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1.
Mar Drugs ; 19(7)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34356816

RESUMO

The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding < -33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of -43.8 and -34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.


Assuntos
Antozoários/química , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Diterpenos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19/virologia , Proteases 3C de Coronavírus/metabolismo , Inibidores de Protease de Coronavírus/química , Inibidores de Protease de Coronavírus/isolamento & purificação , Diterpenos/química , Diterpenos/isolamento & purificação , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , SARS-CoV-2/enzimologia , SARS-CoV-2/patogenicidade , Relação Estrutura-Atividade
2.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202721

RESUMO

Marine natural products are abundant resources for antioxidants, but the antioxidant property of the soft corals-derived sinularin and dihydrosinularin were unknown. This study aimed to assess antioxidant potential and antiproliferation effects of above compounds on cancer cells, and to investigate the possible relationships between them. Results show that sinularin and dihydrosinularin promptly reacted with 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS), and hydroxyl (•OH), demonstrating a general radical scavenger activity. Sinularin and dihydrosinularin also show an induction for Fe+3-reduction and Fe+2-chelating capacity which both strengthen their antioxidant activities. Importantly, sinularin shows higher antioxidant properties than dihydrosinularin. Moreover, 24 h ATP assays show that sinularin leads to higher antiproliferation of breast, lung, and liver cancer cells than dihydrosinularin. Therefore, the differential antioxidant properties of sinularin and dihydrosinularin may contribute to their differential anti-proliferation of different cancer cells.


Assuntos
Antozoários/química , Antineoplásicos , Antioxidantes , Diterpenos , Compostos Heterocíclicos com 3 Anéis , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
3.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202736

RESUMO

Regardless of the prophylactic vaccine accessibility, persistent infections of high-risk human papillomaviruses (hr-HPVs), recognized as an etiology of cervical cancers, continues to represent a major health problem for the world population. An overexpression of viral early protein 6 (E6) is linked to carcinogenesis. E6 induces anti-apoptosis by degrading tumor suppressor proteins p53 (p53) via E6-E6-associated protein (E6AP)-mediated polyubiquitination. Thus, the restoration of apoptosis by interfering with the E6 function has been proposed as a selective medicinal strategy. This study aimed to determine the activities of andrographolide (Androg) on the disturbance of E6-mediated p53 degradation in cervical cancer cell lines using a proteomic approach. These results demonstrated that Androg could restore the intracellular p53 level, leading to apoptosis-induced cell death in HPV16-positive cervical cancer cell lines, SiHa and CaSki. Mechanistically, the anti-tumor activity of Androg essentially relied on the reduction in host cell proteins, which are associated with ubiquitin-mediated proteolysis pathways, particularly HERC4 and SMURF2. They are gradually suppressed in Androg-treated HPV16-positive cervical cancer cells. Collectively, the restoration of p53 in HPV16-positive cervical cancer cells might be achieved by disruption of E3 ubiquitin ligase activity by Androg, which could be an alternative treatment for HPV-associated epithelial lesions.


Assuntos
Apoptose/efeitos dos fármacos , Diterpenos/farmacologia , Proteoma , Proteômica , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/metabolismo , Biomarcadores , Sobrevivência Celular/efeitos dos fármacos , Biologia Computacional , Suscetibilidade a Doenças , Diterpenos/química , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Papillomavirus Humano 16 , Humanos , Estrutura Molecular , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Proteólise , Proteômica/métodos , Transcriptoma , Neoplasias do Colo do Útero/etiologia
4.
Int J Nanomedicine ; 16: 4251-4276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211271

RESUMO

Aim: Retinyl palmitate (RP), the most stable vitamin A derivative, is used to treat photoaging and other skin disorders. The need to minimize the adverse effects of topical drug administration has led to an enhanced interest in loading RP on ethosomes for topical drug delivery. The aim of the current study was to prepare and compare the performance of RP decorated ethosomal hydrogel with tretinoin cream in the treatment of acne vulgaris as an approach to improve drug efficacy and decrease its side effects. Methods: RP-loaded ethosomes were prepared using the injection sonication technique. A Box-Behnken design using Design Expert® software was used for the optimization of formulation variables. Particle size, zeta potential (ZP), entrapment efficiency percent (EE%), % drug release, and permeation over 24 h of different formulations were determined. The optimal formulation was incorporated into a hydrogel. Finally, the efficacy and tolerability of the optimized RP ethosomal hydrogel were clinically evaluated for acne treatment using a split-face comparative clinical study. Results: The optimized ethosomal RP showed particle size of 195.8±5.45 nm, ZP of -62.1±2.85 mV, EE% of 92.63±4.33%, drug release % of 96.63±6.81%, and drug permeation % of 85.98 ±4.79%. Both the optimized RP ethosomal hydrogel and tretinoin effectively reduced all types of acne lesions (inflammatory, non-inflammatory, and total lesions). However, RP resulted in significantly lower non-inflammatory and total acne lesion count than the marketed tretinoin formulation. Besides, RP-loaded ethosomes showed significantly improved tolerability compared to marketed tretinoin with no or minimal skin irritation symptoms. Conclusion: RP ethosomal hydrogel is considerably effective in controlling acne vulgaris with excellent skin tolerability. Therefore, it represents an interesting alternative to conventional marketed tretinoin formulation for topical acne treatment.


Assuntos
Acne Vulgar/tratamento farmacológico , Diterpenos/administração & dosagem , Hidrogéis/química , Hidrogéis/farmacologia , Ésteres de Retinil/administração & dosagem , Administração Cutânea , Adulto , Animais , Diterpenos/efeitos adversos , Diterpenos/química , Diterpenos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Humanos , Hidrogéis/efeitos adversos , Masculino , Tamanho da Partícula , Estudos Prospectivos , Ratos Wistar , Ésteres de Retinil/efeitos adversos , Ésteres de Retinil/química , Ésteres de Retinil/farmacocinética , Absorção Cutânea/efeitos dos fármacos , Testes de Irritação da Pele , Tretinoína/administração & dosagem , Tretinoína/farmacologia
5.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071660

RESUMO

Three new polyoxygenated diterpenoids with a rare 4-isopropyl-1,5,8a-trimethylperhydrophenanthrane structure of the klysimplexane skeleton, briarols A‒C (1‒3), and one eunicellin-based diterpenoid, briarol D (4), were isolated from Briareum violaceum, a gorgonian inhabiting Taiwanese waters. The chemical structures of these compounds were determined by employing extensive analyses of NMR and high-resolution electrospray ionization mass spectrometry (HRESIMS) data. Metabolites 1‒3 were found to possess the rarely found skeleton of the diterpenoid klysimplexin T. All isolated compounds showed very weak cytotoxic activity against the growth of three cancer cell lines. A plausible biosynthetic pathway for briarols A‒C from the coexisting eunicellin diterpenoid briarol D (4) was postulated.


Assuntos
Antozoários/metabolismo , Diterpenos/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Desenho de Fármacos , Células HT29 , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Neoplasias/tratamento farmacológico , Pós , Prótons , Espectrometria de Massas por Ionização por Electrospray , Taiwan , Poluentes Químicos da Água/análise , Purificação da Água
6.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072147

RESUMO

As part of our studies on antiprotozoal activity of approved herbal medicinal products, we previously found that a commercial tincture from Salvia officinalis L. (common Sage, Lamiaceae) possesses high activity against Trypanosoma brucei rhodesiense (Tbr), causative agent of East African Human Trypanosomiasis. We have now investigated in detail the antitrypanosomal constituents of this preparation. A variety of fractions were tested for antitrypanosomal activity and analyzed by UHPLC/+ESI QqTOF MS. The resulting data were used to generate a partial least squares (PLS) regression model that highlighted eight particular constituents that were likely to account for the major part of the bioactivity. These compounds were then purified and identified and their activity against the pathogen tested. All identified compounds (one flavonoid and eight diterpenes) displayed significant activity against Tbr, in some cases higher than that of the total tincture. From the overall results, it can be concluded that the antitrypanosomal activity of S. officinalis L. is, for the major part, caused by abietane-type diterpenes of the rosmanol/rosmaquinone group.


Assuntos
Antiprotozoários/farmacologia , Salvia officinalis/metabolismo , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Abietanos/química , Animais , Calibragem , Cromatografia Líquida de Alta Pressão , Diterpenos/química , Flavonoides/química , Concentração Inibidora 50 , Análise dos Mínimos Quadrados , Espectroscopia de Ressonância Magnética , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Testes de Sensibilidade Parasitária , Extratos Vegetais , Preparações de Plantas/farmacologia , Plantas Medicinais , Ratos , Espectrometria de Massas por Ionização por Electrospray , Tripanossomíase/parasitologia
8.
Molecules ; 26(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069033

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly used, but their adverse effects warrant investigating new therapeutic alternatives. Polyalthic acid, a labdane-type diterpenoid, is known to produce gastroprotection, tracheal smooth muscle relaxation, and antitumoral, antiparasitic and antibacterial activity. This study aimed to evaluate the antinociceptive, antiallodynic, antihyperalgesic and anti-inflammatory effect of polyalthic acid on rats. Moreover, the effectiveness of treating hyperalgesia with a combination of polyalthic acid and naproxen was analyzed, as well as the type of drug-drug interaction involved. Nociception was examined by injecting 1% formalin into the right hind paw and thermal hyperalgesia and inflammation by injecting a 1% carrageenan solution into the left hind paw of rats. Allodynia was assessed on an L5/L6 spinal nerve ligation model. Polyalthic acid generated significant antinociceptive (56-320 mg/kg), antiallodynic (100-562 mg/kg), and antihyperalgesic and anti-inflammatory (10-178 mg/kg) effects. Antinociception mechanisms were explored by pretreating the rats with naltrexone, ODQ and methiothepin, finding the effect blocked by the former two compounds, which indicates the participation of opioid receptors and guanylate cyclase. An isobolographic analysis suggests synergism between polyalthic acid and naproxen in the combined treatment of hyperalgesia.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Diterpenos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Administração Oral , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Diterpenos/administração & dosagem , Diterpenos/química , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Ligadura , Naproxeno/farmacologia , Naproxeno/uso terapêutico , Ratos Wistar , Nervos Espinhais/efeitos dos fármacos , Fatores de Tempo
9.
Acc Chem Res ; 54(10): 2347-2360, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33942612

RESUMO

The taxane diterpenes are a pharmaceutically vital family of natural products, consisting of more than 550 congeners. All taxane diterpenes are isolated from slow growing evergreen shrubs (genus Taxus) commonly known as "yews" and have a history of over 50 years as potent anticancer compounds. The most prominent congener, taxol (paclitaxel = PTX), has been used in clinics for more than 25 years and is one of the top-selling anticancer drugs worldwide, with annual sales reaching 1.5 billion USD in 1999. Within the taxane diterpene family 11 different scaffolds originating from rearrangements, fragmentations, or transannular C-C bond formations of the "classical taxane core" are known. Among them, five different scaffolds alone belong to the so-called complex or cyclotaxane subfamily, their signature structural feature bearing different types and numbers of transannular C-C bonds across the classical taxane backbone. For synthetic chemists, these five scaffolds represent by far the most challenging of all and have thus evaded total synthesis as well as detailed pharmaceutical evaluation-the latter due to extremely poor sourcing from natural producers. The cousinship of complex taxanes to taxol renders them potentially interesting compounds for drug research in the fight against cancer.This Account specifically summarizes the work on nonclassical taxanes from a biosynthetic, as well as a synthetic, point and provides a synthetic perspective on complex taxanes. Special attention is given to the biosynthetic relationship of complex taxanes and their biological emergence from classical taxanes. The transannular C-C bond forming events in the biosynthesis leading to the five individual scaffolds within this subfamily are structured on the basis of the exact type and number of these specific C-C bond formations. Since functionalization of the classical taxane core in the "oxidase phase" of the biosynthesis precedes the formation of complex taxanes, and is in part prerequisite for these transannular cyclization events, a detailed discussion of these oxidations of the classical taxane backbone is provided. Synthetic efforts toward nonclassical taxanes are scarce in literature and are thus presented in a comprehensive manner for abeotaxanes and complex taxanes. The last part of this Account deals with a synthetic perspective on the synthesis of complex taxanes (cyclotaxanes) and how these most intricate scaffolds can potentially be obtained via a deconvolution strategy. This discussion involves in part unpublished results by our group and is based upon synthetic studies in the literature. The deconvolution strategy we advocate aims for selective fragmentations of the signature transannular C-C bonds of the most intricate scaffold represented by the natural product canataxpropellane, which has recently been synthesized by our group. This strategy represents the converse process of the biosynthesis of complex taxanes (e.g., transannular cyclizations) and is enabled and feasible due to our approach to the canataxpropellane scaffold. We show that, by following this deconvolution strategy, all five scaffolds of complex taxanes can thereby be accessed.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Diterpenos/farmacologia , Neoplasias/tratamento farmacológico , Taxoides/farmacologia , Antineoplásicos Fitogênicos/química , Produtos Biológicos/química , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Humanos , Neoplasias/patologia , Taxoides/química
10.
Artigo em Inglês | MEDLINE | ID: mdl-34052752

RESUMO

Detailed metabolic profiling of needles of five Pinus species was investigated using complementary HPLC-MS/MS techniques together with supervised and unsupervised chemometric tools. This resulted in putative identification of 44 compounds belonging to flavonoids, phenolics, lignans, diterpenes and fatty acids. Unsupervised principal component analysis showed that differences were maintained across the metabolites characteristic of each Pinus species, are mainly related to di-O-p-coumaroyltrifolin, p-coumaroyl quinic acid derivative, arachidonic acid, hydroxypalmitic acid, isopimaric acid and its derivative. A supervised Partial Least Squares regression analysis was performed to correlate HPLC-MS/MS profiles with the variation observed in the in vitro anticholinesterase, antiaging and anti-diabetic potential. All investigated Pinus extracts exerted their antiaging activity via increasing telomerase and TERT levels in normal human melanocytes cells compared to the control (untreated cells). Profound inhibition activities of acetylcholinesterase and dipeptidyl peptidase-4 were also observed with P. pinea and P. canariensis extracts having comparable antidiabetic activities to sitagliptin as a standard antidiabetic drug. Our findings suggested that pine needles are a good source of phenolics and diterpenoids that have possible health promoting activities in management and alleviation of diabetic conditions and Alzheimer disease.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Metaboloma/fisiologia , Pinus , Espectrometria de Massas em Tandem/métodos , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Diterpenos/análise , Diterpenos/química , Diterpenos/metabolismo , Flavonoides/análise , Flavonoides/química , Flavonoides/metabolismo , Hipoglicemiantes/análise , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Metabolômica , Pinus/química , Pinus/metabolismo , Extratos Vegetais/química , Substâncias Protetoras/análise , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Extração em Fase Sólida/métodos
11.
Food Funct ; 12(9): 3883-3897, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33978004

RESUMO

We systematically investigated the impact of oil droplet diameter (≈0.15, 1.6, and 11 µm) on the bioaccessibility of three oil-soluble vitamins (vitamin A palmitate, vitamin D, and vitamin E acetate) encapsulated within soybean oil-in-water emulsions stabilized by quillaja saponin. Lipid digestion kinetics decreased with increasing droplet size due to the reduction in oil-water interfacial area. Vitamin bioaccessibility decreased with increasing droplet size from 0.15 to 11 µm: 87 to 39% for vitamin A; 76 to 44% for vitamin D; 77 to 21% for vitamin E. Vitamin bioaccessibility also decreased as their hydrophobicity and molecular weight increased, probably because their tendency to remain inside the oil droplets and/or be poorly solubilized by the mixed micelles increased. Hydrolysis of the esterified vitamins also occurred under gastrointestinal conditions: vitamin A palmitate (∼90%) and vitamin E acetate (∼3%). Consequently, the composition and structure of emulsion-based delivery systems should be carefully designed when creating vitamin-fortified functional food products.


Assuntos
Diterpenos/farmacocinética , Trato Gastrointestinal/fisiologia , Ésteres de Retinil/farmacocinética , Vitamina D/farmacocinética , Vitamina E/farmacocinética , Disponibilidade Biológica , Cápsulas , Digestão , Diterpenos/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Emulsões , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Metabolismo dos Lipídeos , Micelas , Tamanho da Partícula , Ésteres de Retinil/química , Solubilidade , Óleo de Soja/química , Vitamina D/química , Vitamina E/química
12.
Plant Cell ; 33(2): 290-305, 2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33793769

RESUMO

Plants can contain biosynthetic gene clusters (BGCs) that nominally resemble those found in microbes. However, while horizontal gene transmission is often observed in microbes, plants are limited to vertical gene transmission, implying that their BGCs may exhibit distinct inheritance patterns. Rice (Oryza sativa) contains two unlinked BGCs involved in diterpenoid phytoalexin metabolism, with one clearly required for momilactone biosynthesis, while the other is associated with production of phytocassanes. Here, in the process of elucidating momilactone biosynthesis, genetic evidence was found demonstrating a role for a cytochrome P450 (CYP) from the other "phytocassane" BGC. This CYP76M8 acts after the CYP99A2/3 from the "momilactone" BGC, producing a hemiacetal intermediate that is oxidized to the eponymous lactone by a short-chain alcohol dehydrogenase also from this BGC. Thus, the "momilactone" BGC is not only incomplete, but also fractured by the need for CYP76M8 to act in between steps catalyzed by enzymes from this BGC. Moreover, as supported by similar activity observed with orthologs from the momilactone-producing wild-rice species Oryza punctata, the presence of CYP76M8 in the other "phytocassane" BGC indicates interdependent evolution of these two BGCs, highlighting the distinct nature of BGC assembly in plants.


Assuntos
Evolução Biológica , Vias Biossintéticas/genética , Diterpenos/metabolismo , Família Multigênica , Oryza/genética , Diterpenos/química , Regulação da Expressão Gênica de Plantas , Oxirredução , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
13.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33806909

RESUMO

Kirenol (KRL) is a biologically active substance extracted from Herba Siegesbeckiae. This natural type of diterpenoid has been widely adopted for its important anti-inflammatory and anti-rheumatic properties. Despite several studies claiming the benefits of KRL, its cardiac effects have not yet been clarified. Cardiotoxicity remains a key concern associated with the long-term administration of doxorubicin (DOX). The generation of reactive oxygen species (ROS) causes oxidative stress, significantly contributing to DOX-induced cardiac damage. The purpose of the current study is to investigate the cardio-protective effects of KRL against apoptosis in H9c2 cells induced by DOX. The analysis of cellular apoptosis was performed using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining assay and measuring the modulation in the expression levels of proteins involved in apoptosis and Nrf2 signaling, the oxidative stress markers. Furthermore, Western blotting was used to determine cell survival. KRL treatment, with Nrf2 upregulation and activation, accompanied by activation of PI3K/AKT, could prevent the administration of DOX to induce cardiac oxidative stress, remodeling, and other effects. Additionally, the diterpenoid enhanced the activation of Bcl2 and Bcl-xL, while suppressing apoptosis marker proteins. As a result, KRL is considered a potential agent against hypertrophy resulting from cardiac deterioration. The study results show that KRL not only activates the IGF-IR-dependent p-PI3K/p-AKT and Nrf2 signaling pathway, but also suppresses caspase-dependent apoptosis.


Assuntos
Cardiotônicos/farmacologia , Diterpenos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citoesqueleto/metabolismo , Diterpenos/química , Doxorrubicina/efeitos adversos , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Mioblastos Cardíacos/efeitos dos fármacos , Mioblastos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Peptídeos Natriuréticos/metabolismo , Fosforilação , Transporte Proteico
14.
Molecules ; 26(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805414

RESUMO

During a phytochemical investigation of the unripe fruits of Rubus chingii Hu (i.e., Fructus Rubi, a traditional Chinese medicine named "Fu-Pen-Zi"), a number of highly oxygenated terpenoids were isolated and characterized. These included nine ursane-type (1, 2, and 4-10), five oleanane-type (3, 11-14), and six cucurbitane-type (15-20) triterpenoids, together with five ent-kaurane-type diterpenoids (21-25). Among them, (4R,5R,8R,9R,10R,14S,17S,18S,19R,20R)-2,19α,23-trihydroxy-3-oxo-urs-1,12-dien-28-oic acid (rubusacid A, 1), (2R*,4S*,5R*,8R*,9R*,10R*,14S*,17S*, 18S*,19R*,20R*)-2α,19α,24-trihydroxy-3-oxo-urs-12-en-28-oic acid (rubusacid B, 2), (5R,8R,9R,10R, 14S,17R,18S,19S)-2,19α-dihydroxy-olean-1,12-dien-28-oic acid (rubusacid C, 3), and (3S,5S,8S,9R, 10S,13R,16R)-3α,16α,17-trihydroxy-ent-kaur-2-one (rubusone, 21) were previously undescribed. Their chemical structures and absolute configurations were elucidated on the basis of spectroscopic data and electronic circular dichroism (ECD) analyses. Compounds 1 and 3 are rare naturally occurring pentacyclic triterpenoids featuring a special α,ß-unsaturated keto-enol (diosphenol) unit in ring A. Cucurbitacin B (15), cucurbitacin D (16), and 3α,16α,20(R),25-tetrahydroxy-cucurbita-5,23- dien-2,11,22-trione (17) were found to have remarkable inhibitory effects against NF-κB, with IC50 values of 0.08, 0.61, and 1.60 µM, respectively.


Assuntos
Candida albicans/efeitos dos fármacos , Diterpenos , Frutas/química , Rubus/química , Triterpenos , Diterpenos/química , Diterpenos/farmacologia , Células HEK293 , Humanos , Estrutura Molecular , NF-kappa B/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Triterpenos/química , Triterpenos/farmacologia
15.
Molecules ; 26(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805445

RESUMO

Stevia rebaudiana (Bertoni) Bertoni is a plant species native to Brazil and Paraguay well-known by the sweet taste of their leaves. Since the recognition of rebaudioside A and other steviol glycosides as generally recognized as safe by the United States Food and Drug Administration in 2008 and grant of marketing approval by the European Union in 2011, the species has been widely cultivated and studied in several countries. Several efforts have been dedicated to the isolation and structure elucidation of minor components searching for novel non-caloric sugar substitutes with improved organoleptic properties. The present review provides an overview of the main chemical approaches found in the literature for identification and structural differentiation of diterpene glycosides from Stevia rebaudiana: High-performance Thin-Layer Chromatography, High-Performance Liquid Chromatography, Electrospray Ionization Mass Spectrometry and Nuclear Magnetic Resonance Spectroscopy. Modification of diterpene glycosides by chemical and enzymatic reactions together with some strategies to scale up of the purification process saving costs are also discussed. A list of natural diterpene glycosides, some examples of chemically modified and of enzymatically modified diterpene glycosides reported from 1931 to February 2021 were compiled using the scientific databases Google Scholar, ScienceDirect and PubMed.


Assuntos
Diterpenos , Glicosídeos , Stevia/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia em Camada Delgada/métodos , Diterpenos/química , Diterpenos/isolamento & purificação , Glicosídeos/química , Glicosídeos/isolamento & purificação , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos
16.
Molecules ; 26(6)2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33804618

RESUMO

Rosmarinus officinalis L. is a widely known species for its medicinal uses, that is also used as raw material for the food and cosmetic industry. The aim of the present study was to offer a novel perspective on the medicinal product originating from this species and to test its hepatoprotective activity. The tested sample consisted in a tincture obtained from the fresh young shoots. Compounds that are evaluated for this activity are polyphenols and terpenoids, that are identified and quantified by HPLC-UV-MS and GC-MS. Antioxidant activity was assessed in vitro, using the DPPH, FRAP and SO assays. Hepatoprotective activity was tested in rats with experimentally-induced hepatotoxicity. In the chemical composition of the tincture, phenolic diterpenes (carnosic acid, carnosol, rosmanol, rosmadial) and rosmarinic acid were found to be the majority compounds, alongside with 1,8-cineole, camphene, linalool, borneol and terpineol among monoterpenes. In vitro, the tested tincture proved significant antioxidant capacity. Results of the in vivo experiment showed that hepatoprotective activity is based on an antioxidant mechanism. In this way, the present study offers a novel perspective on the medicinal uses of the species, proving significant amounts of polyphenols and terpenes in the composition of the fresh young shoots tincture, that has proved hepatoprotective activity through an antioxidant mechanism.


Assuntos
Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas , Estresse Oxidativo/efeitos dos fármacos , Brotos de Planta/química , Rosmarinus/química , Animais , Antioxidantes/química , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cinamatos/química , Cinamatos/farmacologia , Depsídeos/química , Depsídeos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Monoterpenos/química , Monoterpenos/farmacologia , Ratos
17.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802747

RESUMO

Secondary metabolites are essential for plant survival and reproduction. Wild undomesticated and tropical plants are expected to harbor highly diverse metabolomes. We investigated the metabolomic diversity of two morphologically similar trees of tropical Africa, Erythrophleum suaveolens and E. ivorense, known for particular secondary metabolites named the cassaine-type diterpenoids. To assess how the metabolome varies between and within species, we sampled leaves from individuals of different geographic origins but grown from seeds in a common garden in Cameroon. Metabolites were analyzed using reversed phase LC-HRMS(/MS). Data were interpreted by untargeted metabolomics and molecular networks based on MS/MS data. Multivariate analyses enabled us to cluster samples based on species but also on geographic origins. We identified the structures of 28 cassaine-type diterpenoids among which 19 were new, 10 were largely specific to E. ivorense and five to E. suaveolens. Our results showed that the metabolome allows an unequivocal distinction of morphologically-close species, suggesting the potential of metabolite fingerprinting for these species. Plant geographic origin had a significant influence on relative concentrations of metabolites with variations up to eight (suaveolens) and 30 times (ivorense) between origins of the same species. This shows that the metabolome is strongly influenced by the geographical origin of plants (i.e., genetic factors).


Assuntos
Fabaceae/química , Fabaceae/classificação , Metaboloma , Compostos Fitoquímicos/análise , Árvores/química , Árvores/classificação , África , Camarões , Cromatografia Líquida , Diterpenos/análise , Diterpenos/química , Fabaceae/genética , Fabaceae/metabolismo , Metabolômica , Análise Multivariada , Folhas de Planta/química , Folhas de Planta/genética , Análise de Componente Principal , Metabolismo Secundário , Sementes , Espectrometria de Massas em Tandem , Árvores/metabolismo
18.
J Ind Microbiol Biotechnol ; 48(1-2)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33928347

RESUMO

Forskolin, a class of labdane-type diterpenoid, has significant medicinal value in anticancer, antiasthmatic, antihypertensive, and heart-strengthening treatments. The main source of natural forskolin is its extraction from the cork tissue of the root of Coleus forskohlii. However, conventional modes of extraction pose several challenges. In recent years, the construction of microbial cell factories to produce medicinal natural products via synthetic biological methods has effectively solved the current problems and is a research hotspot in this field. This review summarizes the recent progress in the heterologous synthesis of forskolin via synthetic biological technology, analyzes the current challenges, and proposes corresponding strategies.


Assuntos
Colforsina/metabolismo , Colforsina/química , Diterpenos/química , Diterpenos/metabolismo
19.
Molecules ; 26(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806445

RESUMO

Marine natural products have exhibited uncommon chemical structures with relevant antitumor properties highlighting their potential to inspire the development of new anticancer agents. The goal of this work was to study the antitumor activities of the brominated diterpene sphaerodactylomelol, a rare example of the dactylomelane family. Cytotoxicity (10-100 µM; 24 h) was evaluated on tumor cells (A549, CACO-2, HCT-15, MCF-7, NCI-H226, PC-3, SH-SY5Y, SK-ML-28) and the effects estimated by MTT assay. Hydrogen peroxide (H2O2) levels and apoptosis biomarkers (membrane translocation of phosphatidylserine, depolarization of mitochondrial membrane potential, Caspase-9 activity, and DNA condensation and/or fragmentation) were studied in the breast adenocarcinoma cellular model (MCF-7) and its genotoxicity on mouse fibroblasts (L929). Sphaerodactylomelol displayed an IC50 range between 33.04 and 89.41 µM without selective activity for a specific tumor tissue. The cells' viability decrease was accompanied by an increase on H2O2 production, a depolarization of mitochondrial membrane potential and an increase of Caspase-9 activity and DNA fragmentation. However, the DNA damage studies in L929 non-malignant cell line suggested that this compound is not genotoxic for normal fibroblasts. Overall, the results suggest that the cytotoxicity of sphaerodactylomelol seems to be mediated by an increase of H2O2 levels and downstream apoptosis.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Neoplasias da Mama/tratamento farmacológico , Diterpenos/farmacologia , Fibroblastos/efeitos dos fármacos , Rodófitas/química , Animais , Antineoplásicos/química , Neoplasias da Mama/patologia , Proliferação de Células , Células Cultivadas , Dano ao DNA , Diterpenos/química , Feminino , Humanos , Peróxido de Hidrogênio/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos
20.
Molecules ; 26(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924730

RESUMO

Bioactive-guided phytochemical investigation of Euphorbia antiquorum L. growing in Vietnam led to the isolation of five ent-atisanes, one seco-ent-atisane, and one lathyrane (ingol-type). The structures were elucidated as ent-1α,3α,16ß,17-tetrahydroxyatisane (1), ethyl ent-3,4-seco-4,16ß,17-trihydroxyatisane-3-carboxylate (2), ent-atisane-3-oxo-16ß,17-acetonide (3), ent-3α-acetoxy-16ß,17-dihydroxyatisane (4), ent-16ß,17-dihydroxyatisane-3-one (5), calliterpenone (6), and ingol 12-acetate (7). Their chemical structures were unambiguously determined by analysis of one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) and high resolution mass spectrometry, as well as by comparison with literature data. Among them, 1 is a new compound while 2 is an ethylated artifact of ent-3,4-seco-4,16ß,17-trihydroxyatisane-3-carboxylic acid, a new compound. Isolates were evaluated for alpha-glucosidase inhibition. Compound 3 showed the most significant inhibitory activity against alpha-glucosidase with an IC50 value of 69.62 µM. Further study on mechanism underlying yeast alpha-glucosidase inhibition indicated that 3 could retard the enzyme function by noncompetitive.


Assuntos
Euphorbia/química , Inibidores de Glicosídeo Hidrolases/química , Diterpenos/química , Espectroscopia de Ressonância Magnética
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