometry, and electronic circular dichroism (ECD) calculations. The result of the antimicrobial assay demonstrated that compounds 1 - 6 have inhibitory activity against several human, aquatic, and plant pathogens with minimum inhibitory concentration (MIC) values ranging from 1 to 64 µg/mL. Specially, compounds 2 and 4 showed significant activities against the pathogenic fungus Curvularia spicifera with the MIC value of 1 µg/mL, providing an experimental basis of 2 and 4 with the potential as lead compounds to be developed into biopesticides.


Assuntos
Testes de Sensibilidade Microbiana , Talaromyces , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Relação Dose-Resposta a Droga , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Fungicidas Industriais/isolamento & purificação , Estrutura Molecular , Relação Estrutura-Atividade , Talaromyces/química , Talaromyces/metabolismo , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia
6.
Bull Exp Biol Med ; 176(5): 576-580, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38724808

RESUMO

We performed a comparative in vitro study of the involvement of NF-κB, PI3K, cAMP, ERK1/2, p38, JAKs, STAT3, JNK, and p53-dependent intracellular signaling in the functioning of neural stem cells (NSC) under the influence of basic fibroblast growth factor (FGF) and FGF receptor agonist, diterpene alkaloid songorine. The significant differences in FGFR-mediated intracellular signaling in NSC were revealed for these ligands. In both cases, stimulation of progenitor cell proliferation occurs with the participation of NF-κB, PI3K, ERK1/2, JAKs, and STAT3, while JNK and p53, on the contrary, inhibit cell cycle progression. However, under the influence of songorin, cAMP- and p38-mediated cascades are additionally involved in the transmission of the NSC division-activating signal. In addition, unlike FGF, the alkaloid stimulates progenitor cell differentiation by activating ERK1/2, p38, JNK, p53, and STAT3.


Assuntos
Diferenciação Celular , Proliferação de Células , Diterpenos , Células-Tronco Neurais , Receptores de Fatores de Crescimento de Fibroblastos , Fator de Transcrição STAT3 , Transdução de Sinais , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Animais , Fator de Transcrição STAT3/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/agonistas , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Diferenciação Celular/efeitos dos fármacos , NF-kappa B/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/agonistas , Fosfatidilinositol 3-Quinases/metabolismo , Alcaloides/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , AMP Cíclico/metabolismo , Células Cultivadas , Ratos
7.
Sci Total Environ ; 931: 173024, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38719048

RESUMO

Among the problems caused by water eutrophication, the issue of odor compounds has attracted notable attention. ß-Cyclocitral, a widely distributed and versatile odor compound, is commonly derived from both algae and aquatic plants. Planting aquatic plants is a common method of water purification. However, there is limited study on their impact on ß-cyclocitral levels in water. Here, we conducted a study on the ß-cyclocitral levels in water and the submerged plant leaves under three nutrient levels and six plant density treatments. Our findings revealed the following: (1) Chlorophyll-a (Chla), ß-cyclocitral in the water (Wcyc), ß-cyclocitral in Potamogeton lucens leaves (Pcyc) and the biomass of the submerged plants increase with rising nutrient concentration, which increased about 83 %, 95 %, 450 %, 320 % from eutrophic treatment to oligotrophic treatment, respectively. (2) In water, ß-cyclocitral is influenced not only by algae but also by submerged plants, with primary influencing factors varying across different nutrient levels and plant densities. The main source of ß-cyclocitral in water becomes from plants to algae as the water eutrophication and plant density decrease. (3) As submerged plants have the capability to emit ß-cyclocitral, the release of ß-cyclocitral increases with the density of submerged plants. Hence, when considering planting submerged plants for water purification purposes, it is crucial to carefully manage submerged plant density to mitigate the risk of odor pollution emanating from aquatic plants. This study offers fresh insights into selecting optimal water density for submerged plants and their role in mitigating the release of ß-cyclocitral.


Assuntos
Eutrofização , Odorantes , Poluentes Químicos da Água , Odorantes/análise , Poluentes Químicos da Água/análise , Aldeídos/análise , Plantas , Nutrientes/análise , Monitoramento Ambiental , Diterpenos
8.
Int J Nanomedicine ; 19: 3737-3751, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38699684

RESUMO

Background: Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, when combined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy. Methods: In this study, we synthesized a pH/ROS dual-responsive mPEG-TK-PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG-TK-PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice. Results: The mPEG-TK-PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity. Conclusion: Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.


Assuntos
Apoptose , Clorofilídeos , Diterpenos , Neoplasias Hepáticas , Camundongos Nus , Fenantrenos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Espécies Reativas de Oxigênio , Animais , Humanos , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Células Hep G2 , Neoplasias Hepáticas/tratamento farmacológico , Porfirinas/química , Porfirinas/farmacologia , Porfirinas/administração & dosagem , Porfirinas/farmacocinética , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/farmacocinética , Diterpenos/administração & dosagem , Concentração de Íons de Hidrogênio , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Apoptose/efeitos dos fármacos , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Compostos de Epóxi/administração & dosagem , Nanopartículas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Liberação Controlada de Fármacos , Proliferação de Células/efeitos dos fármacos , Polietilenoglicóis/química , Terapia Combinada
9.
J Exp Clin Cancer Res ; 43(1): 97, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561833

RESUMO

BACKGROUND: CAR T cell therapy is a promising approach to improve outcomes and decrease toxicities for patients with cancer. While extraordinary success has been achieved using CAR T cells to treat patients with CD19-positive malignancies, multiple obstacles have so far limited the benefit of CAR T cell therapy for patients with solid tumors. Novel manufacturing and engineering approaches show great promise to enhance CAR T cell function against solid tumors. However, similar to single agent chemotherapy approaches, CAR T cell monotherapy may be unable to achieve high cure rates for patients with difficult to treat solid tumors. Thus, combinatorial drug plus CAR T cell approaches are likely required to achieve widespread clinical success. METHODS: We developed a novel, confocal microscopy based, high-content screen to evaluate 1114 FDA approved drugs for the potential to increase expression of the solid tumor antigen B7-H3 on the surface of osteosarcoma cells. Western blot, RT-qPCR, siRNA knockdown and flow cytometry assays were used to validate screening results and identify mechanisms of drug-induced B7-H3 upregulation. Cytokine and cytotoxicity assays were used to determine if drug pre-treatment enhanced B7-H3-CAR T cell effector function. RESULTS: Fifty-five drugs were identified to increase B7-H3 expression on the surface of LM7 osteosarcoma cells using a novel high-content, high-throughput screen. One drug, ingenol-3-angelate (I3A), increased B7-H3 expression by up to 100%, and was evaluated in downstream experiments. Validation assays confirmed I3A increased B7-H3 expression in a biphasic dose response and cell dependent fashion. Mechanistic studies demonstrated that I3A increased B7-H3 (CD276) mRNA, total protein, and cell surface expression via protein kinase C alpha activation. Functionally, I3A induced B7-H3 expression enhanced B7-H3-CAR T cell function in cytokine production and cytotoxicity assays. CONCLUSIONS: This study demonstrates a novel high-content and high-throughput screen can identify drugs to enhance CAR T cell activity. This and other high-content technologies will pave the way to develop clinical trials implementing rational drug plus CAR T cell combinatorial therapies. Importantly, the technique could also be repurposed for an array of basic and translational research applications where drugs are needed to modulate cell surface protein expression.


Assuntos
Neoplasias Ósseas , Diterpenos , Osteossarcoma , Humanos , Proteína Quinase C-alfa/metabolismo , Antígenos B7/genética , Antígenos B7/metabolismo , Osteossarcoma/metabolismo , Neoplasias Ósseas/patologia , Linfócitos T , Citocinas/metabolismo , Linhagem Celular Tumoral
10.
Physiol Plant ; 176(2): e14277, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38566271

RESUMO

In order to maintain the dynamic physiological balance, plants are compelled to adjust their energy metabolism and signal transduction to cope with the abiotic stresses caused by complex and changeable environments. The diterpenoid natural compound and secondary metabolites, sclareol, derived from Salvia sclarea, has gained significant attention owing to its economic value as a spice material and diverse physiological activities. Here, we focused on the roles and regulatory mechanisms of the sclareol diterpene synthase gene SsdTPS in the resistance of S. sclarea to abiotic stresses. Our results suggested that abiotic stresses could induce the response and upregulation of SsdTPS expression and isoprenoid pathway in S. sclarea. Ectopic expression of SsdTPS conferred drought tolerance in transgenic Arabidopsis, compared with wild-type. Overexpression of SsdTPS enhanced the transcription of ABA signal transduction synthetic regulators and induced the positive feedback upregulating key regulatory genes in the MEP pathway, thereby promoting the increase of ABA content and improving drought tolerance in transgenic plants. In addition, SsdTPS-overexpressed transgenic Arabidopsis improved the responses of stomatal regulatory genes and ROS scavenging enzyme activities and gene expression to drought stress. This promoted the stomatal closure and ROS reduction, thus enhancing water retention capacity and reducing oxidative stress damage. These findings unveil the potentially positive role of SsdTPS in orchestrating multiple regulatory mechanisms and maintaining homeostasis for improved abiotic stress resistance in S. sclarea, providing a novel insight into strategies for promoting drought resistance and cultivating highly tolerant plants.


Assuntos
Arabidopsis , Diterpenos , Arabidopsis/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Secas , Retroalimentação , Plantas Geneticamente Modificadas/genética , Estresse Fisiológico/genética , Terpenos , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismo , Ácido Abscísico/farmacologia
11.
Int Ophthalmol ; 44(1): 168, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38573375

RESUMO

PURPOSE: To investigate the change in tear production associated with general anesthesia and the protective effect of vitamin A palmitate eye gel on the ocular surface during general anesthesia. METHODS: This double-blind, randomized clinical trial included patients undergoing non-ophthalmic surgery under general anesthesia who randomly received vitamin A palmitate eye gel and taping for one eye (Group A, n = 60) or taping alone for the other eye (Group B, n = 60). Symptom assessment in dry eye (SANDE) score, tear film break-up time (TBUT), corneal fluorescein staining (CFS) score, and Schirmer tear test I (STT-1) were analyzed under a hand-held slit lamp before anesthesia (T0), 0.5 h postoperatively (T1), and 24 h postoperatively (T2). RESULTS: At 0.5 h postoperatively, an increase in CFS score was observed in both groups (P < 0.05 in Group A and P < 0.01 in Group B), and the participants in Group A had less corneal abrasions than those in Group B. STT-1 significantly increased in Group A (P < 0.05), while it significantly decreased in Group B (P < 0.001). The changes between the two groups were statistically significant (P < 0.001). At 24 h postoperatively, both CFS score and STT-1 almost returned to baseline levels in the two groups. In both groups, the SANDE score and TBUT showed little change at 0.5 h and 24 h postoperatively (all P > 0.05). CONCLUSION: Vitamin A palmitate eye gel effectively protected the ocular surface and aqueous supplementation during general anesthesia. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (ChiCTR2100052140) on 20/10/2021.


Assuntos
Diterpenos , Olho , Humanos , Anestesia Geral , Ésteres de Retinil , Géis
12.
PLoS One ; 19(4): e0299920, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38630658

RESUMO

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. However, the HCC treatment is still challenging. Herein, we aimed to reveal the anti-tumor effect of Jolkinolide B in HCC cell lines Huh-7 and SK-Hep-1. The results showed that Jolkinolide B inhibited the migration, invasion, and epithelial-to-mesenchymal transition(EMT) of HCC cells. In addition, Jolkinolide B induced HCC cell apoptosis by upregulating Bax and downregulating BCL-2 expressions. Furthermore, we demonstrated that Jolkinolide B inactivated the ß-catenin signaling and reduced Musashi-2 expression. Finally, we revealed that Musashi-2 overexpression reversed the Jolkinolide B-induced anti-HCC effect. Overall, we proved that Jolkinolide B is a potential candidate for treating HCC.


Assuntos
Carcinoma Hepatocelular , Diterpenos , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Diterpenos/farmacologia , Movimento Celular , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Proliferação de Células
13.
J Am Chem Soc ; 146(15): 10393-10406, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38569115

RESUMO

Covalent chemistry coupled with activity-based protein profiling (ABPP) offers a versatile way to discover ligands for proteins in native biological systems. Here, we describe a set of stereo- and regiochemically defined spirocycle acrylamides and the analysis of these electrophilic "stereoprobes" in human cancer cells by cysteine-directed ABPP. Despite showing attenuated reactivity compared to structurally related azetidine acrylamide stereoprobes, the spirocycle acrylamides preferentially liganded specific cysteines on diverse protein classes. One compound termed ZL-12A promoted the degradation of the TFIIH helicase ERCC3. Interestingly, ZL-12A reacts with the same cysteine (C342) in ERCC3 as the natural product triptolide, which did not lead to ERCC3 degradation but instead causes collateral loss of RNA polymerases. ZL-12A and triptolide cross-antagonized one another's protein degradation profiles. Finally, we provide evidence that the antihypertension drug spironolactone─previously found to promote ERCC3 degradation through an enigmatic mechanism─also reacts with ERCC3_C342. Our findings thus describe monofunctional degraders of ERCC3 and highlight how covalent ligands targeting the same cysteine can produce strikingly different functional outcomes.


Assuntos
Acrilamida , Diterpenos , Fenantrenos , Humanos , Cisteína/química , Proteômica , Compostos de Epóxi
14.
J Agric Food Chem ; 72(15): 8704-8714, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38572931

RESUMO

Miltiradiene serves as a crucial precursor in the synthesis of various high-value abietane-type diterpenes, exhibiting diverse pharmacological activities. Previous efforts to enhance miltiradiene production have primarily focused on the mevalonate acetate (MVA) pathway. However, limited emphasis has been placed on optimizing the supply of acetyl-CoA and NADPH. In this study, we constructed a platform yeast strain for miltiradiene production by reinforcing the biosynthetic pathway of geranylgeranyl diphosphate (GGPP) and acetyl-CoA, and addressing the imbalance between the supply and demand of the redox cofactor NADPH within the cytoplasm, resulting in an increase in miltiradiene yield to 1.31 g/L. Furthermore, we conducted modifications to the miltiradiene synthase fusion protein tSmKSL1-CfTPS1. Finally, the comprehensive engineering strategies and protein modification strategies culminated in 1.43 g/L miltiradiene in the engineered yeast under shake flask culture conditions. Overall, our work established efficient yeast cell factories for miltiradiene production, providing a foothold for heterologous biosynthesis of abietane-type diterpenes.


Assuntos
Diterpenos , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Abietanos , Acetilcoenzima A/metabolismo , NADP/metabolismo , Diterpenos/metabolismo , Engenharia Metabólica/métodos
15.
PLoS One ; 19(4): e0294932, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38603666

RESUMO

An important dietary source of physiologically active compounds, coffee also contains phenolic acids, diterpenes, and caffeine. According to a certain study, some coffee secondary metabolites may advantageously modify a number of anti-cancer defense systems. This research looked at a few coffee chemical structures in terms of edge locating numbers or edge metric size to better understand the mechanics of coffee molecules. Additionally, this research includes graph theoretical properties of coffee chemical structures. The chemicals found in coffee, such as caffeine, diterpene or cafestol, kahweol, chlorogenic, caffeic, gallotannins, and ellagitannins, are especially examined in these publications.


Assuntos
Diterpenos , Neoplasias , Humanos , Café/química , Cafeína , Dieta
16.
Food Chem Toxicol ; 187: 114634, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38582344

RESUMO

The purpose of this study is to determine the effects of grayanotoxin in mad honey on ovarian tissue folliculogenesis in terms of cell death and nitric oxide expression. Three groups of 18 female Sprague-Dawley rats were formed. The first group received mad honey (80 mg/kg), the second group received normal honey (80 mg/kg), and the third group was the control. The first and second groups received normal and mad honey by oral gavage for 30 days before being sacrificed under anesthesia. Caspase 3 immunostaining showed a moderate to strong response, particularly in the mad honey group. In the mad honey group, immunostaining for caspase 8 and caspase 9 revealed a moderate immunoreaction in the granulosa cells of the Graaf follicles. The majority of Graaf follicles exhibited TUNEL positive in the mad honey group. The iNOS immunoreaction revealed a high level of expression in the mad honey group. In all three groups, eNOS immunostaining showed weak reactivity. According to the findings of apoptotic and nitric oxide marker expression, it was determined that mad honey may result in an increase in follicular atresia in ovarian follicles when compared to normal honey and control groups.


Assuntos
Diterpenos , Mel , Ovário , Ratos , Feminino , Animais , Ratos Sprague-Dawley , Óxido Nítrico , Atresia Folicular , Estresse Oxidativo , Apoptose , Células da Granulosa
17.
Biochem Pharmacol ; 223: 116194, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38583812

RESUMO

Glutathione peroxidase 4 (GPX4) is a promising anticancer therapeutic target; however, the application of GPX4 inhibitors (GPX4i) is limited owing to intrinsic or acquired drug resistance. Hence, understanding the mechanisms underlying drug resistance and discovering molecules that can overcome drug resistance are crucial. Herein, we demonstrated that GPX4i killed bladder cancer cells by inducing lipid reactive oxygen species-mediated ferroptosis and apoptosis, and cisplatin-resistant bladder cancer cells were also resistant to GPX4i, representing a higher half-maximal inhibitory concentration value than that of parent bladder cancer cells. In addition, thioredoxin reductase 1 (TrxR1) overexpression was responsible for GPX4i resistance in cisplatin-resistant bladder cancer cells, and inhibiting TrxR1 restored the sensitivity of these cells to GPX4i. In vitro and in vivo studies revealed that Jolkinolide B (JB), a natural diterpenoid and previously identified as a TrxR1 inhibitor, potentiated the antiproliferative efficacy of GPX4i (RSL3 and ML162) against cisplatin-resistant bladder cancer cells. Furthermore, GPX4 knockdown and inhibition could augment JB-induced paraptosis and apoptosis. Our results suggest that inhibiting TrxR1 can effectively improve GPX4 inhibition-based anticancer therapy. A combination of JB and GPX4i, which is well-tolerated and has several anticancer mechanisms, may serve as a promising therapy for treating bladder cancer.


Assuntos
Compostos de Anilina , Diterpenos , Tiofenos , Neoplasias da Bexiga Urinária , Humanos , Cisplatino/farmacologia , Tiorredoxina Redutase 1 , Linhagem Celular Tumoral , Neoplasias da Bexiga Urinária/tratamento farmacológico
18.
Biochemistry (Mosc) ; 89(3): 407-416, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38648761

RESUMO

The synthesis of (p)ppGpp alarmones plays a vital role in the regulation of metabolism suppression, growth rate control, virulence, bacterial persistence, and biofilm formation. The (p)ppGpp alarmones are synthesized by proteins of the RelA/SpoT homolog (RSH) superfamily, including long bifunctional RSH proteins and small alarmone synthetases. Here, we investigated enzyme kinetics and dose-dependent enzyme inhibition to elucidate the mechanism of 4-(4,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)pentanoic acid (DMNP) action on the (p)ppGpp synthetases RelMsm and RelZ from Mycolicibacterium smegmatis and RelMtb from Mycobacterium tuberculosis. DMNP was found to inhibit the activity of RelMtb. According to the enzyme kinetics analysis, DMNP acts as a noncompetitive inhibitor of RelMsm and RelZ. Based on the results of molecular docking, the DMNP-binding site is located in the proximity of the synthetase domain active site. This study might help in the development of alarmone synthetase inhibitors, which includes relacin and its derivatives, as well as DMNP - a synthetic analog of the marine coral metabolite erogorgiaene. Unlike conventional antibiotics, alarmone synthetase inhibitors target metabolic pathways linked to the bacterial stringent response. Although these pathways are not essential for bacteria, they regulate the development of adaptation mechanisms. Combining conventional antibiotics that target actively growing cells with compounds that impede bacterial adaptation may address challenges associated with antimicrobial resistance and bacterial persistence.


Assuntos
Proteínas de Bactérias , Ligases , Mycobacterium tuberculosis , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Cinética , Ligases/antagonistas & inibidores , Ligases/metabolismo , Simulação de Acoplamento Molecular , Mycobacterium smegmatis/enzimologia , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/efeitos dos fármacos , Naftalenos/farmacologia , Naftalenos/química , Diterpenos/farmacologia
19.
Bioorg Chem ; 147: 107367, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38626492

RESUMO

Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an autophagy inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type diterpenoids.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Relação Estrutura-Atividade , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/antagonistas & inibidores , Estrutura Molecular , Diterpenos/farmacologia , Diterpenos/química , Apoptose/efeitos dos fármacos , Animais , Camundongos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química
20.
Bioorg Chem ; 147: 107377, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38653150

RESUMO

The first systematic acylated diversification of naturally scarce premyrsinane diterpenes, together with their biosynthetic precursors lathyrane diterpene were carried out. Two new series of premyrsinane derivates (1a-32a) and lathyrane derivates (1-32) were synthesized from the naturally abundant lathyrane diterpene Euphorbia factor L3 through a bioinspired approach. The cholinesterase inhibitory and neuroprotective activities of these diterpenes were investigated to explore potential anti-Alzheimer's disease (AD) bioactive lead compounds. In general, the lathyrane diterpenes showed the better acetylcholinesterase (AChE) inhibitory activity than that of premyrsinanes. The lathyrane derivative 17 bearing a 3-dimethylaminobenzoyl moiety showed the best AChE inhibition effect with the IC50 value of 7.1 µM. Molecular docking demonstrated that 17 could bond with AChE well (-8 kal/mol). On the other hand, premyrsinanes showed a better neuroprotection profile against H2O2-induced injury in SH-SY5Y cells. Among them, the premyrsinane diterpene 16a had significant neuroprotective effect with the cell viability rate of 113.5 % at 12.5 µM (the model group with 51.2 %). The immunofluorescence, western blot and reactive oxygen species (ROS) analysis were conducted to demonstrate the mechanism of 16a. Furthermore, a preliminary SAR analysis of the two categories of diterpenes was performed to provide the insights for anti-AD drug development.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Inibidores da Colinesterase , Diterpenos , Euphorbia , Fármacos Neuroprotetores , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/síntese química , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/síntese química , Euphorbia/química , Humanos , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Simulação de Acoplamento Molecular , Relação Dose-Resposta a Droga , Sobrevivência Celular/efeitos dos fármacos
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