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1.
Fitoterapia ; 175: 105924, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38537886

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and accumulating evidence suggested that proteostatic imbalance is a key feature of the disease. Traditional Chinese medicine exhibits a multi-target therapeutic effect, making it highly suitable for addressing protein homeostasis imbalance in AD. Dendrobium officinale is a traditional Chinese herbs commonly used as tonic agent in China. In this study, we investigated protection effects of D. officinale phenolic extract (SH-F) and examined its underlying mechanisms by using transgenic Caenorhabditis elegans models. We found that treatment with SH-F (50 µg/mL) alleviated Aß and tau protein toxicity in worms, and also reduced aggregation of polyglutamine proteins to help maintain proteostasis. RNA sequencing results showed that SH-F treatment significantly affected the proteolytic process and autophagy-lysosomal pathway. Furthermore, we confirmed that SH-F showing maintainance of proteostasis was dependent on bec-1 by qRT-PCR analysis and RNAi methods. Finally, we identified active components of SH-F by LC-MS method, and found the five major compounds including koaburaside, tyramine dihydroferulate, N-p-trans-coumaroyltyramine, naringenin and isolariciresinol are the main bioactive components responsible for the anti-AD activity of SH-F. Our findings provide new insights to develop a treatment strategy for AD by targeting proteostasis, and SH-F could be an alternative drug for the treatment of AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Autofagia , Caenorhabditis elegans , Dendrobium , Modelos Animais de Doenças , Extratos Vegetais , Proteostase , Animais , Caenorhabditis elegans/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Dendrobium/química , Proteostase/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Extratos Vegetais/farmacologia , Animais Geneticamente Modificados , Proteínas tau/metabolismo , Fenóis/farmacologia , Fenóis/isolamento & purificação , Flavanonas/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação
2.
BMC Complement Med Ther ; 23(1): 386, 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37891552

RESUMO

BACKGROUND: Liensinine and neferine are the main bisbenzylisoquinoline alkaloids obtained from the seeds of Nelumbo nucifera, which commonly used as edible food and traditional medicine in Asia. It was reported that liensinine and neferine could inhibit the activities of acetylcholinesterase and cross the blood-brain barriers, suggesting their therapeutic potential for the management of Alzheimer's disease. METHODS: Here, we employed SH-SY5Y human neuroblastoma cells stably transfected with the human Swedish amyloid precursor protein (APP) mutation APP695 (APP695swe SH-SY5Y) as an in vitro model and transgenic Caenorhabditis elegans as an in vivo model to investigate the neuroprotective effects and underlying mechanism of liensinine and neferine. RESULTS: We found that liensinine and neferine could significantly improve the viability and reduce ROS levels in APP695swe SH-SY5Y cells, inhibit ß-amyloid and tau-induced toxicity, and enhance stress resistance in nematodes. Moreover, liensinine and neferine had obviously neuroprotective effects by assaying chemotaxis, 5-hydroxytryptamine sensitivity and the integrity of injured neurons in nematodes. Preliminary mechanism studies revealed that liensinine and neferine could upregulate the expression of autophagy related genes (lgg-1, unc-51, pha-4, atg-9 and ced-9) and reduce the accumulation of ß-amyloid induced autophagosomes, which suggested autophagy pathway played a key role in neuroprotective effects of these two alkaloids. CONCLUSIONS: Altogether, our findings provided a certain working foundation for the use of liensinine and neferine to treat Alzheimer's disease based on neuroprotective effects.


Assuntos
Alcaloides , Doença de Alzheimer , Benzilisoquinolinas , Neuroblastoma , Fármacos Neuroprotetores , Animais , Humanos , Caenorhabditis elegans , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase , Doença de Alzheimer/tratamento farmacológico , Benzilisoquinolinas/farmacologia , Alcaloides/farmacologia , Animais Geneticamente Modificados , Autofagia
3.
Cells ; 12(11)2023 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-37296597

RESUMO

Drug-induced liver injury (DILI) is a major contributor to high attrition rates among candidate and market drugs and a key regulatory, industry, and global health concern. While acute and dose-dependent DILI, namely, intrinsic DILI, is predictable and often reproducible in preclinical models, the nature of idiosyncratic DILI (iDILI) limits its mechanistic understanding due to the complex disease pathogenesis, and recapitulation using in vitro and in vivo models is extremely challenging. However, hepatic inflammation is a key feature of iDILI primarily orchestrated by the innate and adaptive immune system. This review summarizes the in vitro co-culture models that exploit the role of the immune system to investigate iDILI. Particularly, this review focuses on advancements in human-based 3D multicellular models attempting to supplement in vivo models that often lack predictability and display interspecies variations. Exploiting the immune-mediated mechanisms of iDILI, the inclusion of non-parenchymal cells in these hepatoxicity models, namely, Kupffer cells, stellate cells, dendritic cells, and liver sinusoidal endothelial cells, introduces heterotypic cell-cell interactions and mimics the hepatic microenvironment. Additionally, drugs recalled from the market in the US between 1996-2010 that were studies in these various models highlight the necessity for further harmonization and comparison of model characteristics. Challenges regarding disease-related endpoints, mimicking 3D architecture with different cell-cell contact, cell source, and the underlying multi-cellular and multi-stage mechanisms are described. It is our belief that progressing our understanding of the underlying pathogenesis of iDILI will provide mechanistic clues and a method for drug safety screening to better predict liver injury in clinical trials and post-marketing.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Células Endoteliais , Humanos , Hepatócitos , Avaliação Pré-Clínica de Medicamentos
4.
Front Pharmacol ; 13: 851267, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35586044

RESUMO

Tiaoganquzhi Decoction (TGQZD) is a traditional Chinese herbal formulation demonstrated to be a clinically effective treatment for nonalcoholic fatty liver disease (NAFLD), although details concerning its clinical mechanism are poor. This study aimed to explore the mechanism of TGQZD on improvement of inflammatory damage and dyslipidemia caused by NAFLD through the CGI-58/ROS/NLRP3 inflammasome pathway. In our research, the in vivo protective effects of TGQZD on HFD-induced liver injury in rats and in vitro using lipopolysaccharide (LPS)+palmitate (PA)-stimulated HepG-2 cells model. Histological changes were evaluated by hematoxylin-eosin and Oil Red O staining. Inflammatory cytokines and protein expression were analyzed by ELISA, Real time PCR and western blotting. Liver function, blood lipids, free fatty acids (FFA), and reactive oxygen species (ROS) were determined by biochemical detection. Our results indicated that TGQZD exhibited anti-inflammatory activity, reduced the severity of NAFLD and ameliorated the pathological changes. Further, TGQZD improved liver function and lipid metabolism in NAFLD rats. TGQZD lowered serum aspartate aminotransferase, alanine aminotransferase, triglyceride, and total cholesterol levels. TGQZD suppressed the formulation of FFA and ROS. It also reduced the expression and release of the inflammatory cytokine interleukin-1ß by promoting CGI-58 expression and inhibiting the expression of FFA, TNF-α, and the NLRP3 inflammasome induced by ROS. TGQZD exhibited anti-inflammatory effects via the CGI-58, ROS and NLRP3 inflammasome pathway in vivo and in vitro, respectively. Our findings demonstrated that TGQZD is a useful and effective therapeutic agent for treating NAFLD via promotion of CGI-58 to inhibit the expression of ROS-induced NLRP3 inflammasome.

5.
Fitoterapia ; 158: 105165, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35218907

RESUMO

Twelve dihydro-ß-agarofuran-type sesquiterpenoids, including five new ones (1-5), were purified from the seeds of Celastrus virens (Wang et Tang) C. Y. Chent et T. C. Kao. Their chemical structures were characterized via comprehensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and computational prediction of ECD, as well as comparison of observed and reported NMR spectral data. Among the isolates, nine abundant dihydro-ß-agarofuran-type sesquiterpenoids were evaluated for their lifespan-extending activity using the nematode Caenorhabditis elegans model. As a result, compounds 1, 2, 5, 6, 8, and 9 (50 µM) significantly extended the mean survival time of C. elegans, respectively, compared with the blank control group (p < 0.05). Further Quantitative RT-PCR showed that the prolonging of lifespan mediated by compounds 1, 6, 8, and 9 were dependent on the transcription factors skn-1 and hsf-1.


Assuntos
Proteínas de Caenorhabditis elegans , Celastrus , Sesquiterpenos , Animais , Caenorhabditis elegans , Celastrus/química , Longevidade , Estrutura Molecular , Sementes/química , Sesquiterpenos/química
6.
Food Funct ; 12(18): 8774-8786, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34374387

RESUMO

Polygonum multiflorum Thunb (PMT), as a traditional Chinese herbal medicine, has been widely used in the prevention and treatment of aging-related diseases, including Alzheimer's disease, Parkinson's disease, hyperlipidemia, atherosclerosis and inflammation. However, the effect of PMT on the lifespan and its molecular mechanisms are still unclear. Here we found that 60% ethanol refined fraction (PMT-E) of Polygonum multiflorum Thunb at 50 µg mL-1, which contained two main bioactive compounds, 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) and emodin-8-O-ß-D-glucoside (EG), could significantly increase the mean lifespan by 19.82%, delay the age-related decline of phenotypes, enhance stress resistance and reduce ROS accumulation in Caenorhabditis elegans. Moreover, we also found that the mitochondrial membrane potential (ΔΨ) and ATP content of worms treated with 50 µg mL-1 PMT-E were obviously improved. Further mechanistic studies revealed that DAF-16, SIR-2.1 and SKN-1 transcription factors were required for PMT-E-mediated lifespan extension. Finally, we found that PMT-E could significantly inhibit the toxicity induced by ß-amyloid (Aß) in Aß transgenic worms. Altogether, these findings laid the foundation for the use of Polygonum multiflorum Thunb to treat aging and age-related diseases.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Fallopia multiflora , Longevidade/efeitos dos fármacos , Envelhecimento , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Quimiotaxia , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Mitocôndrias/metabolismo , Modelos Animais , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sirtuínas/metabolismo , Fatores de Transcrição/metabolismo
7.
Pharm Biol ; 59(1): 683-695, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34110957

RESUMO

CONTEXT: Jian Pi Qing Chang Hua Shi decoction (JPQCHSD) has been considered as an effective remedy for the treatment of inflammatory bowel disease (IBD) in Chinese traditional medicine. OBJECTIVE: We evaluated the efficacy of JPQCHSD on 2-4-6-trinitrobenzene sulphonic acid (TNBS)-induced IBD rats and the responsible mechanisms. MATERIALS AND METHODS: Except the rats of the control group (50% ethanol), Sprague-Dawley rats (180 ± 20 g) induced by TNBS (150 mg/kg in 50% ethanol), received water extract of JPQCHSD daily at 0, 9.5, 19, or 38 g/kg for 12 days. The rats were sacrificed, and their colons were removed to evaluate the disease activity index. Malondialdehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), immunoglobulin A (IgA), tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and nuclear factor-κB were evaluated. RESULTS: JPQCHSD extract significantly reduced the disease activity index of TNBS-induced colitis with a median effective dose (ED50) of 26.93 g/kg. MPO and MDA were significantly reduced in the 19 and 38 g/kg groups (ED50 values 37.38 and 53.2 g/kg, respectively). The ED50 values for the increased SOD and IgA were 48.98 and 56.3 g/kg. ED50 values for inhibition of TNF-α, IL-1ß, and IL-6 were 32.66, 75.72, and 162.06 g/kg, respectively. DISCUSSION: JPQCHSD promoted mucosal healing in IBD rats via its anti-inflammation, immune regulation, and antioxidation properties. CONCLUSIONS: JPQCHSD has healing function on IBD. Further clinical trials are needed to demonstrate its efficacy and tolerance to IBD.


Assuntos
Anti-Inflamatórios/farmacologia , Colite/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Colite/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Doenças Inflamatórias Intestinais/patologia , Masculino , Medicina Tradicional Chinesa , Ratos , Ratos Sprague-Dawley , Ácido Trinitrobenzenossulfônico
8.
Clin Transl Sci ; 14(5): 1659-1680, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33982436

RESUMO

Nonclinical testing has served as a foundation for evaluating potential risks and effectiveness of investigational new drugs in humans. However, the current two-dimensional (2D) in vitro cell culture systems cannot accurately depict and simulate the rich environment and complex processes observed in vivo, whereas animal studies present significant drawbacks with inherited species-specific differences and low throughput for increased demands. To improve the nonclinical prediction of drug safety and efficacy, researchers continue to develop novel models to evaluate and promote the use of improved cell- and organ-based assays for more accurate representation of human susceptibility to drug response. Among others, the three-dimensional (3D) cell culture models present physiologically relevant cellular microenvironment and offer great promise for assessing drug disposition and pharmacokinetics (PKs) that influence drug safety and efficacy from an early stage of drug development. Currently, there are numerous different types of 3D culture systems, from simple spheroids to more complicated organoids and organs-on-chips, and from single-cell type static 3D models to cell co-culture 3D models equipped with microfluidic flow control as well as hybrid 3D systems that combine 2D culture with biomedical microelectromechanical systems. This article reviews the current application and challenges of 3D culture systems in drug PKs, safety, and efficacy assessment, and provides a focused discussion and regulatory perspectives on the liver-, intestine-, kidney-, and neuron-based 3D cellular models.


Assuntos
Alternativas ao Uso de Animais/métodos , Técnicas de Cultura de Células em Três Dimensões , Avaliação Pré-Clínica de Medicamentos/métodos , Alternativas ao Uso de Animais/normas , Células Cultivadas , Técnicas de Cocultura , Avaliação Pré-Clínica de Medicamentos/normas , Humanos , Intestinos/citologia , Rim/citologia , Fígado/citologia , Neurônios , Esferoides Celulares , Testes de Toxicidade/métodos , Testes de Toxicidade/normas , Estados Unidos , United States Food and Drug Administration/normas
9.
Artigo em Inglês | MEDLINE | ID: mdl-34055009

RESUMO

Transplantation of bone marrow mesenchymal stem cells has attracted more and more attention as a regenerative therapy for the treatment of liver diseases. A large number of studies have shown that this kind of cells can inhibit the activation of hepatic stellate cells and regulate tissue homeostasis and immune system via a variety of ways. Meanwhile, bone marrow mesenchymal stem cells can inhibit apoptosis of hepatocyte, improve liver function, and reduce inflammation through multiple pathways. These cells have a broad prospect in the treatment of liver cirrhosis. At present, there are many studies on the specific mechanism of bone marrow mesenchymal stem cells transplantation in the treatment of liver cirrhosis. This paper reviews the pathogenesis of liver cirrhosis and the mechanism of bone marrow mesenchymal stem cells transplantation in the treatment of liver cirrhosis, discusses the effectiveness of traditional Chinese medicine method in enhancing the efficacy of bone marrow mesenchymal stem cells transplantation, and looks forward to its application prospect in the future.

10.
Biogerontology ; 21(2): 245-256, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31960183

RESUMO

Coix seed oil (CSO) has many beneficial effects, but there is limited research on its influence on the processes and mechanisms related to senescence. Here, we used Caenorhabditis elegans as an in vivo model to investigate CSO's bioeffects on longevity. CSO (1 mg/mL) significantly extended the mean lifespan of C. elegans by over 22.79% and markedly improved stress resistance. Gene-specific mutant studies showed that the CSO-mediated increase in life expectancy was dependent on mev-1, hsf-1 and daf-16, but not daf-2. Furthermore, CSO significantly upregulated stress-inducible genes, including daf-16 and its downstream genes (sod-3, hsp-16.2 and gst-4). In addition, four major fatty acids, linoleic, oleic, palmitic and stearic, played leading roles in C. elegans' extended lifespan. Thus, CSO increased the life expectancy of, and enhanced the stress resistance in, C. elegans mainly through daf-16 and its downstream genes, but not through the insulin/insulin-like growth factor 1 signaling pathway.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Coix , Longevidade/efeitos dos fármacos , Óleos de Plantas/administração & dosagem , Sementes , Estresse Fisiológico/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Coix/química , Citocromos b/genética , Citocromos b/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Óleos de Plantas/isolamento & purificação , Sementes/química , Estresse Fisiológico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
11.
Oxid Med Cell Longev ; 2020: 3515609, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33425207

RESUMO

BACKGROUND: Acorus tatarinowii Schott [Shi Chang Pu in Chinese (SCP)] is a traditional Chinese medicine frequently used in the clinical treatment of dementia, amnesia, epilepsy, and other mental disorders. Previous studies have shown the potential efficacy of SCP against Alzheimer's disease (AD). Nevertheless, the active constituents and the modes of action of SCP in AD treatment have not been fully elucidated. PURPOSE: The aim of this study was to investigate the protective effects of SCP on abnormal proteins and clarify its molecular mechanisms in the treatment of AD by using a Caenorhabditis elegans (C. elegans) model. METHODS: This study experimentally assessed the effect of SCP-Oil in CL4176 strains expressing human Aß in muscle cells and CL2355 strains expressing human Aß in pan-neurons. Western blotting, qRT-PCR, and fluorescence detection were performed to determine the oxidative stress and signaling pathways affected by SCP-Oil in nematodes. RESULTS: SCP-Oil could significantly reduce the deposition of misfolded Aß and polyQ proteins and improved serotonin sensitivity and olfactory learning skill in worms. The analysis of pharmacological action mechanism of SCP-Oil showed that its maintaining protein homeostasis is dependent on the autophagy pathway regulated partly by hsf-1 and sir-2.1 genes. CONCLUSION: Our results provide new insights to develop treatment strategy for AD by targeting autophagy, and SCP-Oil could be an alternative drug for anti-AD.


Assuntos
Acorus/metabolismo , Precursor de Proteína beta-Amiloide/biossíntese , Precursor de Proteína beta-Amiloide/toxicidade , Autofagia/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Óleos Voláteis/farmacologia , Extratos Vegetais/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Quimiotaxia , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Homeostase , Peptídeos/química , Dobramento de Proteína , Transdução de Sinais , Especificidade da Espécie
12.
Free Radic Biol Med ; 129: 310-322, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30266681

RESUMO

Lonicera japonica (LJ) is widely used as the local medicine to improve body and prevent ills in China, but mechanisms of its healthy beneficial effects remain largely unclear. Here, we evaluated the anti-aging and healthspan promoting activities of 75% ethanol extract of LJ (LJ-E) in the animal model Caenorhabditis elegans. Our results showed that LJ-E (500 µg/mL) treatment enhanced the mean lifespan of worms by over 21.87% and significantly improved age-associated physiological functions in C. elegans. The 500 µg/mL concentration of LJ-E enhanced the survival rates under oxidative and thermal stresses, and decreased reactive oxygen species (ROS) levels and fat accumulation in the worms. Gene-specific mutant studies showed that LJ-E-mediated lifespan extension was dependent on mev-1, daf-2, daf-16, and hsf-1, but not eat-2 genes. LJ-E could upregulate stress-inducible genes, viz., hsp-16.2, sod-3 and mtl-1. Moreover, we found that the D1086.10 protein interacted with superoxide dismutase (SOD)-3 by functional protein association networks analysis according to RNA-sequencing results. It was confirmed that D1086.10 was needed to promote longevity, and positively regulated expression of sod-3 by using D1086.10 mutants. Furthermore, LJ-E significantly delayed amyloid ß-protein induced paralysis in CL4176 strain. Given the important role of autophagy in aging and protein homeostasis, we observed that LJ-E could remarkably increase the mRNA expression of autophagy gene bec-1 in CL4176 strain, and decrease expression of autophagy substrate p62 protein by more than 40.0% in BC12921 strain. Finally, we found that combination composed of three major compounds (54 µg/mL chlorogenic acid, 15 µg/mL 1,5-dicaffeoylquinic acid and 7.5 µg/mL 1,3-dicaffeoylquinic acid) of 500 µg/mL LJ-E could significantly delay paralysis in CL4176 worms caused by Aß toxicity, comparable to that of LJ-E. Overall, our study may have important implications in using Lonicera japonica to promote healthy aging and have a potency to design therapeutics for age-related diseases.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Lonicera/química , Espécies Reativas de Oxigênio/antagonistas & inibidores , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/crescimento & desenvolvimento , Tecido Adiposo/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Ácido Clorogênico/farmacologia , Cinamatos/farmacologia , Citocromos b/genética , Citocromos b/metabolismo , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Longevidade/genética , Metalotioneína/genética , Metalotioneína/metabolismo , Paralisia/prevenção & controle , Ácido Quínico/análogos & derivados , Ácido Quínico/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Estresse Fisiológico , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-28630632

RESUMO

Erchen decoction (ECD) and Linguizhugan decoction (LGZGD), both are Chinese herbal formula, have been used clinically for the treatment of nonalcoholic fatty liver disease (NAFLD). However, their therapeutic mechanisms are still unclear. Because insulin resistance (IR) is a key etiological factor in the pathology of high-fat diet- (HFD-) induced NAFLD, in this study, the protective effects of ECD and LGZGD on HFD-induced insulin resistance in rats were evaluated and their mechanisms were investigated by OGTT and Western blot. The results showed that treatment with ECD and LGZGD significantly improved insulin resistance and liver damage in rats, evidenced by supported serum aminotransferase levels and the histopathological examination. ECD and LGZGD also showed significant protective effects against HFD-induced hyperlipidemia and the inhibition of the hepatocyte proliferation by palmitate. Furthermore, supplementation of ECD and LGZGD decreased TNF-α, NF-κB, and IRS-1Ser307 phosphorylation expressions in vivo and in vitro. These results indicated that ECD and LGZGD have protective effects against HFD-induced liver IR and their underlying mechanisms involve the TNF-α and insulin pathway. These findings would be beneficial for understanding of the therapeutic effects of ECD and LGZGD in treatment of NAFLD.

14.
Radiat Res ; 187(6): 672-681, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28375680

RESUMO

Cognitive impairments after brain irradiation seriously affect quality of life for patients, and there is currently no effective treatment. In this study using an irradiated rat model, the role of electroacupuncture was investigated for treatment of radiation-induced brain injury. Animals received 10 Gy exposure to the entire brain, and electroacupuncture was administered 3 days before irradiation as well as up to 2 weeks postirradiation. Behavioral tests were performed one month postirradiation, and rats were then sacrificed for histology or molecular studies. Electroacupuncture markedly improved animal performance in the novel place recognition test. In the emotion test, electroacupuncture reduced defecation during the open-field test, and latency to consumption of food in the novelty suppressed feeding test. Brain irradiation inhibited the generation of immature neurons, but did not cause neural stem cell loss. Electroacupuncture partially restored hippocampal neurogenesis. Electroacupuncture decreased the amount of activated microglia and increased resting microglia in the hippocampus after irradiation. In addition, electroacupuncture promoted mRNA and protein expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In conclusion, electroacupuncture could improve cognitive function and hippocampal neurogenesis after irradiation, and the protective effect of electroacupuncture was associated with the modulation of microglia and upregulation of BDNF in the hippocampus.


Assuntos
Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/terapia , Cognição/efeitos da radiação , Eletroacupuntura/métodos , Hipocampo/fisiopatologia , Neurogênese/efeitos da radiação , Lesões por Radiação/terapia , Animais , Transtornos Cognitivos/etiologia , Irradiação Craniana/efeitos adversos , Campos Eletromagnéticos , Hipocampo/efeitos da radiação , Masculino , Lesões por Radiação/etiologia , Lesões por Radiação/fisiopatologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
15.
Drug Metab Dispos ; 45(2): 198-207, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28062541

RESUMO

Metabolism enzyme induction-mediated drug-drug interactions need to be carefully characterized in vitro for drug candidates to predict in vivo safety risk and therapeutic efficiency. Currently, both the Food and Drug Administration and European Medicines Agency recommend using primary human hepatocytes as the gold standard in vitro test system for studying the induction potential of candidate drugs on cytochrome P450 (CYP), CYP3A4, CYP1A2, and CYP2B6. However, primary human hepatocytes are known to bear inherent limitations such as limited supply and large lot-to-lot variations, which result in an experimental burden to qualify new lots. To overcome these shortcomings, a renewable source of human hepatocytes (i.e., Corning HepatoCells) was developed from primary human hepatocytes and was evaluated for in vitro CYP3A4 induction using methods well established by the pharmaceutical industry. HepatoCells have shown mature hepatocyte-like morphology and demonstrated primary hepatocyte-like response to prototypical inducers of all three CYP enzymes with excellent consistency. Importantly, HepatoCells retain a phenobarbital-responsive nuclear translocation of human constitutive androstane receptor from the cytoplasm, characteristic to primary hepatocytes. To validate HepatoCells as a useful tool to predict potential clinical relevant CYP3A4 induction, we tested three different lots of HepatoCells with a group of clinical strong, moderate/weak CYP3A4 inducers, and noninducers. A relative induction score calibration curve-based approach was used for prediction. HepatoCells showed accurate prediction comparable to primary human hepatocytes. Together, these results demonstrate that Corning HepatoCells is a reliable in vitro model for drug-drug interaction studies during the early phase of drug testing.


Assuntos
Indutores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/biossíntese , Hepatócitos/efeitos dos fármacos , Modelos Biológicos , Células Cultivadas , Receptor Constitutivo de Androstano , Citocromo P-450 CYP3A/genética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Genótipo , Hepatócitos/enzimologia , Humanos , Valor Preditivo dos Testes , Cultura Primária de Células , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo
16.
Biomed Res Int ; 2016: 4847296, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27610376

RESUMO

The purpose of this study was to explore relationships between low dose dietary supplementation with chitosan (COS) and body weight, feed intake, intestinal barrier function, and permeability in mice. Twenty mice were randomly assigned to receive an unadulterated control diet (control group) or a dietary supplementation with 30 mg/kg dose of chitosan (COS group) for two weeks. Whilst no significant differences were found between the conditions for body weight or food and water intake, mice in the COS group had an increased serum D-lactate content (P < 0.05) and a decreased jejunal diamine oxidase (DAO) activity (P < 0.05). Furthermore, mice in COS group displayed a reduced expression of occludin and ZO-1 (P < 0.05) and a reduced expression of occludin in the ileum (P < 0.05). The conclusion drawn from these findings showed that although 30 mg/kg COS-supplemented diet had no effect on body weight or feed intake in mice, this dosage may compromise intestinal barrier function and permeability. This research will contribute to the guidance on COS supplements.


Assuntos
Quitosana/administração & dosagem , Quitosana/farmacologia , Suplementos Nutricionais , Intestinos/patologia , Intestinos/fisiopatologia , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Camundongos Endogâmicos ICR , Permeabilidade/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Junções Íntimas/genética , Proteínas de Junções Íntimas/metabolismo
17.
Int Immunopharmacol ; 34: 212-219, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26971224

RESUMO

Osteoclasts (OC) are large multinucleated cells derived from monocyte/macrophage precursors. Suppressing osteoclastogenesis is considered as an effective therapeutic approach to erosive bone disease. The root of Acorus tatarinowii Schott, a well-known traditional Chinese medicine was used to treat rheumatosis and other inflammatory disease. However, the effects of tatarinan O (TO), one of the lignin-like compounds isolated from the roots of Acorus tatarinowii Schott during bone development are still unclear. In the present study, we explored the effect of TO on RANKL-induced osteoclastogenesis in vitro. TO was found to suppress osteoclast differentiation from RANKL-stimulated mouse bone marrow macrophages (BMMs) without significant cytotoxicity. TO also dose-dependently suppressed bone resorption activity of mature osteoclasts. Additionally, TO apparently inhibited the expression of osteoclastic marker genes, such as MMP-9, Cts K and TRAP. Furthermore, our results showed that TO decreased RANKL-induced expression of c-Fos and NFATc1 without influencing NF-κB activation and MAPK phosphorylation. Hence, for the first time we revealed that TO dose-dependently inhibited osteoclastogenesis from RANKL-stimulated mouse BMMs via decreasing the expression of NFATc1 and c-Fos.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Lignanas/farmacologia , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Acorus/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/genética , Osteoclastos/fisiologia , Raízes de Plantas , Proteínas Proto-Oncogênicas c-fos/genética , Ligante RANK/fisiologia
18.
Molecules ; 21(1): 77, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26760995

RESUMO

Acute respiratory distress syndrome (ARDS),which is inflammatory disorder of the lung, which is caused by pneumonia, aspiration of gastric contents, trauma and sepsis, results in widespread lung inflammation and increased pulmonary vascular permeability. Its pathogenesis is complicated and the mortality is high. Thus, there is a tremendous need for new therapies. We have reported that HJB-1, a 17-hydroxy-jolkinolide B derivative, exhibited strong anti-inflammatory effects in vitro. In this study, we investigated its impacts on LPS-induced ARDS mice. We found that HJB-1 significantly alleviated LPS-induced pulmonary histological alterations, inflammatory cells infiltration, lung edema, as well as the generation of inflammatory cytokines TNF-α, IL-1ß and IL-6 in BALF. In addition, HJB-1 markedly suppressed LPS-induced IκB-α degradation, nuclear accumulation of NF-κB p65 subunit and MAPK phosphorylation. These results suggested that HJB-1 improved LPS-induced ARDS by suppressing LPS-induced NF-κB and MAPK activation.


Assuntos
Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Pulmão/efeitos dos fármacos , Edema Pulmonar/tratamento farmacológico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Animais , Anti-Inflamatórios/isolamento & purificação , Líquido da Lavagem Broncoalveolar/química , Modelos Animais de Doenças , Diterpenos/isolamento & purificação , Medicamentos de Ervas Chinesas , Ativação Enzimática/efeitos dos fármacos , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/metabolismo , Injeções Intraperitoneais , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/biossíntese , Interleucina-1beta/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Interleucina-6/imunologia , Lipopolissacarídeos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia
19.
Fitoterapia ; 108: 5-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26586617

RESUMO

A novel tetralignan, tatarinan T (1) with the rare C8-C7' linkage pattern, along with a known monolignan (2) were isolated from the roots of Acorus tatarinowii Schott. Their chemical structures were elucidated on the basis of NMR and X-ray diffraction analysis. We evaluated the protective effects of two rare lignans against ß-amyloid toxicity by using CL4176 transgenic C. elegans model for the first time, and found that they significantly delayed paralysis of worms at the concentration of 100 µM. Compound 2 exhibited the more potential protective effect against ß-amyloid toxicity, its value of PT50 extended up to 62.3% at 100 µM compared with control, especially, it still has 30.8% extension at 10 µM.


Assuntos
Acorus/química , Caenorhabditis elegans/efeitos dos fármacos , Lignanas/farmacologia , Raízes de Plantas/química , Peptídeos beta-Amiloides/toxicidade , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Medicamentos de Ervas Chinesas/química , Lignanas/isolamento & purificação , Estrutura Molecular , Extratos Vegetais/química
20.
Chin J Nat Med ; 13(7): 550-3, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26233846

RESUMO

The present study investigated the chemical constituents of the roots of Stellera chamaejasme (Thymelaeaceae). One new biflavone glucoside (1), along with other thirteen known compounds (2-14), was isolated by repeated column chromatographic methods and their structures were elucidated on the basis of spectral analyses. The cytotoxic activities of selected compounds were evaluated against four human cancer cell lines (A549, BEL-7402, HCT-116, and MDA-MB-231) by the SRB assay method. Compound 9 showed remarkable cytotoxicity against BEL-7402 with IC50 value being 0.65 µg·mL(-1); compounds 7, 8, and 12 exhibited significant cytotoxic activity against A549 with IC50 values being 2.38, 1.57, and 2.35 µg·mL(-1), respectively.


Assuntos
Biflavonoides/isolamento & purificação , Glucosídeos/isolamento & purificação , Extratos Vegetais/química , Thymelaeaceae/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Biflavonoides/química , Biflavonoides/farmacologia , Linhagem Celular Tumoral , Glucosídeos/química , Glucosídeos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química
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