RESUMO
Head and neck squamous cell carcinoma (HNSCC) is among the most common malignant tumors worldwide and has a poor prognosis. Autophagy regulation has been proposed as a possible treatment option for HNSCC. Schisandrin B (Sch B) exerts anticancer effects by regulating apoptosis and autophagy, but the anticancer effect of Sch B in HNSCC remains unclear. This study aimed to investigate the effects of Sch B on human Cal27 HNSCC cells and to further reveal its potential regulatory mechanisms. The anticancer effect of Sch B was evaluated in vitro by flow cytometry, clonogenic assays, and Western blot analysis. The regulatory mechanism of Sch B-induced apoptosis and autophagy was further explored by polymerase chain reaction, luciferase assay, and reactive oxygen species (ROS) detection. The results showed that Sch B significantly induced apoptosis and autophagy in Cal27 cells and that inhibition of autophagy enhanced the apoptotic effect of Sch B on Cal27 cells. Additionally, Sch B-activated autophagy in Cal27 cells was dependent on the nuclear factor-kappa B (NF-κB) pathway, and ROS acted as a regulator of the NF-B pathway. N-acetylcysteine, a scavenger of ROS, inhibited Sch B-dependent autophagy via the NF-κB pathway. Based on the results, Sch B is a potential therapeutic agent for HNSCC and activates the NF-κB pathway by increasing ROS production, which subsequently promotes autophagy in HNSCC cells. Therefore, the strategy of enhancing the anticancer effect of Sch B by inhibiting autophagy deserves further attention.
Assuntos
Neoplasias de Cabeça e Pescoço , Lignanas , NF-kappa B , Compostos Policíclicos , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , NF-kappa B/metabolismo , Transdução de Sinais , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Autofagia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Linhagem Celular Tumoral , Ciclo-OctanosRESUMO
Epilepsy is a prevalent and severe neurological disorder and approximately 30% of patients are resistant to existing medications. It is of utmost importance to develop alternative therapies to treat epilepsy. Schisandrin B (SchB) is a major bioactive constituent of Schisandra chinensis (Turcz.) Baill and has multiple neuroprotective effects, sedative and hypnotic activities. In this study, we investigated the antiseizure effect of SchB in various mouse models of seizure and explored the underlying mechanisms. Pentylenetetrazole (PTZ), strychnine (STR), and pilocarpine-induced mouse seizure models were established. We showed that injection of SchB (10, 30, 60 mg/kg, i.p.) dose-dependently delayed the onset of generalized tonic-clonic seizures (GTCS), reduced the incidence of GTCS and mortality in PTZ and STR models. Meanwhile, injection of SchB (30 mg/kg, i.p.) exhibited therapeutic potential in pilocarpine-induced status epilepticus model, which was considered as a drug-resistant model. In whole-cell recording from CHO/HEK-239 cells stably expressing recombinant human GABAA receptors (GABAARs) and glycine receptors (GlyRs) and cultured hippocampal neurons, co-application of SchB dose-dependently enhanced GABA or glycine-induced current with EC50 values at around 5 µM, and application of SchB (10 µM) alone did not activate the channels in the absence of GABA or glycine. Furthermore, SchB (10 µM) eliminated both PTZ-induced inhibition on GABA-induced current (IGABA) and strychnine (STR)-induced inhibition on glycine-induced current (Iglycine). Moreover, SchB (10 µM) efficiently rescued the impaired GABAARs associated with genetic epilepsies. In addition, the homologous mutants in both GlyRs-α1(S267Q) and GABAARs-α1(S297Q)ß2(N289S)γ2L receptors by site-directed mutagenesis tests abolished SchB-induced potentiation of IGABA and Iglycine. In conclusion, we have identified SchB as a natural positive allosteric modulator of GABAARs and GlyRs, supporting its potential as alternative therapies for epilepsy.
Assuntos
Epilepsia , Lignanas , Compostos Policíclicos , Receptores de Glicina , Camundongos , Animais , Humanos , Pilocarpina/efeitos adversos , Estricnina/farmacologia , Estricnina/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Receptores de GABA-A , Glicina/farmacologia , Hipnóticos e Sedativos , Ácido gama-Aminobutírico , Ciclo-OctanosRESUMO
Vascular dementia (VD) a heterogenous group of brain disorders in which cognitive impairment is attributable to vascular risk factors and cerebrovascular disease. A common phenomenon in VD is a dysfunctional cerebral regulatory mechanism associated with insufficient cerebral blood flow, ischemia and hypoxia. Under hypoxic conditions oxygen supply to the brain results in neuronal death leading to neurodegenerative diseases including Alzheimer's (AD) and VD. In conditions of hypoxia and low oxygen perfusion, expression of hypoxia-inducible factor 1 alpha (HIF-1α) increases under conditions of low oxygen and low perfusion associated with upregulation of expression of hypoxia-upregulated mitochondrial movement regulator (HUMMR), which promotes anterograde mitochondrial transport by binding with trafficking protein kinesin 2 (TRAK2). Schisandrin B (Sch B) an active component derived from Chinese herb Wuweizi prevented ß-amyloid protein induced morphological alterations and cell death using a SH-SY5Y neuronal cells considered an AD model. It was thus of interest to determine whether Sch B might also alleviate VD using a rat bilateral common carotid artery occlusion (BCAO) dementia model. The aim of this study was to examine the effects of Sch B in BCAO on cognitive functions such as Morris water maze test and underlying mechanisms involving expression of HIF-1α, TRAK2, and HUMMR levels. The results showed that Sch B improved learning and memory function of rats with VD and exerted a protective effect on the hippocampus by inhibition of protein expression of HIF-1α, TRAK2, and HUMMR factors. Evidence indicates that Sch B may be considered as an alternative in VD treatment.
Assuntos
Demência Vascular , Lignanas , Neuroblastoma , Compostos Policíclicos , Ratos , Humanos , Animais , Demência Vascular/tratamento farmacológico , Demência Vascular/etiologia , Demência Vascular/metabolismo , Aprendizagem em Labirinto/fisiologia , Hipóxia , Cognição , Hipocampo , Oxigênio/farmacologia , Ciclo-OctanosRESUMO
Pyroptosis, an inflammatory programmed cell death, has been suggested as a novel molecular mechanism for the treatment of hepatocellular carcinoma (HCC) with chemotherapeutic agents. Recent studies showed that natural killer (NK) cells could inhibit apoptosis and regulate the progression of pyroptosis in tumor cells. Schisandrin B (Sch B), a lignan isolated from Schisandrae chinensis (Turcz.) Baill. (Schisandraceae) Fructus, has various pharmacological activities including anti-cancer effects. The purpose of this study was to investigate the effect of NK cells on Sch B's regulation of pyroptosis in HCC cells and the molecular mechanisms implicated. The results showed that Sch B alone could decrease cell viability and induce apoptosis in HepG2 cells. However, Sch B induced apoptosis in HepG2 cells was transformed into pyroptosis in the presence of NK cells. The mechanisms underlying NK cell's effect on pyroptosis in Sch B-treated HepG2 cells was related to its activation of caspase 3-Gasdermin E (GSDME). Further studies revealed that NK cell induced caspase 3 activation was derived from its activation of perforin-granzyme B pathway. This study explored the effect of Sch B and NK cells on pyroptosis in HepG2 cells and revealed that perforin-granzyme B-caspase 3-GSDME pathway is involved in the process of pyroptosis. These results proposed an immunomodulatory mechanism of Sch B on HepG2 cells pyroptosis and suggested Sch B as a promising immunotherapy combination partner for the treatment of HCC.
Assuntos
Carcinoma Hepatocelular , Lignanas , Neoplasias Hepáticas , Humanos , Piroptose , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Células Hep G2 , Caspase 3/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Lignanas/farmacologia , Células Matadoras Naturais/metabolismoRESUMO
Panitumumab is an approved monoclonal antibody for the treatment of colorectal cancer (CRC); however, mutations in EGFR signaling pathway resulted in poor response. Schisandrin-B (Sch-B) is a phytochemical that was suggested to protect against inflammation, oxidative stress, and cell proliferation. The present study aimed to investigate the potential effect of Sch-B on panitumumab-induced cytotoxicity in wild-type Caco-2, and mutant HCT-116 and HT-29 CRC cell lines, and the possible underlying mechanisms. CRC cell lines were treated with panitumumab, Sch-B, and their combination. The cytotoxic effect of drugs was determined by MTT assay. The apoptotic potential was assessed in-vitro by DNA fragmentation and caspase-3 activity. Additionally, autophagy was investigated via microscopic detection of autophagosomes and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) measurement of Beclin-1, Rubicon, LC3-II, and Bcl-2 expression. The drug pair enhanced panitumumab cytotoxicity in all CRC cell lines where IC50 of panitumumab was decreased in Caco-2 cell line. Apoptosis was induced through caspase-3 activation, DNA fragmentation, and Bcl-2 downregulation. Caco-2 cell line treated with panitumumab showed stained acidic vesicular organelles, contrariwise, all cell lines treated with Sch-B or the drug pair displayed green fluorescence indicating the lack of autophagosomes. qRT-PCR revealed the downregulation of LC3-II in all CRC cell lines, Rubicon in mutant cell lines, and Beclin-1 in HT-29 cell line only. Sch-B at 6.5 µM promoted panitumumab-induced apoptotic cell death, in-vitro, via caspase-3 activation and Bcl-2 downregulation, rather than autophagic cell death. This novel combination therapy against CRC, allows the reduction of panitumumab dose to guard against its adverse effects.
Assuntos
Apoptose , Neoplasias Colorretais , Humanos , Panitumumabe/farmacologia , Panitumumabe/uso terapêutico , Células CACO-2 , Proteína Beclina-1/metabolismo , Caspase 3 , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Autofagia , Proteínas Proto-Oncogênicas c-bcl-2RESUMO
OBJECTIVE: To investigate the role and possible molecular mechanism of Schisandrin B-induced cell autophagy in the prevention and treatment of APAP-induced liver injury. METHODS: Molecular docking method was used to predict the interaction between Schisandrin B and the EGFR protein. HepG2 cells were treated with different concentrations of Schisandrin B for 24 h. Schisandrin B-induced autophagy of HepG2 cells was determined using real-time label-free cell analysis (RTCA), flow cytometry, immunofluorescence, PCR, and western blot. Flow cytometry and western blot were used to explore whether Schisandrin B-induced autophagy plays a role in the prevention and treatment of liver injury via the EGFR/TFEB signaling pathway. RESULTS: Schisandrin B treatment of APAP-induced HepG2 cells inhibited the production of TNF-α and IL-1ß. Further, Schisandrin B downregulated EGFR protein expression and activated the EGFR/TFEB signaling pathway. Autophagy inhibition promoted APAP-induced apoptosis of HepG2 cells. Moreover, the protein expression levels of TFEB, LC3 and Beclin-1 were upregulated, whereas those of ATG3 and EGFR were downregulated. CONCLUSION: Schisandrin B can induce autophagy in HepG2 cells. Autophagy may play a role in the prevention and treatment of liver injury via the EGFR/TFEB signaling pathway. Activation of autophagy enhances the effect of Schisandrin B on APAP-induced liver injury.
Assuntos
Acetaminofen , Doença Hepática Crônica Induzida por Substâncias e Drogas , Humanos , Simulação de Acoplamento Molecular , Autofagia , Receptores ErbBRESUMO
The aim of this study is to evaluate the anticonvulsant potential of schisandrin B, a main ingredient of Schisandra chinensis extracts. Schisandrin B showed anticonvulsant activity in the zebrafish larva pentylenetetrazole acute seizure assay but did not alter seizure thresholds in the intravenous pentylenetetrazole test in mice. Schisandrin B crosses the blood-brain barrier, which we confirmed in our in silico and in vivo analyses; however, the low level of its unbound fraction in the mouse brain tissue may explain the observed lack of anticonvulsant activity. Molecular docking revealed that the anticonvulsant activity of the compound in larval zebrafish might have been due to its binding to a benzodiazepine site within the GABAA receptor and/or the inhibition of the glutamate NMDA receptor. Although schisandrin B showed a beneficial anticonvulsant effect, toxicological studies revealed that it caused serious developmental impairment in zebrafish larvae, underscoring its teratogenic properties. Further detailed studies are needed to precisely identify the properties, pharmacological effects, and safety of schisandrin B.
Assuntos
Anticonvulsivantes , Peixe-Zebra , Animais , Camundongos , Anticonvulsivantes/toxicidade , Simulação de Acoplamento Molecular , Pentilenotetrazol/toxicidade , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Ácido Glutâmico , Larva , Receptores de GABA-ARESUMO
Diabetic kidney disease is a common complication of diabetes and remains the primary cause of end-stage kidney disease in the general population. Schisandrin B (Sch B) is an active ingredient in Schisandra chinensis. Our study illustrates that Sch B can mitigate renal tubular cell (RTC) epithelial-mesenchymal transition (EMT) and mitochondrial dysfunction in db/db mice, accompanied by the downregulation of TGF-ß1 and the upregulation of PGC-1α. Similarly, Sch B demonstrated a protective effect by reducing the expression of TGF-ß1, α-SMA, fibronectin, and Col I, meanwhile enhancing the expression of E-cadherin in human RTCs (HK2 cells) stimulated with high glucose. Moreover, under high glucose conditions, Sch B effectively increased mitochondrial membrane potential, lowered ROS production, and increased the ATP content in HK2 cells, accompanied by the upregulation of PGC-1α, TFAM, MFN1, and MFN2. Mechanistically, the RNA-seq results showed a significant increase in KCP mRNA levels in HK2 cells treated with Sch B in a high glucose culture. The influence of Sch B on KCP mRNA levels was confirmed by real-time PCR in high glucose-treated HK2 cells. Depletion of the KCP gene reversed the impact of Sch B on TGF-ß1 and PGC-1α in HK2 cells with high glucose level exposure, whereas overexpression of the KCP gene blocked EMT and mitochondrial dysfunction. Furthermore, the PI3K/Akt pathway was inhibited and the AMPK pathway was activated in HK2 cells exposed to a high concentration of glucose after the Sch B treatment. Treatment with the PI3K/Akt pathway agonist insulin and the AMPK pathway antagonist compound C attenuated the Sch B-induced KCP expression in HK2 cells exposed to a high level of glucose. Finally, molecular autodock experiments illustrated that Sch B could bind to Akt and AMPK. In summary, our findings suggested that Sch B could alleviate RTC EMT and mitochondrial dysfunction by upregulating KCP via inhibiting the Akt pathway and activating the AMPK pathway in DKD.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Doenças Mitocondriais , Camundongos , Animais , Humanos , Nefropatias Diabéticas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Regulação para Cima , Proteínas Quinases Ativadas por AMP/metabolismo , Glucose/metabolismo , Transição Epitelial-Mesenquimal , RNA Mensageiro , Adenosina/farmacologiaRESUMO
Type 2 diabetes mellitus (T2DM) is a metabolic risk factor associated with non-alcoholic liver disease (NAFLD). Schisandrin B (Sch B) is a promising agent for NAFLD. However, the actions of Sch B on diabetes-associated NAFLD and the underlying mechanisms are not characterized. This study aimed to assess whether Sch B has beneficial effects on T2DM-associated NAFLD. Sch B (50 mg/kg, gavage) was administrated to C57BL/KSJ db/db mice for 2 weeks. Body weight, liver weight, blood glucose, and insulin resistance were measured. Serum lipid level and liver function were detected using the biochemistry analyzer. Quantitative Real-Time PCR assay was used to evaluate mRNA levers of lipid metabolism genes. Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) staining was performed to measure apoptosis in the liver. Pathological analysis and immunohistochemistry assessment were used to analyze hepatic steatosis and inflammatory infiltration. Sch B supplementation significantly decrease body weight, related liver weight, blood glucose, and serum insulin, and improved insulin resistance in db/db mice. Sch B obviously corrected NAFLD phenotypes including lipid deposition, steatohepatitis, and high levels of hepatic enzymes and serum lipid. In addition, mRNA levels of Sterol response element-bind protein 1c (SREBP-1c), fatty acid synthetase (Fasn), and acetyl-CoA carboxylase (ACC) were markedly downregulated by Sch B treatment. TUNEL-positive cells were also decreased by Sch B. Furthermore, Sch B inhibited the Kupffer cells, IL-1ß, and TNF-α infiltration to the liver. Sch B ameliorated insulin resistance and lipid accumulation under high glucose conditions, which was partly associated with its inhibition of apoptosis and anti-inflammatory actions.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Glicemia/metabolismo , Peso Corporal , Ciclo-Octanos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Resistência à Insulina/genética , Lignanas , Metabolismo dos Lipídeos , Lipídeos , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Compostos Policíclicos , RNA Mensageiro/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/farmacologiaRESUMO
Schisandrin B (Sch B) is the major active constituent of the traditional Chinese medicine Schisandra chinensis and has anti-inflammatory activity, but the target of Sch B remains unclear. T helper 17 (TH17) cells have been involved in the pathogenesis of many autoimmune and inflammatory diseases. Here, we showed that Sch B could decrease IL-17A production of CD4+ T cells by targeting STAT3 in vitro. Importantly, Sch B has therapeutic effects on DSS-induced acute and chronic colitis, CD4+CD45RBhigh T cell-induced colitis. Furthermore, we identified TH17 cells as the direct target of Sch B for mediating its anti-inflammatory activity. Sch B could serve as a lead for developing new therapeutics against TH17 cells or IL-17A cytokine-driven diseases.
Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Lignanas/uso terapêutico , Compostos Policíclicos/uso terapêutico , Células Th17/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Feminino , Humanos , Doenças Inflamatórias Intestinais/patologia , Lignanas/farmacologia , Camundongos Endogâmicos C57BL , Compostos Policíclicos/farmacologia , Células Th17/patologiaRESUMO
Atherosclerosis, a chronic multifactorial disease, is closely related to the development of cardiovascular diseases and is one of the predominant causes of death worldwide. Normal vascular endothelial cells play an important role in maintaining vascular homeostasis and inhibiting atherosclerosis by regulating vascular tension, preventing thrombosis and regulating inflammation. Currently, accumulating evidence has revealed that endothelial cell apoptosis is the first step of atherosclerosis. Excess apoptosis of endothelial cells induced by risk factors for atherosclerosis is a preliminary event in atherosclerosis development and might be a target for preventing and treating atherosclerosis. Interestingly, accumulating evidence shows that natural medicines have great potential to treat atherosclerosis by inhibiting endothelial cell apoptosis. Therefore, this paper reviewed current studies on the inhibitory effect of natural medicines on endothelial cell apoptosis and summarized the risk factors that may induce endothelial cell apoptosis, including oxidized low-density lipoprotein (ox-LDL), reactive oxygen species (ROS), angiotensin II (Ang II), tumor necrosis factor-α (TNF-α), homocysteine (Hcy) and lipopolysaccharide (LPS). We expect this review to highlight the importance of natural medicines, including extracts and monomers, in the treatment of atherosclerosis by inhibiting endothelial cell apoptosis and provide a foundation for the development of potential antiatherosclerotic drugs from natural medicines.
Assuntos
Apoptose/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Ensaios Clínicos como Assunto , Células Endoteliais/patologia , Humanos , Lipoproteínas LDL/toxicidade , Extratos Vegetais/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Schisandrin B (Sch B), a lignan compound in Schisandra, possesses antioxidant, anti-inflammatory, and antiobesity activities. The effect of Sch B on melanogenesis and molecular mechanisms are still unknown. Therefore, we aimed to investigate the antimelanogenic effects of Sch B on α-melanocyte-stimulating hormone-induced B16F10 cells and elucidate the underlying molecular mechanisms. We found that Sch B significantly suppressed melanin content and mushroom tyrosinase (TYR) activity. Sch B treatment decreased the expression of TYR, melanocyte-inducing transcription factor (MITF), tyrosinase-related protein (TRP) 1, and TRP2. Moreover, Sch B modulated the phosphorylation of p38, extracellular-regulated protein kinase, c-Jun N-terminal kinase, and cAMP-response element binding protein (CREB), implying that these pathways may be involved in suppressing melanogenesis. Furthermore, we found that Sch B decreased melanogenesis by downregulating MITF and melanogenic enzymes via MAPK and CREB pathways. Overall, these findings indicate that Sch B has the potential use in whitening.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação para Baixo/efeitos dos fármacos , Lignanas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melaninas/biossíntese , Melanoma Experimental/patologia , Compostos Policíclicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , alfa-MSH/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Ciclo-Octanos/farmacologia , CamundongosRESUMO
INTRODUCTION: Although oxidative stress has been demonstrated to mediate acute ethanol-induced changes in autophagy in the heart, the precise mechanism behind redox regulation in acute ethanol heart disease remains largely unknown. METHODS: Wild-type C57BL/6 mice were intraperitoneally injected with ethanol (3 g/kg/day) for 3 consecutive days. The effects of ethanol on cultured primary cardiomyocytes and H9c2 myoblasts were also studied in vitro. Levels of autophagic flux, cardiac apoptosis and function, reactive oxygen species (ROS) accumulation, NOX4, and NOX2 were examined. The NOX4 gene was knocked down with NOX4 siRNA. RESULTS: In this study, we demonstrated that schisandrin B inhibited acute ethanol-induced autophagy and sequent apoptosis. In addition, schisandrin B treatment improved cardiac function in ethanol-treated mice. Furthermore, NOX4 protein expression was increased during acute ethanol exposure, and the upregulation of NOX4 was significantly inhibited by schisandrin B treatment. The knockdown of NOX4 prevented ROS accumulation, cell autophagy, and apoptosis. CONCLUSION: These results highlight that NOX4 is a critical mediator of ROS and elaborate the role of the NOX4/ROS axis in the effect of schisandrin B on autophagy and autophagy-mediated apoptosis in acute ethanol exposure, which suggests a therapeutic strategy for acute alcoholic cardiomyopathy.
Assuntos
Autofagia/efeitos dos fármacos , Cardiomiopatia Alcoólica/prevenção & controle , Traumatismos Cardíacos/prevenção & controle , Lignanas/farmacologia , NADPH Oxidase 4/metabolismo , Compostos Policíclicos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/genética , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Regulação para Baixo , Etanol/toxicidade , Técnicas de Silenciamento de Genes , Traumatismos Cardíacos/induzido quimicamente , Traumatismos Cardíacos/metabolismo , Lignanas/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/genética , Compostos Policíclicos/uso terapêutico , Cultura Primária de Células , Substâncias Protetoras/uso terapêutico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Non-small cell lung cancer (NSCLC) is a malignant cancer characterized by easy invasion, metastasis and poor prognosis, so that conventional chemotherapy cannot inhibit its invasion and metastasis. Doxorubicin (DOX), as a broad-spectrum antitumour drug, cannot be widely used in clinic because of its poor targeting, short half-life, strong toxicity and side effects. Therefore, the aim of our study is to construct a kind of PFV modified DOX plus schisandrin B liposomes to solve the above problems, and to explore its potential mechanism of inhibiting NSCLC invasion and metastasis. The antitumour efficiency of the targeting liposomes was carried out by cytotoxicity, heating ablation, wound healing, transwell, vasculogenic mimicry channels formation and metastasis-related protein tests in vitro. Pharmacodynamics were evaluated by tumour inhibition rate, HE staining and TUNEL test in vivo. The enhanced anti-metastatic mechanism of the targeting liposomes was attributed to the downregulation of vimentin, vascular endothelial growth factor, matrix metalloproteinase 9 and upregulation of E-cadherin. In conclusion, the PFV modified DOX plus schisandrin B liposomes prepared in this study provided a treatment strategy with high efficiency for NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Linhagem Celular Tumoral , Ciclo-Octanos , Doxorrubicina/farmacologia , Transição Epitelial-Mesenquimal , Humanos , Lignanas , Lipossomos , Neoplasias Pulmonares/tratamento farmacológico , Compostos Policíclicos , Fator A de Crescimento do Endotélio VascularRESUMO
Gastric cancer is one of the leading causes of cancer-related death worldwide with a poor prognosis. Gastric cancer is usually treated with surgery and chemotherapy, accompanied by a high rate of metastasis and recurrence. In this paper, R8 (RRRRRRRR) modified vinorelbine plus schisandrin B liposomes had been successfully constructed for treating gastric cancer. In the liposomes, R8 was used to enhance the intracellular uptake, schisandrin B was incorporated into liposomes for inhibiting tumor cells metastasis, and vinorelbine was encapsulated into liposomes as antitumor drugs. Studies were performed on BGC-823 cells in vitro and were verified in the BGC-823 cell xenografts nude mice in vivo. Results in vitro demonstrated that the targeting liposomes could induce BGC-823 cells apoptosis, inhibit the metastasis of tumor cells, and increase targeting effects to tumor cells. Meanwhile, action mechanism studies showed that the targeting liposomes could down-regulate VEGF, VE-Cad, HIF-1a, PI3K, MMP-2, and FAK to inhibit tumor metastasis. In vivo results exhibited that the targeting liposomes displayed an obvious antitumor efficacy by accumulating selectively in tumor site and induce tumor cell apoptosis. Hence, R8 modified vinorelbine plus schisandrin B liposomes might provide a safe and efficient therapy strategy for gastric cancer.
Assuntos
Lipossomos , Neoplasias Gástricas , Vinorelbina/química , Animais , Apoptose , Linhagem Celular Tumoral , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Lignanas/química , Lignanas/farmacologia , Camundongos , Camundongos Nus , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Vinorelbina/farmacologiaRESUMO
The activation of hepatic stellate cells (HSC) plays a key role in the progression of hepatic fibrosis, it is essential to remove activated HSC through apoptosis to reverse hepatic fibrosis. Schisandrin B (Sch B) is the main chemical component of schisandrin lignan, and it has been reported to have good hepatoprotective effects. However, Schisandrin B on HSC apoptosis remains unclear. In our study, we stimulated the HSC-T6 and LX-2 cell lines with TGF-ß1 to induce cell activation, and the proliferation and apoptosis of the activated HSC-T6 and LX-2 cells were detected after treatment with different doses of Schisandrin B. Flow cytometry results showed that Sch B significantly reduced the activity of activated HSC-T6 and LX-2 cells and significantly induced apoptosis. In addition, the cleaved-Caspase-3 levels were increased, the Bax activity was increased, and the Bcl-2 expression was decreased in HSC-T6 and LX-2 cells treated with Sch B. Our study showed that Sch B inhibited the TGF-ß1-induced activity of hepatic stellate cells by promoting apoptosis.
Assuntos
Antifibróticos/farmacologia , Apoptose/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Lignanas/farmacologia , Cirrose Hepática/prevenção & controle , Compostos Policíclicos/farmacologia , Animais , Linhagem Celular , Ciclo-Octanos/farmacologia , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/patologia , Substâncias Protetoras/farmacologia , RatosRESUMO
Purpose/Aim: Pulmonary fibrosis (PF) is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function.Objective: The present study investigated the potential protective effects of schisandrin B (Sch B) on the Wingless/Integrase-1 (Wnt) signaling pathway in attenuating inflammation and oxidative stress in ICR mice.Methods: Sixty healthy ICR mice were randomly divided into the following groups: control group, bleomycin (BLM) group, Sch B low dose (Sch B-L) group, Sch B medium dose (Sch B-M) group, Sch B high dose (Sch B-H) group, and dexamethasone (DXM) group. The expression of transforming growth factor (TGF)-ß1 was examined by ELISA. In addition, the levels of superoxide dismutase (SOD), hydroxyproline (HYP), and the total antioxidant capacity (T-AOC) were determined. The protein and mRNA levels of matrix metalloproteinase 7 (MMP7) and ß-catenin in mice were analyzed by western blot and quantitative real -quantitative time PCR (qRT-PCR), respectively.Results: Lung tissues from the BLM group exhibited significantly more inflammatory changes and a significantly greater number of collagen fibers than lung tissues from the control group. In addition, the lung tissues from these BLM-treated mice exhibited slightly increased MMP7 and ß-catenin protein expression. Lung tissues from the Sch B-H group exhibited fewer inflammatory changes and fewer collagen fibers than lung tissues from the BLM group. Furthermore, the lung tissues from the Sch B-H mice exhibited decreased HYP and TGF-ß1 levels, but increased SOD and T-AOC levels.Conclusions: The present study provided evidence that Sch B may be a potential therapeutic agent for the treatment of PF.
Assuntos
Bleomicina/farmacologia , Integrases/metabolismo , Lignanas/farmacologia , Compostos Policíclicos/farmacologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteína Wnt1/metabolismo , Animais , Ciclo-Octanos/farmacologia , Hidroxiprolina/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Fibrose Pulmonar/metabolismo , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
As a malignant tumor, breast cancer is very prone to metastasis. Chemotherapy is one of the most common means for treating breast cancer. However, due to the serious metastasis and the poor targeting effect of traditional chemotherapeutic drugs, even after years of efforts, the therapeutic effect is still unsatisfied. Therefore, in this study, we constructed a kind of PFV modified epirubicin plus schisandrin B liposomes to solve the above disadvantages. In vitro experiments showed that the targeting liposomes with ideal physicochemical property could increase the cytotoxicity of MDA-MB-435S cells, destroy the formation of vasculogenic mimicry (VM), and inhibit tumor invasion and migration. Action mechanisms indicated that the inhibition of targeting liposomes on tumor metastasis was attributed to the regulation of the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), vimentin (VIM), and E-cadherin (E-cad). In vivo pharmacodynamic experiments showed that the targeting liposomes could significantly improve the antitumor effect in mice. H&E staining and TUNEL results showed that the targeting liposomes could promote the apoptosis of tumor cells. Hence, the PFV modified epirubicin plus schisandrin B liposomes constructed in this study provided a new therapeutic strategy for breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Epirubicina/administração & dosagem , Lignanas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Compostos Policíclicos/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide , Ciclo-Octanos/administração & dosagem , Feminino , Humanos , Lipossomos , Neoplasias Pulmonares/secundário , Camundongos , Invasividade Neoplásica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The synergistic anti-tumor effect of schisandrin B (Sch.B) and apatinib was investigated in vitro. The CCK-8 assay revealed that Sch.B enhanced the inhibition of apatinib on cell proliferation by arresting cell cycle in G0/G1 phase. Sch.B also potentiated the suppression of apatinib on cell migration and invasion, by means of wound-healing and transwell invasion assay. Flow cytometry results showed that Sch.B enhanced apoptosis induced by apatinib. The results were confirmed by western blot analysis of the proteins MMP-9, and Bax caspase-9, and -12. These results suggest that combining apatinib and Sch.B is an effective therapeutic strategy for preventing GC progression. [Formula: see text].
Assuntos
Apoptose , Ciclo-Octanos , Linhagem Celular Tumoral , Proliferação de Células , Lignanas , Estrutura Molecular , Compostos Policíclicos , PiridinasRESUMO
In the current study, schisandrin B(SchB)-loaded F127 modified lipid-polymer hybrid nanoparticles(SchB-F-LPNs) were developed to improve the inhibition of breast cancer lung metastasis. Modified nanoprecipitation method was used to prepare SchB-F-LPNs. The nanoparticles were spherical in shape with shell-core structure by TEM observation. SchB-F-LPNs showed a mean particle size of(234.60±6.11) nm with zeta potential of(-5.88±0.49) mV. XRD results indicated that SchB existed in the nanoparticles in an amorphous state. The apparent permeability coefficient through porcine mucus of F-LPNs was 1.43-fold of that of LPNs as shown in the in vitro mucus penetration study. The pharmacokinetics study showed that the C_(max) of SchB was(369.06±146.94) µg·L~(-1),(1 121.34±91.65) µg·L~(-1) and(2 951.91±360.53) µg·L~(-1) respectively in SchB suspensions group, SchB-LPNs group and SchB-F-LPNs group after oral administration in rats. With SchB suspensions as the reference formulation, the relative bioavailability of SchB-F-LPNs was 568.60%. SchB-F-LPNs inhibited the morphological change during transforming growth factor-ß1(TGF-ß1)-induced epithelial-mesenchymal transition. In addition, SchB-F-LPNs significantly decreased the number of metastatic pulmonary nodules in 4 T1 tumor-bearing mice, suggesting that SchB-F-LPNs may inhibit the metastasis of breast cancer. These results reveal the promising potential of SchB-F-LPNs in treatment of breast cancer lung metastasis.