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1.
Life Sci ; 258: 118161, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730835

RESUMO

AIMS: Tubulointerstitial inflammation is recognized as a key determinant of progressive sepsis-induced acute kidney injury (AKI). Schisantherin A (SchA) has been shown to be capable of regulating inflammatory processes. In the present study, we explored the possibility of SchA in preventing lipopolysaccharide (LPS)-induced kidney inflammation and injury. MATERIALS AND METHODS: AKI was induced by a single intraperitoneal injection of LPS in CD1 mice, administration of SchA was used for treatment. The protective effect of SchA on renal function and inflammation were analyzed respectively; the NRK-52E cell line was employed for the in vitro study and relative molecular mechanism was explored. KEY FINDINGS: Administration with SchA markedly attenuated LPS-induced damage on renal function and histopathological changes of the kidney. Additionally, pretreatment with SchA could inhibit the expression of inflammatory factors in the kidneys. In NRK-52E cells, SchA treatment significantly inhibited LPS-induced NF-κB activation and pro-inflammatory cytokine expression. Moreover, SchA could promote NRF2 pathway activation, and further blockade of NRF2 activation reversed the SchA-induced inhibition of NF-κB activation. SIGNIFICANCE: These presented results indicated that SchA may have great potential for protecting against sepsis-induced AKI.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/etiologia , Anti-Inflamatórios/uso terapêutico , Ciclo-Octanos/uso terapêutico , Dioxóis/uso terapêutico , Lignanas/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Sepse/complicações , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Linhagem Celular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Ratos , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/patologia , Transdução de Sinais/efeitos dos fármacos
2.
Life Sci ; 256: 117983, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32565252

RESUMO

Estrogen receptor (ER) positive accounts for a large proportion of breast cancer. Although there are many targeted therapeutic drugs, the emergence of drug resistance urgently requires the development of new drugs. Arctigenin (Arc), a lignan found in certain plants of the Asteraceae, has the effect on inhibiting breast cancer, but its molecular mechanism has not been clear. AIMS: To this end, the current study focuses on understanding the mechanism of Arc on ER-positive breast cancer cells. MAIN METHODS: Colony formation experiments and sulforhodamine B methods were used to determine the growth-inhibitory effect of Arc. The cell cycle and apoptosis were analyzed by flow cytometry. Alterations of signaling proteins were measured by Western blotting. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. KEY FINDINGS: The experimental results show that Arc did not induce apoptosis in ER-positive breast cancer cell, rather caused G1 cycle arrest by decreasing cyclin D1 levels without effect on altering CDK4/6 levels. Moreover, we have demonstrated that Arc decreases cyclin D1 levels through prompting Akt/GSK3ß-mediated degradation. SIGNIFICANCE: These findings warrant the potential of Arc as a candidate treatment for ER-positive breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Ciclina D1/metabolismo , Furanos/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Lignanas/farmacologia , Receptores Estrogênicos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Relação Dose-Resposta a Droga , Feminino , Furanos/uso terapêutico , Humanos , Lignanas/uso terapêutico , Células MCF-7 , Proteólise/efeitos dos fármacos
3.
J Neuroimmunol ; 345: 577286, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32559555

RESUMO

We investigated the effects of matairesinol (MAT) in the experimental autoimmune uveitis (EAU), a classical animal model of uveitis. We found that treatment with MAT could alleviate intraocular inflammation of EAU. Notably, Th17 cells in eyes of EAU mice could be predominantly restrained by MAT. Furthermore, MAT could inhibit Th17 differentiation in vitro. In addition, MAT inhibited the signaling of MAPK and ROR-γt, a pivotal transcription factor for Th17 cell differentiation in vitro and in vivo. Taken together, these results suggested that MAT had immune-suppressive effects on autoimmune inflammation through Th17 cells.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Proteínas do Olho/antagonistas & inibidores , Furanos/uso terapêutico , Lignanas/uso terapêutico , Proteínas de Ligação ao Retinol/antagonistas & inibidores , Células Th17/efeitos dos fármacos , Uveíte/tratamento farmacológico , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Proteínas do Olho/imunologia , Proteínas do Olho/metabolismo , Feminino , Adjuvante de Freund/toxicidade , Furanos/farmacologia , Lignanas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Ligação ao Retinol/imunologia , Proteínas de Ligação ao Retinol/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Uveíte/imunologia , Uveíte/metabolismo
4.
Exp Anim ; 69(3): 363-373, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32336744

RESUMO

Schisandrin, an active component extracted from Schisandra chinensis (Turcz.) Baill has been reported to alleviate the cognitive impairment in neurodegenerative disorder like Alzheimer's disease (AD). However, the mechanism by which schisandrin regulates the cognitive decline is still unclear. In our study, intracerebroventricular injection of streptozotocin (STZ) was employed to establish AD model in male Wistar rats, and indicated dose of schisandrin was further administered. The Morris water maze test was performed to evaluate the ability of learning and memory in rats with schisandrin treatment. The results indicated that schisandrin improved the capacity of cognition in STZ-induced rats. The contents of pro-inflammatory cytokines in brain tissue were determined by ELISA, and the expressions of these cytokines were assessed by western-blot and immunohistochemistry. The results showed that treatment of schisandrin significantly reduced the production of inflammation mediators including tumor necrosis factor-α, interleukin-1ß and interleukin-6. Further study suggested a remarkable decrease in the expressions of ER stress maker proteins like C/EBP-homologous protein, glucose-regulated protein 78 and cleaved caspase-12 in the presence of schisandrin, meanwhile the up-regulation of sirtuin 1 (SIRT1) was also observed in the same group. Additionally, the results of western-blot and EMSA demonstrated that schisandrin inhibited NF-κB signaling in the brain of STZ-induced rats. In conclusion, schisandrin ameliorated STZ-induced cognitive dysfunction, ER stress and neuroinflammation which may be associated with up-regulation of SIRT1. Our study provides novel mechanisms for the neuroprotective effect of schisandrin in AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Lignanas/farmacologia , Lignanas/uso terapêutico , Fitoterapia , Compostos Policíclicos/farmacologia , Compostos Policíclicos/uso terapêutico , Schisandra/química , Estreptozocina , Animais , Modelos Animais de Doenças , Masculino , Ratos Wistar , Sirtuína 1/metabolismo , Regulação para Cima/efeitos dos fármacos
5.
J Med Food ; 23(5): 491-498, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32186941

RESUMO

Changing consumption patterns and increasing health awareness, especially in Europe, are resulting in an increased demand for sesame seeds. In 2016, Asia imported the highest quantity of sesame seeds, followed by Europe and North America. We examined, for the first time, the effects of treatment with sesame oil and sesamin in hearing impairment models. Sesame oil exhibited an ameliorative effect on auditory impairment in a hair cell line in zebrafish and mice. In ototoxic zebrafish larvae, neuromasts and otic cells increased in numbers because of sesame oil. Furthermore, auditory function in noise-induced hearing loss (NIHL) was studied through auditory brainstem response to evaluate the therapeutic effects of sesame oil. Sesame oil reduced the hearing threshold shift in response to clicks and 8, 16-kHz tone bursts in NIHL mice. Auditory-protective effect of sesame oil was seen in zebrafish and mice; therefore, we used chromatographic analysis to study sesamin, which is the major effective factor in sesame oil. To investigate its effects related to auditory function, we studied the hearing-related gene, Tecta, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) assay. Auditory cell proliferation was induced by treatment with sesame oil and sesamin using Tecta (Tectorin Alpha) regulation. The expression of Tecta increases in the apex area of the cochlear hair cells as they grow, and their activity is enhanced by sesame oil and sesamin. These results provide a novel mechanistic insight into the sesame oil activities and suggest that sesamin, the key constituent in sesame oil, is responsible for its auditory function related benefits, including protection of auditory cells and reversal of their impairments.


Assuntos
Dioxóis/análise , Dioxóis/uso terapêutico , Células Ciliadas Auditivas/efeitos dos fármacos , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Lignanas/análise , Lignanas/uso terapêutico , Óleo de Gergelim/uso terapêutico , Animais , Linhagem Celular , Expressão Gênica , Larva , Camundongos , Peixe-Zebra
6.
Toxicol Appl Pharmacol ; 391: 114913, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32032644

RESUMO

Pulmonary fibrosis (PF) is an epithelial/fibroblastic crosstalk disorder of the lungs with highly complex etiopathogenesis. Limited treatment possibilities are responsible for poor prognosis and mean survival rate of 3 to 5 years of PF patients after definite diagnosis. Once thought to be an irreversible disorder, recent evidences have brought into existence the concept of organ fibrosis reversibility due to plastic nature of fibrotic tissues. These findings have kindled interest among the scientific community and given a new direction for research in the arena of fibrosis for developing new anti-fibrotic therapies. The current study is designed to evaluate the anti-fibrotic effects of Honokiol (HNK), a neolignan active constituent from Magnolia officinalis. This study has been conducted in TGF-ß1 induced in vitro model and 21 day in vivo murine model of Bleomycin induced PF. The findings of our study suggest that HNK was able to inhibit fundamental pathways of epithelial to mesenchymal transition (EMT) and TGF-ß/Smad signaling both in vitro and in vivo. Additionally, HNK also attenuated collagen deposition and inflammation associated with fibrosis. We also hypothesized that HNK interfered with IL-6/CD44/STAT3 axis. As hypothesized, HNK significantly mitigated IL-6/CD44/STAT3 axis both in vitro and in vivo as evident from outcomes of various protein expression studies like western blotting, immunohistochemistry and ELISA. Taken together, it can be concluded that HNK reversed pulmonary fibrotic changes in both in vitro and in vivo experimental models of PF and exerted anti-fibrotic effects majorly by attenuating EMT, TGF-ß/Smad signaling and partly by inhibiting IL-6/CD44/STAT3 signaling axis.


Assuntos
Compostos de Bifenilo/uso terapêutico , Lignanas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Compostos de Bifenilo/farmacologia , Bleomicina , Líquido da Lavagem Broncoalveolar , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Colágeno/metabolismo , Citocinas/sangue , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Receptores de Hialuronatos , Interleucina-6 , Lignanas/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fator de Transcrição STAT3/efeitos dos fármacos , Proteínas Smad/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos
7.
Int J Biochem Cell Biol ; 121: 105701, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32007602

RESUMO

As one of the major global health issues, allergic disease represents a considerable burden both on individual patients and public health. (-)-Asarinin (Asa), a lignan isolated from the roots of Asiasari radix, was reported to be associated with anti-allergic effect, but its efficacy and mechanism of action remain unclear. This study investigated the inhibitory effect of Asa on allergic reaction and its mechanism of action. Asa significantly suppressed Ag-sensitized human mast cell line LAD2 calcium mobilization, degranulation, and secretion. It also could reduce OVA-induced local and system anaphylaxis of mice in vivo. Further experiments revealed that Asa inhibit the mast cell activation by preventing the phosphorylation of Src family kinases. Moreover, after the IgE-dependent murine model of allergic rhinitis was treated with Asa, not only the concentration of histamine, total IgE, and IL-4 decreased, but also the inflammatory infiltrates and nasal mucosa incrassation were attenuated significantly. Meanwhile, Asa also inhibited the activation of mast cells induced by Compound48/80 in vivo and in vitro. In conclusion, Asa may serve as a potential novel Src family kinase inhibitor to inhibit IgE-dependent andIgE-independent allergic reaction and treat anaphylactic disease.


Assuntos
Dioxóis/uso terapêutico , Lignanas/uso terapêutico , Mastócitos/metabolismo , Quinases da Família src/antagonistas & inibidores , Animais , Dioxóis/farmacologia , Humanos , Lignanas/farmacologia , Camundongos
8.
Cancer Res ; 80(7): 1498-1511, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32041837

RESUMO

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.


Assuntos
Inibidores da Angiogênese/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Adulto , Idoso , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína 1 Semelhante à Quitinase-3/metabolismo , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Glioblastoma/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Lignanas/farmacologia , Lignanas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Microambiente Tumoral/efeitos dos fármacos , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem , Homeobox 1 de Ligação a E-box em Dedo de Zinco/antagonistas & inibidores
9.
Phytother Res ; 34(6): 1397-1408, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31971313

RESUMO

α-Conidendrin is a polyphenolic compound found mainly in Taxus yunnanensis, as the source of chemotherapy drug paclitaxel, which has been used in traditional medicine for treatment of cancer. This study aimed to investigate the anticancer activity and molecular mechanisms of α-conidendrin on breast cancer cell lines. The results of the present study show that α-conidendrin possesses potent antiproliferative effects on breast cancer cell lines MCF-7 and MDA-MB-231. α-Conidendrin significantly induced apoptosis in breast cancer cells via reactive oxygen species generation, upregulation of p53 and Bax, downregulation of Bcl-2, depolarization of mitochondrial membrane potential (MMP), release of cytochrome c from mitochondria, and activation of caspases-3 and -9. α-Conidendrin remarkably inhibited the proliferation of breast cancer cells through induction of cell cycle arrest by upregulating p53 and p21 and downregulating cyclin D1 and CDK4. Unlike breast cancer cells, the antiproliferative effect of α-conidendrin on human foreskin fibroblast cells (normal cells) was very small. In normal cells, reactive oxygen species levels, loss of MMP, release of cytochrome c, mRNA expression of p53, p21, cyclin D1, CDK4, Bax, and Bcl-2 as well as mRNA expression and activity of caspases-3 and -9 were significantly less affected by α-conidendrin compared with cancer cells. These results suggest that α-conidendrin can be a promising agent for treatment of breast cancer with little or no toxicity against normal cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Lignanas/uso terapêutico , Taxus/química , Tetra-Hidronaftalenos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Lignanas/farmacologia , Tetra-Hidronaftalenos/farmacologia
10.
Molecules ; 25(1)2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31947789

RESUMO

In this review article, the occurrence of nor-lignans and their biological activities are explored and described. Nor-lignans have proven to be present in several different families also belonging to chemosystematically distant orders as well as to have many different beneficial pharmacological activities. This review article represents the first one on this argument and is thought to give a first overview on these compounds with the hope that their study may continue and increase, after this.


Assuntos
Lignanas/química , Lignanas/uso terapêutico , Plantas/química , Animais , Humanos
11.
Life Sci ; 240: 117096, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760097

RESUMO

Aim Liver fibrosis represents a massive global health burden with limited therapeutic options. Thus, the need for curative options is evident. Thus, this study aimed to assess the potential antifibrotic effect of honokiol in Concanavalin A (Con A) induced immunological model of liver fibrosis as well the possible underlying molecular mechanisms. METHODS: Male Sprague-Dawley rats were treated with either Con A (20 mg/kg, IV) and/or honokiol (10 mg/kg, orally) for 4 weeks. Hepatotoxicity indices were as well as histopathological evaluation was done. Hepatic fibrosis was assessed by measuring alpha smooth muscle actin (α-SMA) expression and collagen fibers deposition by Masson's trichrome stain and hydroxyproline content. To elucidate the underlying molecular mechanisms, the effect of honokiol on oxidative stress, inflammatory markers as well as transforming growth factor beta (TGF-ß)/SMAD and mitogen-activated protein kinase (MAPK) pathways was assessed. KEY FINDINGS: Honokiol effectively reversed the hepatotoxicity indices elevations and abnormal histopathological changes induced by Con A. Besides, honokiol attenuated Con A-induced liver fibrosis by down-regulation of hydroxyproline levels, α-SMA expression together with a marked decrease in collagen fibers deposition. Mechanistically Con A induced oxidative stress, provocation of inflammatory responses and activation of TGF-ß/SMAD/MAPK pathways. Contrariwise, honokiol co-treatment significantly restored antioxidant defence mechanisms, down-regulated inflammatory cascades and inhibited TGF-ß/SMAD/MAPK signaling pathways. CONCLUSION: The results provide an evidence for the promising antifibrotic effect of honokiol that could be partially due to suppressing oxidative stress and inflammatory processes as well as inhibition of TGF-ß/SMAD/MAPK signaling pathways.


Assuntos
Compostos de Bifenilo/uso terapêutico , Lignanas/uso terapêutico , Cirrose Hepática/prevenção & controle , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Actinas/metabolismo , Animais , Concanavalina A , Hidroxiprolina/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida
12.
Acta Trop ; 202: 105248, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31676458

RESUMO

This paper reports the synthesis of (±)-licarin A 1, a dihydrobenzofuran neolignan, resultant of an oxidative coupling reaction of isoeugenol and horseradish peroxidase (HRP) enzyme. Following, three semi-synthetic derivatives from this compound were obtained: benzylated (±)-licarin A 2, methylated (±)-licarin A 3 and acetylated (±)-licarin A 4. After structural elucidation and assignment by Nuclear Magnetic Resonance of 1H, 13C and DEPT, all compounds were evaluated in vitro against Trypomastigote forms of Trypanosoma cruzi (T. cruzi), the etiologic agent of Chagas disease, and Schistosoma mansoni (S. mansoni) worms, the etiologic agent of schistosomiasis. Compound (4) was the most active against S. mansoni adult worms, displaying worm viability reduction at 25 µM and mortality of all worms at 100 and 200 µM within 24 h. Compound 1 was the second most active, showing worm viability reduction at 50 µM and mortality of 25% and 100% of worms in 24h at concentrations of 100 and 200 µM, respectively. In addition, theoretical calculations aiming at finding molecular properties that showed the correlation for schistosomicidal and trypanocidal activities of (±)-licarin A and three of its semi-synthetic derivatives were also performed.


Assuntos
Lignanas/síntese química , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/síntese química , Tripanossomicidas/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Animais , Doença de Chagas/tratamento farmacológico , Simulação por Computador , Lignanas/farmacologia , Lignanas/uso terapêutico , Esquistossomose/tratamento farmacológico , Esquistossomicidas/farmacologia , Tripanossomicidas/farmacologia
13.
Physiol Res ; 69(1): 61-72, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31852200

RESUMO

Nephrotoxicity of cisplatin (CP) involves renal oxidative stress and inflammation, and sesamin (a major liganin in many plants) has strong antioxidant and antiinflammatory actions. Therefore, we investigated here the possible mitigative action of sesamin on CP nephrotoxicity in rats. Sesamin was given orally (5 mg/kg/day, 10 days), and on the 7th day, some of the treated rats were injected intraperitoneally with either saline or CP (5 mg/kg). On the 11th day, rats were sacrificed, and blood and urine samples and kidneys were collected for biochemical estimation of several traditional and novel indices of renal damage in plasma and urine, several oxidative and nitrosative indices in kidneys, and assessment of histopathological renal damage. CP significantly and adversely altered all the physiological, biochemical and histopathological indices of renal function measured. Kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with sesamin. Sesamin treatment did not significantly alter the renal CP concentration. The results suggested that sesamin had ameliorated CP nephrotoxicity in rats by reversing the CP-induced oxidative stress and inflammation. Pending further pharmacological and toxicological studies sesamin may be considered a potentially useful nephroprotective agent.


Assuntos
Antioxidantes/uso terapêutico , Dioxóis/uso terapêutico , Nefropatias/tratamento farmacológico , Lignanas/uso terapêutico , Fitoterapia , Sesamum , Animais , Antineoplásicos/efeitos adversos , Antioxidantes/farmacologia , Cisplatino/efeitos adversos , Dioxóis/farmacologia , Avaliação Pré-Clínica de Medicamentos , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Lignanas/farmacologia , Masculino , Extratos Vegetais/uso terapêutico , Ratos Wistar
14.
Nat Commun ; 10(1): 4523, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586053

RESUMO

Arctigenin (ATG) is a major component of Fructus Arctii, a traditional herbal remedy that reduced proteinuria in diabetic patients. However, whether ATG specifically provides renoprotection in DKD is not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectrometry analysis identified protein phosphatase 2 A (PP2A) as one of the top ATG-interacting proteins in renal cells. Enhanced PP2A activity by ATG reduces p65 NF-κB-mediated inflammatory response and high glucose-induced migration in cultured podocytes via interaction with Drebrin-1. Importantly, podocyte-specific Pp2a deletion in mice exacerbates DKD injury and abrogates the ATG-mediated renoprotection. Collectively, our results demonstrate a renoprotective mechanism of ATG via PP2A activation and establish PP2A as a potential target for DKD progression.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Furanos/farmacologia , Lignanas/farmacologia , Podócitos/efeitos dos fármacos , Proteína Fosfatase 2/metabolismo , Animais , Arctium/química , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Progressão da Doença , Furanos/uso terapêutico , Humanos , Lignanas/uso terapêutico , Masculino , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Óxido Nítrico Sintase Tipo III/genética , Podócitos/patologia , Podócitos/ultraestrutura , Proteína Fosfatase 2/genética , Estreptozocina/toxicidade , Resultado do Tratamento
15.
Int Immunopharmacol ; 76: 105867, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520994

RESUMO

Mast cells (MCs) play critical roles in allergic reactions and modulating the activation of MCs could be an effective strategy to treat allergic diseases, which cause a rapidly increasing threat to the public health. Herein, we described that Magnolin, a major component from Flos magnoliae could inhibit IgE-dependent MCs activation. We found Magnolin inhibited IgE/Ag-induced calcium mobilization, degranulation, and cytokines release in LAD2 cells. Magnolin was also found to attenuate IgE/Ag-induced mice paw swelling in a dose-dependent manner. Further mechanistic studies suggested a possible anti-allergic and anti-inflammatory effects of Magnolin in IgE/Ag-induced anaphylactic reactions. Thereby, Magnolin could be a potential therapeutic agent for preventing mast cell-related immediate and delayed allergic diseases.


Assuntos
Antialérgicos/uso terapêutico , Hipersensibilidade/tratamento farmacológico , Lignanas/uso terapêutico , Anafilaxia/prevenção & controle , Animais , Antialérgicos/farmacologia , Antígenos , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Edema/tratamento farmacológico , Histamina/metabolismo , Humanos , Hipersensibilidade/imunologia , Imunoglobulina E , Lignanas/farmacologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Peptídeo Hidrolases/metabolismo
16.
Metab Brain Dis ; 34(6): 1689-1703, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31422511

RESUMO

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases which seriously affect the quality of life of the elderly. Schisandrin (SCH) and nootkatone (NKT) are the two marked active components in ASHP. In this study, the effects of Alpinia oxyphylla-Schisandra chinensis herb pair (ASHP) as well as its bioactive components on cognitive deficiency and dementia were revealed via Aß1-42-induced AD in mouse. Morris water maze test showed that acute administration of ASHP and SCH + NKT treatments had higher discrimination index in the object recognition task, more quadrant dwell time and shorter escape latency compared with those in the Morris water maze. The levels of TNF-α, IL-1ß and IL-6 were decreased after ASHP and SCH + NKT treatment. The inflammatory response was attenuated by inhibiting TLR4/ NF-κB/ NLRP3 pathway. In addition, ASHP and SCH + NKT treatments significantly restored the activities of superoxide dismutase (SOD), glutathione S-transferase (GST), cyclooxygenase-2 (COX-2), total antioxidant capacity (T-AOC) and inducible nitric oxide syntheses (iNOS), and the levels of glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO). The histopathological changes of hippocampus were noticeably improved after ASHP and SCH + NKT treatments. These findings demonstrate that ASHP as well as its bioactive components exerted a protective effects on cognitive disorder, inflammatory reaction and oxidative stress.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ciclo-Octanos/uso terapêutico , Lignanas/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Compostos Policíclicos/uso terapêutico , Sesquiterpenos Policíclicos/uso terapêutico , Doença de Alzheimer/metabolismo , Animais , Ciclo-Octanos/farmacologia , Modelos Animais de Doenças , Glutationa/metabolismo , Lignanas/farmacologia , Malondialdeído/metabolismo , Camundongos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Compostos Policíclicos/farmacologia , Sesquiterpenos Policíclicos/farmacologia , Superóxido Dismutase/metabolismo
17.
J Ethnopharmacol ; 245: 112103, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31336134

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cholestasis is a clinical syndrome caused by toxic bile acid retention that will lead to serious liver diseases. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only two FDA-approved drugs for its treatment. Thus, there is a clear need to develop new therapeutic approaches for cholestasis. Here, anti-cholestasis effects of the lignans from a traditional Chinese herbal medicine, Schisandra sphenanthera, were investigated as well as the involved mechanisms. MATERIALS AND METHODS: Adult male C57BL/6J mice were randomly divided into 9 groups including the control group, LCA group, LCA with specific lignan treatment of Schisandrin A (SinA), Schisandrin B (SinB), Schisandrin C (SinC), Schisandrol A (SolA), Schisandrol B (SolB), Schisantherin A (StnA) and Schisantherin B (StnB), respectively. Mice were treated with each drug (qd) for 7 days, while the administration of lithocholic acid (LCA) (bid) was launched from the 4th day. Twelve hours after the last LCA injection, mice were sacrificed and samples were collected. Serum biochemical measurement and histological analysis were conducted. Metabolomics analysis of serum, liver, intestine and feces were performed to study the metabolic profile of bile acids. RT-qPCR and Western blot analysis were conducted to determine the hepatic expression of genes and proteins related to bile acid homeostasis. Dual-luciferase reporter gene assay was performed to investigate the transactivation effect of lignans on human pregnane X receptor (hPXR). RT-qPCR analysis was used to detect induction effects of lignans on hPXR-targeted genes in HepG2 cells. RESULTS: Lignans including SinA, SinB, SinC, SolA, SolB, StnA, StnB were found to significantly protect against LCA-induced intrahepatic cholestasis, as evidenced by significant decrease in liver necrosis, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) activity. More importantly, serum total bile acids (TBA) and total bilirubin (Tbili) were also significantly reduced. Metabolomics analysis revealed these lignans accelerated the metabolism of bile acids and increased the bile acid efflux from liver into the intestine or feces. Gene analysis revealed these lignans induced the hepatic expressions of PXR-target genes such as Cyp3a11 and Ugt1a1. Luciferase reporter gene assays illustrated that these bioactive lignans can activate hPXR. Additionally, they can all upregulate hPXR-regulate genes such as CYP3A4, UGT1A1 and OATP2. CONCLUSION: These results clearly demonstrated the lignans from Schisandra sphenanthera exert hepatoprotective effects against LCA-induced cholestasis by activation of PXR. These lignans may provide an effective approach for the prevention and treatment of cholestatic liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Colestase/tratamento farmacológico , Lignanas/uso terapêutico , Receptor de Pregnano X/genética , Substâncias Protetoras/uso terapêutico , Schisandra , Animais , Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/induzido quimicamente , Colestase/metabolismo , Colestase/patologia , Fezes/química , Células HEK293 , Células Hep G2 , Humanos , Mucosa Intestinal/metabolismo , Lignanas/farmacologia , Ácido Litocólico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia
18.
Phytother Res ; 33(9): 2421-2428, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31309643

RESUMO

Inflammation is one of the main characteristics of rheumatoid arthritis. Based on the antiinflammatory properties of sesame, this study was conducted to evaluate the sesamin supplement effects on serum levels of some proteolytic enzymes, inflammatory biomarkers, and clinical indices in women with rheumatoid arthritis. In this randomized, triple-blind, placebo-controlled clinical trial, 44 patients were randomly divided in intervention and control groups. Patients received 200-mg/day sesamin supplement or placebo in the intervention and control group for 6 weeks. Serum levels of proteolytic enzymes (hyaluronidase, aggrecanase, and matrix metalloproteinases-3) and inflammatory biomarkers (hs-CRP, IL-1ß, IL-6, TNF-α, and cyclooxygenase-2) were measured with enzyme-linked immunosorbent assay method at the beginning and end of the study. After intervention, serum levels of hyaluronidase and matrix metalloproteinases-3 decreased significantly in sesamin group. Also, serum levels of hs-CRP, TNF-α, and cyclooxygenase-2 in intervention group were significantly decreased in intervention group compared with placebo group. Sesamin supplementation also caused a significant reduction in the number of tender joints and severity of pain in these patients. According to the results, it seems that the sesamin by reducing inflammatory mediators can relieve clinical symptoms and pathological changes that caused by inflammatory impairment in patients with rheumatoid arthritis.


Assuntos
Antioxidantes/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/sangue , Dioxóis/uso terapêutico , Inflamação/sangue , Lignanas/uso terapêutico , Peptídeo Hidrolases/metabolismo , Antioxidantes/farmacologia , Artrite Reumatoide/patologia , Suplementos Nutricionais , Dioxóis/farmacologia , Método Duplo-Cego , Feminino , Humanos , Lignanas/farmacologia , Pessoa de Meia-Idade
19.
Acta Pharmacol Sin ; 40(9): 1219-1227, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31235819

RESUMO

Honokiol (HNK), an active compound isolated from traditional Chinese medicine Magnolia officinalis, has shown potent anticancer activities. In the present study, we investigated the effects of HNK on breast cancer metastasis in vitro and in vivo, as well as the underlying molecular mechanisms. We showed that HNK (10-70 µmol/L) dose-dependently inhibited the viability of human mammary epithelial tumor cell lines MCF7, MDA-MB-231, and mouse mammary tumor cell line 4T1. In the transwell and scratch migration assays, HNK (10, 20, 30 µmol/L) dose-dependently suppressed the invasion and migration of the breast cancer cells. We demonstrated that HNK (10-50 µmol/L) dose-dependently upregulated the epithelial marker E-cadherin and downregulated the mesenchymal markers such as Snail, Slug, and vimentin at the protein level in breast cancer cells. Using a puromycin incorporation assay, we showed that HNK decreased the Snail translation efficiency in the breast cancer cells. In a mouse model of tumor metastasis, administration of HNK (50 mg/kg every day, intraperitoneal (i.p.), 6 times per week for 30 days) significantly decreased the number of metastatic 4T1 cell-derived nodules and ameliorated the histological alterations in the lungs. In addition, HNK-treated mice showed decreased Snail expression and increased E-cadherin expression in metastatic nodules. In conclusion, HNK inhibits EMT in the breast cancer cells by downregulating Snail and Slug protein expression at the mRNA translation level. HNK has potential as an integrative medicine for combating breast cancer by targeting EMT.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Lignanas/uso terapêutico , Fatores de Transcrição da Família Snail/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Compostos de Bifenilo/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Humanos , Lignanas/farmacologia , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos BALB C
20.
Biomed Res Int ; 2019: 1847130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240205

RESUMO

Over years, various biological constituents are isolated from Traditional Chinese Medicine and confirmed to show multifunctional activities. Magnolol, a hydroxylated biphenyl natural compound isolated from Magnolia officinalis, has been extensively documented and shows a range of biological activities. Many signaling pathways include, but are not limited to, NF-κB/MAPK, Nrf2/HO-1, and PI3K/Akt pathways, which are implicated in the biological functions mediated by magnolol. Thus, magnolol is considered as a promising therapeutic agent for clinic research. However, the low water solubility, the low bioavailability, and the rapid metabolism of magnolol dramatically limit its clinical application. In this review, we will comprehensively discuss the last five-year progress of the biological activities of magnolol, including anti-inflammatory, antimicroorganism, antioxidative, anticancer, neuroprotective, cardiovascular protection, metabolism regulation, and ion-mediating activity.


Assuntos
Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Lignanas/metabolismo , Lignanas/farmacologia , Medicina Tradicional Chinesa , Anti-Inflamatórios/análise , Antineoplásicos/análise , Antioxidantes/análise , Compostos de Bifenilo/química , Compostos de Bifenilo/uso terapêutico , Fármacos Cardiovasculares/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Lignanas/química , Lignanas/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Magnolia/química , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/análise , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
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