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1.
Biomed Pharmacother ; 153: 113423, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076543

RESUMO

ß-caryophyllene (BCP) is a volatile bicyclic sesquiterpenoid found in essential oils obtained from several spices such as black pepper, oregano, basil, rosemary, cinnamon, and clove. BCP is a selective agonist of cannabinoid receptor 2 (CB2 receptor), and orally administered BCP exhibits various biological activities, including anti-inflammatory, antioxidant, and neuroprotective effects. However, it is still unclear how volatile BCP affects living organisms. We previously reported that inhaled BCP is transferred to sera and organs in mice; additionally, metabolomic analysis revealed inhaled BCP affect the dynamics of metabolites in the livers of mice. These data suggest that inhaled BCP may affect several biological activities by stimulating biological systems. In this study, we evaluated the effects of BCP inhalation on nicotine-induced degeneration of the aortic wall. In the group of mice which inhaled volatile BCP, nicotine-induced increases in elastic fiber degradation and matrix metalloproteinase-2 (MMP-2)-positive areas were attenuated. In addition, BCP improved the nicotine-induced stiffness of aortae and vulnerability to aortic rupture. In cultured aortae, the suppressive effects of BCP were inhibited by the CB2 receptor inhibitor AM630. These results suggest that inhaled BCP is incorporated into the aortic wall and prevents nicotine-induced degeneration of the aorta via a CB2 receptor-dependent pathway.


Assuntos
Nicotina , Sesquiterpenos , Animais , Aorta , Metaloproteinase 2 da Matriz , Camundongos , Sesquiterpenos Policíclicos , Receptor CB2 de Canabinoide , Sesquiterpenos/farmacologia
2.
Biomed Pharmacother ; 153: 113478, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076580

RESUMO

Valencene (VLN) is a sesquiterpene found in juices and essential oils of citrus species such as Cyperus rotundus. Considering the evidence that this species has anti-inflammatory effects, the present study aims to evaluate the anti-inflammatory activity of VLN in vivo and in silico. Swiss mice (n = 6) were orally treated according to their treatment groups as follows: VLN (10, 100 or 300 mg/kg), negative control (0.9% saline), and positive controls (indomethacin 25 mg/kg or promethazine 6 mg/kg). The anti-inflammatory activity was evaluated in murine models of acute and chronic inflammation. The inhibition of acute inflammation was evaluated in models of paw edema induced by different inflammatory agents (carrageenan, dextran, histamine, and arachidonic acid (AA)) and carrageenan-induced pleurisy and peritonitis. The modulation of chronic inflammation was evaluated in a granuloma model induced cotton pellets implantation. The interaction with inflammatory targets was evaluated in silico using molecular docking analysis. The administration of VLN to challenged mice significantly inhibited paw edema formation with no significant difference between the administered doses. The compound also reduced albumin extravasation, leukocyte recruitment, and the production of myeloperoxidase (MPO), IL-1ß, and TNF-α in both pleural and peritoneal lavages. According to the mathematical-statistical model observed in silico analysis, this compound has favorable energy to interact with the cyclooxygenase enzyme (COX-2) and the histamine 1 (H1) receptor. Finally, animals treated with the sesquiterpene showed a reduction in both granuloma weight and concentration of total proteins in a chronic inflammation model. Given these findings, it is concluded that NLV presents promising pharmacological activity in murine models of acute and chronic inflammation.


Assuntos
Anti-Inflamatórios não Esteroides , Sesquiterpenos , Animais , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacologia , Carragenina/uso terapêutico , Ciclo-Oxigenase 2 , Edema/induzido quimicamente , Edema/tratamento farmacológico , Granuloma/tratamento farmacológico , Histamina , Inflamação/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Extratos Vegetais/farmacologia , Sesquiterpenos/efeitos adversos
3.
J Pharmacol Sci ; 150(2): 110-122, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36055749

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, and there are no effective drugs available so far. Lactucin and Lactucopicrin belong to sesquiterpene lactones and are extracted from Cichorium glandulosum Boiss. et Huet (CG) possesses multiple biopharmacological activities. However, the therapeutic effects of both Lactucin and Lactucopicrin on many diseases and their underlying mechanisms remain largely unknown. Here, we analyzed the both natural compounds hypolipidemic effects on FFA-induced HepG2 cells and their potential mechanisms based on transcriptomics and experimental tests. Our results indicated that Lactucin (10 µM) and Lactucopicrin (20 µM) remarkably reduced TG accumulation. Transcriptomics analysis identified 1960, 1645, and 1791 differentially expressed genes (DEGs) and obtained 611 and 635 specific genes in different comparisons, respectively. The enrichment analysis and experimental validations (RT-qPCR and Western Blot) showed that their hypolipidemic activities were most probably exerted via regulating numerous key DEGs involved in lipid metabolism. Taken together, both Lactucin and Lactucopicrin may represent potent hepatoprotective agents. Both of them exhibited therapeutic effects against liver diseases such as NAFLD by regulating multi-gene and proteins like HADHA, ADAM17, SQSTM1, and GBA and modulating multi-pathways like fatty acid oxidation metabolic signaling.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Sesquiterpenos , Células Hep G2 , Humanos , Lactonas/farmacologia , Lactonas/uso terapêutico , Metabolismo dos Lipídeos/genética , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Forbóis , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico
4.
Bioorg Chem ; 128: 106040, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36049320

RESUMO

Five new suberosanone-purine hybrids, namely subergorgines A-E (1-5), were isolated from the South China Sea gorgonian Subergorgia suberosa. Their structures were elucidated on the basis of extensive spectroscopic data and the absolute configurations were clarified by the theoretical ECD calculation. Compounds 1-5 were rare purine alkaloids merged with the same suberosanone moiety via different C (6)-N bridges. Cytotoxic activities of the isolates were tested. Compound 4 was found to be the most active against the HL-60 cancer cell line with an IC50 value of 14.3 µM. A plausible biosynthetic pathway for suberosanone-purine hybrids was also discussed.


Assuntos
Antozoários , Antineoplásicos , Sesquiterpenos , Animais , Antozoários/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Estrutura Molecular , Purinas/química , Sesquiterpenos/química
5.
Microb Cell Fact ; 21(1): 190, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36104783

RESUMO

BACKGROUND: Eukaryotic algae have recently emerged as hosts for metabolic engineering efforts to generate heterologous isoprenoids. Isoprenoid metabolic architectures, flux, subcellular localization, and transport dynamics have not yet been fully elucidated in algal hosts. RESULTS: In this study, we investigated the accessibility of different isoprenoid precursor pools for C15 sesquiterpenoid generation in the cytoplasm and chloroplast of Chlamydomonas reinhardtii using the Abies grandis bisabolene synthase (AgBS) as a reporter. The abundance of the C15 sesquiterpene precursor farnesyl pyrophosphate (FPP) was not increased in the cytosol by co-expression and fusion of AgBS with different FPP synthases (FPPSs), indicating limited C5 precursor availability in the cytoplasm. However, FPP was shown to be available in the plastid stroma, where bisabolene titers could be improved several-fold by FPPSs. Sesquiterpene production was greatest when AgBS-FPPS fusions were directed to the plastid and could further be improved by increasing the gene dosage. During scale-up cultivation with different carbon sources and light regimes, specific sesquiterpene productivities from the plastid were highest with CO2 as the only carbon source and light:dark illumination cycles. Potential prenyl unit transporters are proposed based on bioinformatic analyses, which may be in part responsible for our observations. CONCLUSIONS: Our findings indicate that the algal chloroplast can be harnessed in addition to the cytosol to exploit the full potential of algae as green cell factories for non-native sesquiterpenoid generation. Identification of a prenyl transporter may be leveraged for further extending this capacity.


Assuntos
Chlamydomonas reinhardtii , Microalgas , Sesquiterpenos , Carbono/metabolismo , Chlamydomonas reinhardtii/genética , Chlamydomonas reinhardtii/metabolismo , Microalgas/metabolismo , Neopreno , Plantas , Fosfatos de Poli-Isoprenil , Sesquiterpenos/metabolismo , Terpenos/metabolismo
6.
Sci Rep ; 12(1): 15564, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114273

RESUMO

Mosquitoes are vectors for a variety of infectious illnesses, and chemical synthetic insecticides have made it possible to control them effectively. Mosquito repellents are a typical means of keeping mosquitos at bay. Because of its main effectiveness of skin permeability, N,N-Diethyl-meta-toluamide (DEET) is one of the most extensively used mosquito repellents but a dangerous synthetic chemical. DEET was identified about a decade ago to inhibit mosquito's Odorant Binding Protein 1 (OBP1), impairing the mosquito's ability to recognise the host body odour. OBP1 has been identified as a possible target for the development of new mosquito repellents since its discovery. Essential oils from different plants, on the other hand, have been used to repel mosquitos since antiquity. One essential oil from the Curcuma longa (Zingiberales: Zingiberaceae) rhizome display mosquito repellent properties, according to the literature. Furthermore, one of the phytochemicals found in abundance in C. longa essential oil, ar-turmerone, exhibits mosquito repellency as comparable to synthetic DEET. Till date studies on in-silico interaction of natural ar-turmerone with OBP1, which we depict in our current work are scarce. Further, there exist no published reports demonstrating the literary evidence on detailed insights of interaction of DEET with OBP1 along with Molecular Dynamics (MD) simulation studies. We further performed detailed molecular investigations using pharmacophore analysis of ar-turmerone and compared it with DEET, where our findings in the current manuscript unveils for the first time that ar-turmerone is a functional, structural and pharmacophoric analogue of DEET.


Assuntos
Repelentes de Insetos , Inseticidas , Óleos Voláteis , Animais , DEET/farmacologia , Repelentes de Insetos/química , Repelentes de Insetos/farmacologia , Cetonas , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Sesquiterpenos
7.
J Am Chem Soc ; 144(37): 17277-17294, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36098550

RESUMO

Detailed herein are our synthesis studies of longiborneol and related natural products. Our overarching goals of utilizing a "camphor first" strategy enabled by skeletal remodeling of carvone, and late-stage diversification using C-H functionalizations, led to divergent syntheses of the target natural products. Our initial approach proposed a lithiate addition to unite two fragments followed by a Conia-ene or Pd-mediated cycloalkylation reaction sequence to install the seven-membered ring emblematic of the longibornane core. This approach was unsuccessful and evolved into a revised plan that employed a Wittig coupling and a radical cyclization to establish the core. A reductive radical cyclization, which was explored first, led to a synthesis of copaborneol, a structural isomer of longiborneol. Alternatively, a metal-hydride hydrogen atom transfer-initiated cyclization was effective for a synthesis of longiborneol. Late-stage C-H functionalization of the longibornane core led to a number of hydroxylated longiborneol congeners. The need for significant optimization of the strategies that were employed as well as the methods for C-H functionalization to implement these strategies highlights the ongoing challenges in applying these powerful reactions. Nevertheless, the reported approach enables functionalization of every natural product-relevant C-H bond in the longibornane skeleton.


Assuntos
Produtos Biológicos , Sesquiterpenos , Produtos Biológicos/química , Cânfora , Hidrogênio/química
8.
Biomed Res Int ; 2022: 1129297, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36124067

RESUMO

This study investigated the healing effects of topical application of zerumbone, a well-known anti-inflammatory compounds loaded on nanostructured lipid carrier gel (Carbopol 940) (ZER-NLCG) on excisional wounds in streptozotocin-induced diabetic rats. Diabetic rats with inflicted superficial skin wound were topically treated with ZER-NLCG, empty NLCG, and silver sulfadiazine cream (SSDC) once daily for 21 days. Wound tissue samples were analyzed for proinflammatory cytokines, namely, interleukin-6 (IL-6), interleukin-1 ß (IL-1ß), and tumor necrosis factor-α (TNF-α), hydroxyproline contents, catalase, superoxide dismutase activities, and lipid peroxidation level, and were subjected to histopathological analysis, respectively. Among the treated groups, ZER-NLCG was the most effective at decreasing proinflammatory cytokine level and inflammatory cell infiltration while increasing antioxidant enzyme activities, hydroxyproline content, and granulation of wound tissues of diabetic rats. ZER-NLCG is a potent formulation for the enhancement of wound healing in diabetic rats through its anti-inflammatory, antioxidant, and tissue repair activities.


Assuntos
Diabetes Mellitus Experimental , Fator de Necrose Tumoral alfa , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Catalase , Citocinas/farmacologia , Diabetes Mellitus Experimental/patologia , Hidroxiprolina , Interleucina-1beta/farmacologia , Interleucina-6 , Lipídeos/farmacologia , Ratos , Ratos Wistar , Sesquiterpenos , Sulfadiazina de Prata/farmacologia , Estreptozocina/farmacologia , Superóxido Dismutase , Fator de Necrose Tumoral alfa/farmacologia , Cicatrização
9.
Allergol. immunopatol ; 50(5): 39-46, sept. 2022. graf
Artigo em Inglês | IBECS | ID: ibc-ADZ-5

RESUMO

Sepsis induces multiple organ dysfunction syndromes, such as acute kidney, liver, or lung injury. Septic lung injury is associated with excessive apoptosis and inflammatory responses in hepatocytes. Deoxyelephantopin is a sesquiterpene lactone found in Elephantopus scaberL, and has immunomodulatory, antibacterial, anti-inflammatory, and antifungal properties. The role of deoxyelephantopin in sepsis-associated lung injury was investigated. First, human bronchial epithelial cells (BEAS-2B) and human pulmonary artery endothelial cells (HPAEC) were treated with lipopolysaccharide to induce cytotoxicity. Treatment with lipopolysac-charide reduced cell viability of BEAS-2B and HPAEC, and promoted cell apoptosis through down-regulation of poly (ADP-ribose) polymerase (PARP) and B-cell lymphoma 2 (Bcl-2), and up-regulation of cleaved PARP and B-cell lymphoma-associated X protein (Bax). Second, lipo-polysaccharide-treated BEAS-2B and HPAEC were incubated with increasing concentrations of deoxyelephantopin, that is, 1, 5, or 10 μM. Deoxyelephantopin enhanced cell viability and reduced cell apoptosis of lipopolysaccharide-treated BEAS-2B and HPAEC. Third, deoxyele-phantopin attenuated lipopolysaccharide-induced decrease of superoxide dismutase and glutathione, and increase of malondialdehyde and myeloperoxidase in BEAS-2B and HPAEC. Moreover, deoxyelephantopin also weakened lipopolysaccharide-induced increase of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. Finally, deoxyelephantopin decreased pro-tein expression of p-p65 and p-signal transducer and activator of transcription 3 (STAT3) in lipopolysaccharide-treated BEAS-2B and HPAEC. In conclusion, deoxyelephantopin exhibited anti-oxidative and anti-inflammatory effects against lipopolysaccharide-treated BEAS-2B and HPAEC through inactivation of nuclear factor kappa B/STAT3 signaling (AU)


Assuntos
Humanos , Anti-Inflamatórios/farmacologia , Lesão Pulmonar/metabolismo , Sepse/metabolismo , Células Endoteliais/metabolismo , Lactonas , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Poli Adenosina Difosfato Ribose , Inibidores de Poli(ADP-Ribose) Polimerases , Fator de Transcrição STAT3 , Sesquiterpenos
10.
Zhongguo Zhong Yao Za Zhi ; 47(16): 4292-4304, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046855

RESUMO

Sesquiterpene pyridine alkaloids are important components in Tripterygium plants, possessing a wide range of pharmacological activities, such as anti-inflammation immunosuppression, anti-tumor, anti-virus, and deinsectization, and are of great research value. They are composed of highly oxidized dihydro-ß-furansquiterpene and pyridine dicarboxylic acid through ester bonds. According to the structural characteristics of pyridine dicarboxylic acid fragments, they can be divided into various structural subtypes. Up to now, more than 110 sesquiterpene pyridine alkaloids have been isolated and identified from Tripterygium plants. This study reviewed the structural features and spectral(i.e., UV, IR, MS, and NMR) characteristics of sesquiterpene pyridine alkaloids and summarized the structural elucidation process in detail to provide references for their further research and development.


Assuntos
Alcaloides , Medicamentos de Ervas Chinesas , Sesquiterpenos , Alcaloides/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Tripterygium/química
11.
Zhongguo Zhong Yao Za Zhi ; 47(16): 4385-4390, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046866

RESUMO

Eight sesquiterpenoids were isolated from petroleum ether extract of Aquilariae Lignum Resinatum by various column chromatography techniques including silica gel, ODS, and semi-preparative HPLC. Their structures were identified on the basis of physicochemical properties, UV, IR, MS, and NMR spectroscopic data as(4S,5S,7R,10S)-5,7-dihydroxy-11-en-eudesmane(1),(7R,10S)-eudesma-4-en-11,15-diol(2),(2R,4S,5R,7R)-2-hydroxyeremophila-9,11-dien-8-one(3), 7α-H-9(10)-ene-11,12-epoxy-8-oxoeremophilane(4),(+)-9ß,10ß-epoxyeremophila-11(13)-en(5), 4(14)-eudesmene-8α,11-diol(6), 12,15-dioxo-selina-4,11-dien(7), and 2ß,8 aα-dihydroxy-11-en-eremophilane(8). Compounds 1 and 2 are new compounds, and their absolute configurations were determined by calculating ECD. Compounds 1, 4, and 6-8 could significantly improve taurocholic acid(TCA)-induced gastric mucosal GES-1 cell injury at a concentration of 20 µmol·L~(-1), and the cell protection rates were 23.51%±2.79%, 16.10%±1.25%, 24.45%±4.89%, 17.48%±2.93%, and 21.44%±2.39%, respectively.


Assuntos
Sesquiterpenos , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Sesquiterpenos/química
12.
Zhongguo Zhong Yao Za Zhi ; 47(16): 4436-4445, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046873

RESUMO

This study aims to investigate the effect of atractylenolide Ⅲ(ATL-Ⅲ) on hydrogen peroxide(H_2O_2)-induced endoplasmic reticulum stress and apoptosis of H9 c2 cells via the ROS/GRP78/caspase-12 signaling pathway.The binding activity of ATL-Ⅲ to GRP78 was determined by molecular docking.The result showed that ATL-Ⅲ had a good binding activity to GRP78, and the binding activity of ATL-Ⅲ was stronger than that of its specific inhibitor.The endoplasmic reticulum stress model of H9 c2 was established by H_2O_2(100 µmol·L~(-1)) treatment.Five groups were designed: blank control group, model group, and ATL-Ⅲ(15, 30, and 60 µmol·L~(-1)) groups.Apoptosis was detected by Hoechst/PI double staining and flow cytometry.The levels of superoxide dismutase(SOD), malondialdehyde(MDA), and lactate dehydrogenase(LDH) were measured by colorimetry.The levels of reactive oxygen species(ROS) and calcium(Ca~(2+)) in cytoplasm were determined by the fluorescence probe DCFH-DA and the calcium fluorescence probe Flou-4, respectively.The protein levels of GRP78, caspase-12, and caspase-3 were determined by Western blot, and the mRNA levels of GRP78 and caspase-12 by RT-qPCR.N-acetyl-L-cysteine(NAC) and 4-phenylbutyric acid(4-PBA) were respectively used to inhibit ROS and GRP78, and then the mechanism of ATL-Ⅲ in protecting the cells from endoplasmic reticulum stress induced by H_2O_2 were deduced.ATL-Ⅲ(15, 30, and 60 µmol·L~(-1)) decreased the apoptosis rate and ROS, MDA, and LDH levels(P<0.01), increased the SOD activity(P<0.01), and down-regulated the protein levels of GRP78, caspase-12, and caspase-3 and the mRNA levels of GRP78 and caspase-12(P<0.05).The addition of NAC decreased the apoptosis rate and ROS, MDA, GRP78, caspase-12, and caspase-3 levels(P<0.01), while it elevated the SOD level(P<0.01).The addition of 4-PBA also decreased the apoptosis rate and the levels of GRP78, caspase-12, caspase-3, and Ca~(2+)(P<0.01).The effect of inhibitors were consistent with that of ATL-Ⅲ.In conclusion, ATL-Ⅲ can protect H9 c2 cardiomyocytes by regulating ROS/GRP78/caspase-12 signaling pathway to inhibit H_2O_2-induced endoplasmic reticulum stress and apoptosis.


Assuntos
Cálcio , Chaperona BiP do Retículo Endoplasmático , Apoptose , Cálcio/farmacologia , Caspase 12/genética , Caspase 12/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Estresse do Retículo Endoplasmático , Lactonas , Simulação de Acoplamento Molecular , RNA Mensageiro , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos , Transdução de Sinais , Superóxido Dismutase/metabolismo
13.
Allergol Immunopathol (Madr) ; 50(5): 39-46, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36086962

RESUMO

Sepsis induces multiple organ dysfunction syndromes, such as acute kidney, liver, or lung injury. Septic lung injury is associated with excessive apoptosis and inflammatory responses in hepatocytes. Deoxyelephantopin is a sesquiterpene lactone found in Elephantopus scaber L, and has immunomodulatory, antibacterial, anti-inflammatory, and antifungal properties. The role of deoxyelephantopin in sepsis-associated lung injury was investigated. First, human bronchial epithelial cells (BEAS-2B) and human pulmonary artery endothelial cells (HPAEC) were treated with lipopolysaccharide to induce cytotoxicity. Treatment with lipopolysaccharide reduced cell viability of BEAS-2B and HPAEC, and promoted cell apoptosis through down-regulation of poly (ADP-ribose) polymerase (PARP) and B-cell lymphoma 2 (Bcl-2), and up-regulation of cleaved PARP and B-cell lymphoma-associated X protein (Bax). Second, lipopolysaccharide-treated BEAS-2B and HPAEC were incubated with increasing concentrations of deoxyelephantopin, that is, 1, 5, or 10 µM. Deoxyelephantopin enhanced cell viability and reduced cell apoptosis of lipopolysaccharide-treated BEAS-2B and HPAEC. Third, deoxyelephantopin attenuated lipopolysaccharide-induced decrease of superoxide dismutase and glutathione, and increase of malondialdehyde and myeloperoxidase in BEAS-2B and HPAEC. Moreover, deoxyelephantopin also weakened lipopolysaccharide-induced increase of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. Finally, deoxyelephantopin decreased protein expression of p-p65 and p-signal transducer and activator of transcription 3 (STAT3) in lipopolysaccharide-treated BEAS-2B and HPAEC. In conclusion, deoxyelephantopin exhibited anti-oxidative and anti-inflammatory effects against lipopolysaccharide-treated BEAS-2B and HPAEC through inactivation of nuclear factor kappa B/STAT3 signaling.


Assuntos
Lesão Pulmonar , Sepse , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Células Endoteliais/metabolismo , Humanos , Lactonas , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases , Fator de Transcrição STAT3 , Sepse/tratamento farmacológico , Sesquiterpenos
14.
J Agric Food Chem ; 70(36): 11336-11343, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36047715

RESUMO

Longifolene as an important sesquiterpene had enormous biological benefits. However, the low productivity of longifolene relying on chemical catalysis and plant extraction limited its wide application. Herein, the longifolene biosynthetic pathway was introduced into Saccharomyces cerevisiae, and multiple genetic strategies were applied to debottleneck the synthesis of longifolene, including the regulation of the rate-limiting enzymes, the elimination of the competitive pathways, the screening of the molecular chaperone to improve synthase activity, and the enhancement of the precursor supply. After combinationally applying these optimum strategies, the production of longifolene reached 27.30 mg/L in shake flasks and 1249 mg/L in fed-batch fermentation, respectively, which was the highest yield of longifolene reported thus far. It was demonstrated that the strategies applied in our work were effective in promoting the biosynthesis of longifolene, which not only laid a significant foundation for its industrial production but also provided a platform for the synthesis of other terpenoids.


Assuntos
Proteínas de Saccharomyces cerevisiae , Sesquiterpenos , Engenharia Metabólica , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Sesquiterpenos/metabolismo
15.
Nutrients ; 14(17)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36079888

RESUMO

The aim of the study was to explain the effects of sesquiterpene lactones (SLs) from chicory (Cichorium intybus L.) root extracts as inhibitors of acetylcholinesterase (AChE) at the molecular level and to determine the inhibition of AChE activity by specific SLs (lactucin and lactucopicrin) and different chicory extracts. The obtained SLs-rich extracts were purified by the countercurrent partition chromatography (CPC) technique. AChE inhibitors were analyzed using two models: isothermal titration calorimetry (ITC) and docking simulation. The results of ITC analysis of the enzyme and the ligands' complexation showed strong interactions of SLs as well as extracts from chicory with AChE. In a test of enzyme activity inhibition after introducing acetylcholine into the model system with SL, a stronger ability to inhibit the hydrolysis of the neurotransmitter was observed for lactucopicrin, which is one of the dominant SLs in chicory. The inhibition of enzyme activity was more efficient in the case of extracts, containing different enzyme ligands, exhibiting complementary patterns of binding the AChE active site. The study showed the high potential of using chicory to decrease the symptoms of Alzheimer's disease.


Assuntos
Chicória , Sesquiterpenos , Acetilcolinesterase/metabolismo , Calorimetria , Chicória/química , Inibidores da Colinesterase/farmacologia , Lactonas/química , Lactonas/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Compostos Fitoquímicos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia
16.
Arch Microbiol ; 204(10): 609, 2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-36085195

RESUMO

A novel, mustard yellow-pigmented aerobic bacterial strain designated AR01T was isolated from hypocotyl tissue of a sandalwood seedling from Bangalore, India. The 16S rRNA gene of strain AR01T had the highest 98.97% sequence similarity with Rothia halotolerans YIM 90716T (KCTC 19172) followed by Rothia kristinae PM 129T (NBRC 15354T) (97.31%) and Rothia koreensis P31T (JCM 15915) (97.11%), respectively. The strain AR01T was coccoid-shaped, non-motile, non-spore forming, oxidase negative and catalase positive. The strain AR01T has a genome size of 3.31 Mb containing 2993 protein-coding genes including 48 tRNA and 10 rRNAs spread across 84 contigs. The genomic DNA G + C content was 71.77 mol%. The calculated dDDH was 31.10% and the OrthoANI value was 85.27% when compared with its closest related type strain Rothia halotolerans YIM 90716T. The predominant cellular fatty acids were C16:0 iso, C15:0 anteiso and C17:0 anteiso. The strain AR01T contains major polar lipids including diphosphatidylglycerol and phosphatidylglycerol. The distinct physiological, biochemical characteristics and genotypic relatedness indicated that AR01T represents a novel species of the genus Rothia, for which the name Rothia santali sp. nov. (Type strain AR01T = MCC 4800T = JCM 35593T) is proposed.


Assuntos
Óleos Voláteis , Santalum , Sesquiterpenos , Bactérias , Índia , Micrococcaceae , RNA Ribossômico 16S/genética , Santalum/genética , Plântula
17.
J Enzyme Inhib Med Chem ; 37(1): 2403-2416, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36065895

RESUMO

A series of novel N-alkyl-N-hydroxyl carboximates derived from ß-elemene were fortuitously discovered. Most of them showed more potent anti-proliferative activities than their lead compound ß-elemene (1). Notably, compound 11i exhibited significant inhibitory effects on the proliferation of three lung cell lines (H1975, A549 and H460) and several other tumour cell lines (H1299, U87MG, MV4-11, and SU-DHL-2). Preliminary mechanistic studies revealed that compound 11i could significantly induce cell apoptosis. Further in vivo study in the H460 xenograft mouse model validated the anti-tumour activities of 11i with a greater tumour growth inhibition (TGI, 68.3%) than ß-elemene and SAHA (50.1% and 55.9% respectively) at 60 mg/kg ip dosing, without obvious body weight loss and toxicity. Thus, such N-alkyl-N-hydroxyl carboximate class of compounds exemplified as 11i demonstrated potent anticancer activities both in vitro and in vivo, and should warrant further investigation for potential anticancer therapy.


Assuntos
Neoplasias Pulmonares , Sesquiterpenos , Animais , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Sesquiterpenos/farmacologia
18.
Int J Nanomedicine ; 17: 3443-3456, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35959279

RESUMO

Purpose: While developing huperzine A (HupA) to explore new approaches to treating Alzheimer's disease (AD), intranasal administration was proposed as an alternative route to deliver drugs into the brain. This study aimed to prepare nanoemulsions (NEs) of HupA to investigate their potential "nose-to-brain" pathways and to evaluate their pharmacokinetic and brain-targeting parameters. Methods: HupA-NE and Lf-HupA-NE that underwent surface modification with lactoferrin (Lf) were characterized to determine various physicochemical properties, such as their size, PDI, zeta potential, pH, and loading efficiency; in addition, transmission electron microscopy and stability assessments were performed. We utilized an aggregation-caused quenching (ACQ) probe to monitor intact NEs in the brains of olfactory nerve transection model and normal rats. Immunohistochemistry, pharmacokinetic and targeting index analyses were performed to investigate the in vivo effects of HupA-NE and Lf-HupA-NE. Results: Based on the live imaging results, HupA-NE and Lf-HupA-NE could be transported into the brain via nerve and blood circulation pathways. Immunohistochemical staining tests demonstrated that the efflux proteins P-gp, MRP1, and BCRP were expressed in brain tissue. NEs can inhibit efflux pumps to improve drug concentrations in the brain. The findings of this study showed that NEs (especially Lf-HupA-NE) had better pharmacokinetic profiles and a better nose-to-brain drug transport efficiency than free HupA. Conclusion: The newly designed formulations might contribute to the transport and accumulation of HupA to achieve therapeutic results. The delivery system may be a promising strategy for the brain-targeted delivery of HupA.


Assuntos
Encéfalo , Proteínas de Neoplasias , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Administração Intranasal , Alcaloides , Animais , Sistemas de Liberação de Medicamentos/métodos , Mucosa Nasal/metabolismo , Proteínas de Neoplasias/metabolismo , Ratos , Sesquiterpenos
19.
Pharm Biol ; 60(1): 1511-1519, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35952383

RESUMO

CONTEXT: Ambrosia artemisiifolia L. (Asteraceae) contains sesquiterpene lactones as characteristic secondary metabolites. Many of these compounds exert antiproliferative and cytotoxic effects. OBJECTIVE: To isolate the sesquiterpene lactones from the aerial part of A. artemisiifolia and to elucidate their cytotoxic, antiproliferative and antibacterial effects. MATERIALS AND METHODS: The compounds were identified by one-dimensional (1D) and 2D NMR, HR-MS spectroscopy from the methanol extract. Isolated compounds were investigated for their cytotoxic and antiproliferative effects on human colonic adenocarcinoma cell lines and human embryonal lung fibroblast cell line using MTT assay. The selectivity of the sesquiterpenes was calculated towards the normal cell line. To check the effect of drug interactions between compounds and doxorubicin, multidrug-resistant Colo 320 cells were used. RESULTS: A new seco-psilostachyinolide derivative, 1,10-dihydro-1'-noraltamisin, and seven known compounds were isolated from the methanol extract. Acetoxydihydrodamsin had the most potent cytotoxic effect on sensitive (Colo205) cell line (IC50 = 7.64 µM), also the strongest antiproliferative effect on Colo205 (IC50 = 5.14 µM) and Colo320 (IC50 = 3.67 µM) cell lines. 1'-Noraltamisin (IC50 = 8.78 µM) and psilostachyin (IC50 = 5.29 µM) showed significant antiproliferative effects on the multidrug-resistant Colo320 cell line and had moderate selectivity against human embryonal lung fibroblast cell line. Psilostachyin C exhibited cytotoxic effects on Colo205 cells (IC50 = 26.60 µM). None of the isolated compounds inhibited ABCB1 efflux pump (EP; P-glycoprotein) or the bacterial EPs. DISCUSSION AND CONCLUSIONS: Acetoxydihydrodamsin, 1'-noraltamisin, and psilostachyin showed the most remarkable cytotoxic and antiproliferative activity on tumour cell lines and exerted selectivity towards MRC-5 cell line.


Assuntos
Adenocarcinoma , Antineoplásicos , Sesquiterpenos , Adenocarcinoma/tratamento farmacológico , Ambrosia/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Lactonas/farmacologia , Metanol , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia
20.
Biomater Adv ; 140: 213069, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35961188

RESUMO

The combination therapy of strengthening inflammation regression and mucosal repair may overcome the "therapeutic ceiling" of ulcerative colitis (UC). However, poor targeting is an outstanding challenge in the preparation of drug delivery systems for UC treatment. Here, we developed anti-inflammatory drug (patchouli alcohol, PA)-loaded nanoparticles (NPs) derived from natural silk fibroin (SF) and subjected to surface functionalization with cyclo RGD peptide (cRGD). Self-assembled SF NPs realized sustained drug release. Meanwhile, cRGD functionalization yielded notably targeted drug delivery to inflamed colon, and thereby enhanced the anti-inflammatory and barrier repair capabilities of NPs. Moreover, cRGD-PASFNs regulated innate immune responses and exerted a potent therapeutic efficacy against acute colitis. Surprisingly, the cRGD-PASFNs also modulated the abnormal level of amino acids which are crucial to the integrity of the intestinal barrier. Additionally, oral delivery of this nanomedicine displayed an excellent safety profile in the mouse model. This study confers confidence for the further development of targeted precision therapy for UC and other inflammatory diseases.


Assuntos
Colite Ulcerativa , Colite , Fibroínas , Nanopartículas , Animais , Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Fibroínas/química , Camundongos , Nanopartículas/química , Peptídeos Cíclicos , Sesquiterpenos
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