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1.
Biomed Pharmacother ; 117: 109135, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31226634

RESUMO

Cisplatin is one of the most frequently used chemotherapeutic agents for treatment of a wide range of cancer types. Nevertheless, the intrinsic or acquired resistance to cisplatin remains a major obstacle for cancer therapy. There are a number of factors contributing to the onset of this phenotype resistance. Signal transducers and activators of transcription 3 (STAT3) is constitutively activated in many cancer types, and such hyperactivation is associated with a poor clinical prognosis. In addition, STAT3 inhibitors have shown the ability to enhance the anti-tumor efficacy of cisplatin. In this review, we summarized the current knowledge of the STAT3 pathway in cancer treatment and its contribution to cisplatin resistance. Moreover, this review focuses on targeting STAT3 inhibition to overcome cisplatin resistance.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Cisplatino/uso terapêutico , Humanos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fator de Transcrição STAT3/metabolismo
2.
Biomed Pharmacother ; 112: 108647, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30797149

RESUMO

Cisplatin remains the standard first-line chemotherapeutic agent in the treatment of many types of cancers, but its clinical application is hindered by its severe nephrotoxicity. Previous studies reported that scutellarin enhanced the anti-cancer activity of cisplatin in lung cancer cells, with no confirmation on cisplatin-induced renal damage. Here, we investigated the nephroprotective effect of scutellarin on cisplatin-induced renal injury and its underlying mechanisms. Renal function, histological change, inflammation, apoptosis, autophagy and involved pathways were investigated. Pretreatment with scutellarin prevented cisplatin-induced decline of renal function including BUN, CRE, and histological damage. Scutellarin also reduced renal inflammation by suppressing the levels of pro-inflammatory cytokine, TNF-α and IL-6. Similarly, scutellarin administration inhibited apoptosis triggered by cisplatin through reducing the expressions of Cleaved caspase-3, Cleaved PARP, p53, and the ratio of Bax/Bcl-2. Moreover, scutellarin prevented cisplatin-induced inhibition of autophagy via enhancing LC3-II/LC3-I and Atg7, and inhibition of p62. Of note, the activations of JNK, ERK, p38 and stat3 induced by cisplatin were strikingly attenuated in scutellarin-treated mice. Thus, these results provide compelling evidence that scutellarin is a novel nephroprotectant against cisplatin-induced renal toxicity.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/prevenção & controle , Apigenina/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cisplatino/toxicidade , Glucuronatos/uso terapêutico , Lesão Renal Aguda/patologia , Animais , Apigenina/farmacologia , Apoptose/fisiologia , Autofagia/fisiologia , Glucuronatos/farmacologia , Inflamação/induzido quimicamente , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Distribuição Aleatória
3.
Biomed Pharmacother ; 110: 518-527, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30530287

RESUMO

Cisplatin-based chemotherapeutic regimens are the most frequently used adjuvant treatments for many types of cancer. However, the development of chemoresistance to cisplatin results in treatment failure. Despite the significant developments in understanding the mechanisms of cisplatin resistance, effective strategies to enhance the chemosensitivity of cisplatin are lacking. Phytochemicals are naturally occurring plant-based compounds that can augment the anti-cancer activity of cisplatin, with minimal side effects. Notably, some novel phytochemicals, such as curcumin, not only increase the efficacy of cisplatin but also decrease toxicity induced by cisplatin. However, the exact mechanisms underlying this process remain unclear. In this review, we discussed the progress made in utilizing phytochemicals to enhance the anti-cancer efficacy of cisplatin. We also presented some ideal phytochemicals as novel agents for counteracting cisplatin-induced organ damage.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Animais , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Neoplasias/metabolismo , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/farmacologia
4.
Cancer Chemother Pharmacol ; 83(1): 17-26, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30353226

RESUMO

Autophagy is a ubiquitous catabolic process by which damaged or harmful intracellular components are delivered to the lysosomes for self-digestion and recycling. It is critical in cancer treatment. Therapy-induced autophagy predominantly acts as a pro-survival mechanism, but progressive autophagy can lead to non-apoptotic cell death, also known as autophagic cell death. Plants or herbs contain various natural compounds that are widely used in the treatment of many types of malignancies. Emerging evidence indicates that phytochemicals targeting the autophagic pathway are promising agents for cancer treatment. However, these compounds play different roles in autophagy. In this review, we discussed the role of autophagy in cancer development and therapy, and focussed on elucidating the anti-cancer activities of autophagic modulators, especially phytochemicals. Notably, we described a novel premise that the dynamic role of phytochemicals should be evaluated in regulation of autophagy in cancer.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Autofagia , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
5.
J Cancer ; 9(18): 3247-3256, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271483

RESUMO

Curative molecular therapy for non-small cell lung cancer (NSCLC) is still lacking. Scutellarin, an active flavone extracted from Erigeron breviscapus Hand-Mazz, displays anti-tumor property in diverse cancer types, yet its tumor-suppressive effect on NSCLC is not reported. In this study, we found that scutellarin significantly inhibited the proliferation of NSCLC cells, induced cell apoptosis, and triggered autophagy. Notably, inhibition of autophagy with inhibitor HCQ attenuated the anti-proliferative activity of scutellarin, indicating that scutellarin-induced autophagy is antineoplastic. In addition, HCQ treatment reduced scutellarin-induced apoptosis. Further study demonstrated that scutellarin stimulated phosphorylation of ERK1/2, and inhibition of ERK1/2 with inhibitor U0126 markedly attenuated scutellarin-induced autophagy. Similarly, scutellarin downregulated the expression of p-AKT, and AKT inhibitor MK-2206 induced autophagy. Moreover, there also existed crosstalk between ERK and AKT pathways. Finally, in vivo xenograft nude mice experiment proved that scutellarin treatment significantly reduced tumor growth and increased the levels of LC3-II and p-ERK1/2, suppressed p-AKT in mice tumors. Thus, our study for the first time uncovered the anti-cancer function of scutellarin on NSCLC cells, and might provide a potential novel therapy for treatment of patients with NSCLC.

6.
Front Pharmacol ; 9: 615, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29962947

RESUMO

Bleomycin (BLM) is a broad spectrum anti-tumor drug and inducing pulmonary fibrosis. As an anti-tumor drug without immunosuppression, it is urgent to find a drug that reduces the side effects of BLM. Scutellarin (SCU), a flavone extracted from Erigeron breviscapus (Vant.) Hand-Mazz, has anti-inflammatory activity and ability to inhibit tumor cell growth, migration, and invasion. However, the combined role of SCU and BLM treatment in tumor is unclear. This study aimed to investigate the possible effect and related mechanisms of BLM combined with SCU in the treatment of tumor through in vivo and in vitro experiments. In vivo experiments showed that BLM combined with SCU in the treatment of mice bearing H22 ascites tumor prolonged the survival time, alleviated BLM-induced pulmonary fibrosis, reduced the production of TNF-α; IL-6, and the levels of MDA and MPO. BLM combined with SCU increased the apoptotic rate of H22 ascites cells and the levels of cleaved-caspases-3 and -8. Furthermore, BLM combined with SCU increased the protein expression of p53 and gene expression of miR-29b, and decreased the expression of TGF-ß1. In vitro experiment results showed that BLM combined with SCU inhibited the viability of H22 cells and MRC-5 cells, promoted H22 cell apoptosis, up-regulated the protein expression of p53 and down-regulated the protein expression of α-SMA and collagen-I in MRC-5 cells. These experimental results suggested that SCU could enhance the anti-tumor effect of BLM and reduce BLM-induced pulmonary fibrosis, indicating SCU as a potential adjuvant for BLM in the future.

7.
Int Immunopharmacol ; 62: 15-22, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29966943

RESUMO

Pogostone (PO), a major component of Pogostemon cablin, displays potent protective effects against lipopolysaccharide-induced acute lung injury (ALI) in mice. This study aimed to investigate the protective effect of PO on TNF-α-induced cell injury in human alveolar epithelial cells in vitro and its underlying mechanism. The cell viability was measured using the MTS method. The cell apoptosis was determined using flow cytometry. The activities of reactive oxygen species (ROS) were detected using a fluorescence microscope. The pro-inflammatory cytokines and antioxidant genes were assessed using reverse transcription-polymerase chain reaction. The protein expression of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha (IκBα), and nuclear factor-kappa B (NF-κB) p65 was analyzed using the Western blot analysis. PO alleviated cell apoptosis and inhibited ROS production. It alleviated TNF-α-induced cell injury, suppressed the levels of inflammatory cytokines [interleukin (IL)-6, IL-1ß, and IL-8], and enhanced the expression of antioxidant genes (quinine oxidoreductase 1, glutamate cysteine ligase catalytic subunit, heme oxygenase-1). It increased the expression of Keap1 and promoted the activation of Nrf2. However, the phosphorylation of IκBα and the nuclear expression of NF-κB p65 decreased. The anti-inflammatory and antioxidant effects of PO were abrogated following Nrf2 and NF-κB p65 knockdown. The results indicated a protective effect of PO against TNF-α-induced cell injury in A549 cells by modulating the balance between Nrf2 and NF-κB p65 signaling pathways. They verified PO as a promising anti-inflammatory adjuvant drug for treating ALI.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/antagonistas & inibidores , Óleos Voláteis/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Células A549 , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
8.
Front Pharmacol ; 9: 92, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29487530

RESUMO

Cisplatin, as the first-line anti-tumor agent, is widely used for treatment of a variety of malignancies including non-small cell lung cancer (NSCLC). However, the acquired resistance has been a major obstacle for the clinical application. Scutellarin is a active flavone extracted from Erigeron breviscapus Hand-Mazz that has been shown to exhibit anticancer activities on various types of tumors. Here, we reported that scutellarin was capable of sensitizing A549/DDP cells to cisplatin by enhancing apoptosis and autophagy. Mechanistic analyses indicated that cisplatin-induced caspase-3-dependent apoptosis was elevated in the presence of scutellarin through activating extracellular signal-regulated kinases (ERK)-mediated p53 pathway. Furthermore, scutellarin also promoted cisplatin-induced cytotoxic autophagy, downregulated expression of p-AKT and c-met. Deficiency of c-met reduced p-AKT level, and inhibition of p-AKT or c-met improved autophagy in A549/DDP cells. Interestingly, loss of autophagy attenuated the synergism of this combination. In vivo, the co-treatment of cisplatin and scutellarin notably reduced the tumor size when compared with cisplatin treatment alone. Notably, scutellarin significantly reduced the toxicity generated by cisplatin in tumor-bearing mice. This study identifies the unique role of scutellarin in reversing cisplatin resistance through apoptosis and autophagy, and suggests that combined cisplatin and scutellarin might be a novel therapeutic strategy for patients with NSCLC.

9.
Mol Med Rep ; 15(6): 4239-4246, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28440419

RESUMO

Osthole is the primary active component of a number of herbal plants such as the Cnidium monnieri fruit. In traditional Chinese herb medicine, osthole is commonly used in combination with borneol to obtain improved pharmacological effects. The aim of the present study was to investigate the effect of borneol enantiomers on the pharmacokinetics of osthole. An appropriate high­performance liquid chromatography (HPLC) method was applied to determine the concentrations of osthole in plasma. Following oral administration of osthole alone or combined with borneol in rats, blood samples were collected and analyzed by HPLC. The results demonstrated that there were statistically significant differences in the pharmacokinetic parameters of osthole between osthole administration alone and co­administration with borneol. When combined with synthetic borneol, the AUC0­t, AUC0­∞ and Cmax of osthole increased by 48.153, 104.708 and 92.630%, respectively, while the CL/F decreased by 51.251%. When combined with (+)­borneol, the AUC0­t, AUC0­∞ and Cmax of osthole were increased by 61.561, 78.167, and 51.769%, respectively, while the CL/F decreased by 44.174% (P<0.01). In addition, when combined with (­)­borneol, the AUC0­t, AUC0­∞ and Cmax of osthole increased by 115.856, 167.786 and 271.289%, respectively, while the CL/F decreased by 60.686% (P<0.01). These results indicated that borneol may enhance gastrointestinal absorption and inhibit the metabolism of osthole. In addition, the promotional effect of (­)­borneol on the pharmacokinetic parameters of osthole was greater than that of (+)­borneol.


Assuntos
/farmacologia , Cumarínicos/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Medicamentos de Ervas Chinesas/farmacocinética , Masculino , Medicina Tradicional Chinesa/métodos , Ratos , Ratos Sprague-Dawley
10.
Int Immunopharmacol ; 46: 146-155, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28284148

RESUMO

Usnic acid (UA) can be found in certain lichen species. Growing evidence suggests that UA possesses antitumoral, antioxidative and anti-inflammatory activities. Bleomycin (BLM) is widely used in the treatment of malignant ascites, however, it unexpectedly causes pulmonary fibrosis (PF). Researches show that excessive inflammatory response and oxidative stress in lung tissue is conspicuous causes of BLM-induced PF. Here we investigated mechanism underlying the effect-enhancing and toxicity-reducing activity of UA on H22-bearing mice treated with BLM. UA combined with BLM was significantly more effective than BLM alone in inhibiting the tumor growth, arresting the cell cycle at G0/G1 phase, and promoting the cleaved caspase-3 and cleaved caspase-8 activities to induce cancer cellular apoptosis. The mechanism may be associated with the transcriptional regulation of p53/p21/Cyclin pathway. Furthermore, UA effectively moderated the histopathological changes, reduced the content of MDA, HYP, TNF-α, IL-1ß, IL-6 and TGF-ß1, and increased the level of SOD when combined with BLM in lung tissues of H22-bearing mice, which was believed to be related to the inhibition on the protein level of p-Smad2/3 and enhancement of Smad7 expression. These findings suggested that UA might be a potential effect-enhancing and toxicity-reducing candidate for BLM in the treatment of malignant ascites.


Assuntos
Antineoplásicos/uso terapêutico , Ascite/tratamento farmacológico , Benzofuranos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Neoplasias Hepáticas/tratamento farmacológico , Fibrose Pulmonar/prevenção & controle , Adjuvantes Farmacêuticos , Animais , Apoptose/efeitos dos fármacos , Ascite/complicações , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Carcinoma Hepatocelular/complicações , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Líquens/imunologia , Neoplasias Hepáticas/complicações , Masculino , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais , Fibrose Pulmonar/etiologia , Proteínas Smad/metabolismo
11.
Int J Mol Sci ; 18(3)2017 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-28245556

RESUMO

Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-ß1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Bleomicina/farmacologia , Chrysanthemum/química , Extratos Vegetais/farmacologia , Animais , Antibióticos Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Bleomicina/efeitos adversos , Dióxido de Carbono , Caspase 3/metabolismo , Caspase 8/metabolismo , Linhagem Celular Tumoral , Citocinas/biossíntese , Modelos Animais de Doenças , Sinergismo Farmacológico , Fibrose , Extração Líquido-Líquido/métodos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Neoplasias/patologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Oncotarget ; 8(70): 114945-114955, 2017 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-29383132

RESUMO

There is an urgent need for effective molecular therapies for hepatocellular carcinoma (HCC), the third-leading cause of cancer-related deaths worldwide. Norcantharidin (NCTD), a demethylated derivative of cantharidin, reportedly exhibits anticancer activity against various types of tumors, including HCC, though the mechanisms involved remain largely unknown. Here, we report that NCTD reduces viability of human MHCC-97H (97H) and HepG2 HCC cells, and induces cell death by triggering high levels of autophagy. Moreover, a significant attenuation of tumor growth was observed after NCTD treatment of HepG2 tumors in vivo, and this effect was enhanced by co-treatment with the c-Met inhibitor crizotinib. Interestingly, western blot analyses showed that the cytotoxic autophagy induced by NCTD correlates with a reduction in the phosphorylation status of both c-Met and m-TOR. These results suggest that cytotoxic autophagy resulting from inhibition of c-Met/mTOR signaling may be achieved in HCC by combined NCTD and crizotinib administration. Further studies to validate the therapeutic potential of this approach are warranted.

13.
Food Funct ; 7(11): 4545-4555, 2016 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-27714005

RESUMO

Accumulating evidence has shown that chronic injection of d-galactose (d-gal) can mimic natural aging, with accompanying liver and brain injury. Oxidative stress and apoptosis play a vital role in the aging process. In this study, the antioxidant ability of polydatin (PD) was investigated using four established in vitro systems. An in vivo study was also conducted to investigate the possible protective effect of PD on d-gal-induced liver and brain damage. The results showed that PD had remarkable in vitro free radical scavenging activity on 2,2-diphenyl-1-picryl-hydrazyl (DPPH˙), 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) (ABTS+˙) radical ions, and hydroxyl and superoxide anions. Results in vivo indicated that, in a group treated with d-gal plus PD, PD remarkably decreased the depression of body weight and organ indexes, reduced the levels of the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and alleviated alterations in liver and brain histopathology. PD also significantly decreased the level of MDA and elevated SOD, GSH-Px, CAT activity and T-AOC levels in the liver and brain. In addition, the levels of inflammatory mediators, such as TNF-α, IL-1ß and IL-6 in serum were markedly reduced after PD treatment. Western blotting results revealed that PD treatment noticeably attenuated the d-gal-induced elevation of Bcl-2/Bax ratio and caspase-3 protein expression in liver and brain. Overall, our findings indicate that PD treatment could effectively attenuate d-gal-induced liver and brain damage, and the mechanism might be associated with decreasing the oxidative stress, inflammation and apoptosis caused by d-gal. PD holds good potential for further development into a promising pharmaceutical candidate for the treatment of age-associated diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Encefalopatias/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Galactose/toxicidade , Glucosídeos/farmacologia , Estilbenos/farmacologia , Envelhecimento , Animais , Anti-Inflamatórios/química , Antioxidantes/química , Apoptose/efeitos dos fármacos , Encefalopatias/prevenção & controle , Citocinas , Relação Dose-Resposta a Droga , Glucosídeos/administração & dosagem , Glucosídeos/química , Fígado , Malondialdeído , Camundongos , Estrutura Molecular , Estresse Oxidativo , Estilbenos/administração & dosagem , Estilbenos/química
14.
J Ethnopharmacol ; 186: 91-102, 2016 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-27036629

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Kegan Liyan oral liquid (KGLY), a Chinese prescription modified from classic formulas Yin-Qiao-San (from TCM classic Wenbing Tiaobian) and Shen-Jie-San (first mentioned in Shanghan Wenyi Tiaobian), has been reported to exert heat-clearing and detoxifying effects and used extensively for the treatment of severe pulmonary diseases in clinics including influenza, cough and pneumonia. AIM OF THIS STUDY: The purpose of this study was to investigate the protective effect of KGLY on lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice and to illuminate the underlying mechanisms. MATERIALS AND METHODS: Mice were orally administrated with KGLY (50, 100 and 150mg/kg) before intratracheal instillation of LPS. 24h post LPS challenge, lung tissues and the bronchoalveolar lavage fluid (BALF) were collected for lung wet/dry (W/D) weight ratio, histopathological examinations and biochemical analyses. The cell counts, protein concentration, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), necrosis factor-α (TNF-α), macrophage inflammatory protein-2 (MIP-2) in BALF, superoxide dismutase (SOD), glutathione (GSH), myeloperoxidase (MPO) and malondialdehyde (MDA) levels were detected. Meanwhile, the activation of toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), as well as matrix metalloproteinases 9 (MMP-9) were determined by western blot assay. RESULTS: KGLY significantly prolonged mice survival time and ameliorated LPS-induced edema, thickening of alveolar septa and inflammatory cell infiltration in a dose-dependent manner. Additionally, KGLY markedly attenuated LPS-induced acute pulmonary inflammation via decreasing the expressions of cytokines and chemokines (IL-1ß, IL-6, TNF-α, and MIP-2), enhanced the activities of anti-oxidative indicators (SOD and GSH), suppressed the levels of MPO and MDA, and down-regulated the expressions of TLR4, NF-κB and MMP9. CONCLUSIONS: The results suggested that the relieving effect of KGLY against LPS-induced ALI might be partially due to suppression of oxidative stress and inflammatory response, inhibition of TLR4-mediated NF-κB activation, and down-regulation of MMP9 expression, indicating it may be a potential therapeutic agent for ALI.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Medicamentos de Ervas Chinesas/farmacologia , Lipopolissacarídeos/toxicidade , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores , Lesão Pulmonar Aguda/tratamento farmacológico , Administração Oral , Animais , Antioxidantes/metabolismo , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/genética , Citocinas/metabolismo , Medicamentos de Ervas Chinesas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Metaloproteinase 9 da Matriz/genética , Camundongos , Estrutura Molecular , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
15.
Int Immunopharmacol ; 32: 55-61, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26800098

RESUMO

Pogostone, a major component of Pogostemon cablin, has been demonstrated to possess antibacterial, anti-fungal, immunosuppressive and anti-inflammatory properties. To investigate the potential therapeutic effect of pogostone on lipopolysaccharide (LPS)-induced acute lung injury (ALI), mice were pretreated with pogostone prior to LPS exposure. After LPS challenge, the lungs were excised and the histological changes, wet to dry weight ratios, MPO activity reflecting neutrophil infiltration, and MDA activity reflecting oxidative stress were examined. The inflammatory cytokines in the BALF were determined by ELISA assay. Moreover, the expressions of p65 and phosphorylated p65 subunit of NF-κB, and Nrf2 in the nucleus in lung tissues were measured by Western blot analysis, and meanwhile the dependent genes of NF-κB and Nrf2 were assessed by RT-qPCR. The results showed that pretreatment with pogostone markedly improved survival rate, attenuated the histological alterations in the lung, reduced the MPO and MDA levels, decreased the wet/dry weight ratio of lungs, down-regulated the level of pro-inflammatory mediators including TNF-a, IL-1ß and IL-6. Furthermore, pretreatment with pogostone enhanced the Nrf2 dependent genes including NQO-1, GCLC and HO-1 but suppressed NF-κB regulated genes including TNF-α, IL-1ß and IL-6. The mechanism behind the protective effect was correlated with its regulation on the balance between Keap1-Nrf2 and NF-κB signaling pathways. Therefore, pogostone may be considered as a potential therapeutic agent for preventing and treating ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Óleos Voláteis/farmacologia , Óleos Voláteis/uso terapêutico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Citocinas/imunologia , Proteínas do Citoesqueleto/imunologia , Proteína 1 Associada a ECH Semelhante a Kelch , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Peroxidase/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Huan Jing Ke Xue ; 37(10): 3955-3962, 2016 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-29964432

RESUMO

The process of dissimilatory nitrate reduction to ammonium (DNRA) plays an important role in the presence and conversion of ammonium ions in nature. However, the influencing factors and mechanisms of DNRA process in sulfate-reducing bacteria (SRB) have not yet been identified. The ability, influencing factors and mechanisms of DNRA was investigated in Desulfovibrio sp. CMX isolated previously in our laboratory. The results showed that the production rate of ammonium reached 85.8% and 97.3% respectively with NO3- and NO2- (10 mmol·L-1) as the sole electron donor and nitrogen source. Meanwhile, there was no by-products such as N2 and N2O. Then the effects of different extra nitrogen sources and initial concentrations of sulfate and sulfide on DNRA process were also investigated. As a result, extra nitrogen, yeast extract, could promote DNRA process by improving both growth and metabolism of the strain. In another study, sulfate promoted the nitrate reduction stage while inhibited the nitrite reduction. Overall, the DNRA process by Desulfovibrio sp. CMX was inhibited by sulfate. In addition, both the growth and two stages of the DNRA process were inhibited in the presence of sulfide. Dose effect of sulfide was observed. Inhibition was enhanced with the increase of sulfide concentration. It's noticeable that the inhibition on nitrate reduction was stronger than the inhibition on nitrite reduction with 6 mmol·L-1 of sulfide, leading to the lower reduction rate of nitrate than that of nitrite. In this condition, no accumulation of nitrite was observed in the system.


Assuntos
Compostos de Amônio/metabolismo , Desulfovibrio/metabolismo , Nitratos/metabolismo , Nitritos/metabolismo , Oxirredução
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