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PURPOSE: Type 1 diabetes (T1DM) is a chronic metabolic disorder that can cause damage to multiple organs including the spleen. Sole insulin therapy is not satisfactory. This study aims to investigate the effects and mechanisms of combined treatment with insulin and N-acetylcysteine (NAC) on spleen damage in T1DM canines, in order to identify drugs that may better assist patients in the management of diabetes and its complications. METHODS: The canine model of T1DM was established by intravenous injection of alloxan (ALX) and streptozotocin (STZ). The therapeutic effects of insulin and NAC were evaluated by clinical manifestations, spleen protein and mRNA expression. RESULTS: The results indicate that the combined treatment of insulin and NAC can alleviate hyperglycemia and hematologic abnormalities, improve splenic histopathological changes, prevent fibrous tissue proliferation, and glycogen deposition. In addition, we observed that this combination treatment significantly suppressed the protein expression of p-P65/P65 (17.6 %, P < 0.05), NLRP3 (46.8 %, P < 0.05), and p-P38/P38 (37.1 %, P < 0.05) induced by T1DM when compared to insulin treatment alone. Moreover, it also significantly decreased the mRNA expression of TLR4 (45.0 %, P < 0.01), TNF-α (30.3 %, P < 0.05), and NLRP3 (43.3 %, P < 0.05). CONCLUSIONS: This combination has the potential to mitigate splenic inflammatory injury in T1DM canines by suppressing the activation of MAPKs-NF-κB pathway and pyroptosis. These findings provide a reference for the treatment strategies of diabetes and its complications.
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Acetilcisteína , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Quimioterapia Combinada , Insulina , NF-kappa B , Piroptose , Transdução de Sinais , Baço , Animais , Cães , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , NF-kappa B/metabolismo , Piroptose/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Masculino , Baço/efeitos dos fármacos , Baço/patologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Esplenopatias/tratamento farmacológico , Esplenopatias/etiologia , Esplenopatias/complicações , Sistema de Sinalização das MAP Quinases/efeitos dos fármacosRESUMO
Background: Cardiovascular surgery is usually associated with higher degree of postoperative pain that influences a patient's physical recovery. Multiple clinical measures have been taken to avoid overuse of opioid agents for postoperative pain management, which led to the development of clinical pathways for analgesic drug treatment using a multimodal approach. Objective: To evaluate the effectiveness and safety of a multimodal postoperative analgesic drug pathway (ADP) for pain management following cardiovascular surgery. Methods: This retrospective, controlled, nonrandomized study evaluated a postoperative ADP in patients undergoing cardiovascular surgery in a tertiary general hospital in Qingdao, China. Effectiveness and safety outcomes were compared before and after the implementation of the ADP. Outcome indicators included postoperative pain scores, consumption of opioids in analgesic pumps, and incidence of adverse events. Results: Patients who underwent cardiovascular surgery from September to November 2021 before the implementation of the ADP (nâ¯=â¯193) and from September to November 2022 after the implementation of the ADP (nâ¯=â¯218) were enrolled. Pain scores were reduced on day 1, 3, and 5 after surgery and the reduction was most significant in mild pain (P < .001). Opioids in analgesic pumps consumption was also significantly reduced and there was decreased incidence of adverse events such as nausea and vomiting (Pâ¯=â¯.026), respiratory inhibition (Pâ¯=â¯.027), and dizziness and headache (Pâ¯=â¯.028) in cardiovascular surgery patients after implementation of the ADP. Conclusions: Improved effectiveness and safety were observed following the implementation of the ADP. Multimodal analgesic ADP methodology can be effectively used for postoperative pain management in patients undergoing cardiovascular surgery.
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Acute myocardial injury (AMI) induced by lipopolysaccharide (LPS) can cause cardiovascular dysfunction and lead to death in poultry. Traditional antibiotic therapy has been found to have many limitations and negative effects. Asiatic acid (AA) is a naturally occurring pentacyclic triterpenoid that is extracted from Centella asiatica and has anti-inflammatory, antioxidant, and anticancer pharmacological properties. Previously, we studied the effect of AA on LPS-induced liver and kidney injury; however, the impact of AA on LPS-induced AMI remained unclear. Sixty 1-day-old broilers were randomly divided into control group, LPS group, LPS + AA 15 mg/kg group, LPS + AA 30 mg/kg group, LPS + AA 60 mg/kg group, and control + AA 60 mg/kg group. The histopathology of cardiac tissues was detected by hematoxylin and eosin (H&E) staining. The mRNA and protein expressions related to mitochondrial dynamics and mitophagy were detected by quantitative real-time PCR, western blot, immunofluorescence, and immunohistochemistry. Disorganized myocardial cells and fractured myocardial fibers were found in the LPS group, and obvious red-blood-cell filling can be seen in the gaps between the myocardial fibers in the low-dose AA group. Nevertheless, the medium and high dose of AA obviously attenuated these changes. Our results showed that AA significantly restored the mRNA and protein expressions related to mitochondrial dynamic through further promoting mitophagy. This study revealed the effect of AA on LPS-induced AMI in broilers. Mechanically, AA regulated mitochondrial dynamic homeostasis and further promoted mitophagy. These novel findings indicate that AA may be a potential drug for LPS-induced AMI in broilers.
El ácido asiático como mitigante de las lesiones miocárdicas agudas inducidas por lipopolisacáridos al promover la mitofagia y regular la dinámica mitocondrial en pollos de engorde. La lesión miocárdica aguda (con siglas en inglés IAM) inducida por lipopolisacáridos (LPS) puede causar disfunción cardiovascular y provocar la muerte en las aves comerciales. Se ha descubierto que la terapia tradicional con antibióticos tiene muchas limitaciones y efectos negativos. El ácido asiático (AA) es un triterpenoide pentacíclico natural que se extrae de la planta Centella asiática y que tiene propiedades farmacológicas antiinflamatorias, antioxidantes y anticancerígenas. Anteriormente, se estudió el efecto del ácido asiático sobre la lesión hepática y renal inducida por lipopolisacáridos; sin embargo, el impacto del ácido asiático en las lesiones miocárdicas agudas inducidas por lipopolisacáridos continua sin estar completamente determinada. Sesenta pollos de engorde de un día de edad se dividieron aleatoriamente en los siguientes grupos experimentales: grupo control, grupo que recibió LPS solamente, grupo LPS + ácido asiático 15 mg/kg, grupo LPS + ácido asiático 30 mg/kg, grupo LPS + ácido asiático 60 mg/kg y control + ácido asiático 60 mg./kg grupo. La histopatología de los tejidos cardíacos se detectó mediante tinción con hematoxilina y eosina (H&E). Las expresiones de ARN mensajero y proteínas relacionadas con la dinámica mitocondrial y la mitofagia se detectaron mediante PCR cuantitativa en tiempo real, inmunotransferencia Western, inmunofluorescencia e inmunohistoquímica. Se encontraron células miocárdicas desorganizadas y fibras miocárdicas fracturadas en el grupo que recibió lipopolisacáridos, y se puede observar un evidente acúmulo de glóbulos rojos en los espacios entre las fibras miocárdicas en el grupo de dosis bajas de ácido asiático. Sin embargo, las dosis medias y altas de ácido asiático obviamente atenuaron estos cambios. Nuestros resultados mostraron que el ácido asiático restableció significativamente las expresiones de ARN mensajero y proteínas relacionadas con la dinámica mitocondrial mediante la promoción adicional de la mitofagia. Este estudio reveló el efecto del ácido asiático sobre las lesiones miocárdicas agudas inducidas por lipopolisacáridos en pollos de engorde. Basicamente, el ácido asiático reguló la homeostasis dinámica mitocondrial y promovió aún más la mitofagia. Estos nuevos hallazgos indican que el ácido asiático puede ser un fármaco potencial para mitigar lesiones miocárdicas agudas inducidas por lipopolisacáridos en pollos de engorde.
Assuntos
Galinhas , Lipopolissacarídeos , Mitofagia , Triterpenos Pentacíclicos , Doenças das Aves Domésticas , Animais , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/administração & dosagem , Doenças das Aves Domésticas/induzido quimicamente , Mitofagia/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Distribuição AleatóriaRESUMO
The exact pathogenesis of type 1 diabetes mellitus (DM) is still unclear. Numerous organs, including the heart, will suffer damage and malfunction as a result of long-term hyperglycemia. Currently, insulin therapy alone is still not the best treatment for type 1 DM. In order to properly treat and manage patients with type 1 DM, it is vital to seek a combination that includes both insulin and additional medications. This study aims to explore the therapeutic effect and mechanism of N-acetylcysteine (NAC) combined with insulin on type 1 DM. By giving beagle canines injections of streptozotocin (STZ) and alloxan (ALX) (20 mg/kg each), a model of type 1 DM was created. The results showed that this combination could effectively control blood sugar level, improve heart function, avoid the damage of mitochondria and myocardial cells, and prevent the excessive apoptosis of myocardial cells. Importantly, the combination can activate nuclear factor kappa-B (NF-κB) by promoting linear ubiquitination of receptor-interacting protein kinase 1 (RIPK1) and NF-κB-essential modulator (NEMO) and inhibitor of NF-κB (IκB) phosphorylation. The combination can increase the transcription and linear ubiquitination of Cellular FLICE (FADD-like IL-1ß-converting enzyme) -inhibitory protein (c-FLIP), diminish the production of cleaved-caspase-8 p18 and cleaved-caspase-3 to reduce apoptosis. This study confirmed that NAC combined with insulin can promote the linear ubiquitination of RIPK1, NEMO and c-FLIP and regulate the apoptosis pathway mediated by TNF-α to attenuate the myocardial injury caused by type 1 DM. Meanwhile, the research served as a resource when choosing a clinical strategy for DM cardiac complications.
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Diabetes Mellitus Tipo 1 , NF-kappa B , Humanos , Animais , Cães , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa , Insulina/metabolismo , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Apoptose , UbiquitinaçãoRESUMO
Nanoplastics (NPs) are defined as a group of emerging pollutants. However, the adverse effect of NPs and/or heavy metals on mammals is still largely unclear. Therefore, we performed a 35-day chronic toxicity experiment with mice to observe the impacts of exposure to Cadmium (Cd) and/or polystyrene nanoplastics (PSNPs). This study revealed that combined exposure to Cd and PSNPs added to the mice's growth toxicity and kidney damage. Moreover, Cd and PSNPs co-exposure obviously increased the MDA level and expressions of 4-HNE and 8-OHDG while decreasing the activity of antioxidase in kidneys via inhibiting the Nrf2 pathway and its downstream genes and proteins expression. More importantly, the results suggested for the first time that Cd and PSNPs co-exposure synergistically increased iron concentration in kidneys, and induced ferroptosis through regulating expression levels of SLC7A11, GPX4, PTGS2, HMGB1, FTH1 and FTL. Simultaneously, Cd and PSNPs co-exposure further increased the expression levels of Pink, Parkin, ATG5, Beclin1, and LC3 while significantly reducing the P62 expression level. In brief, this study found that combined exposure to Cd and PSNPs synergistically caused oxidative stress, ferroptosis and excessive mitophagy ultimately aggravating kidney damage in mice, which provided new insight into the combined toxic effect between heavy metals and PSNPs on mammals.
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Cádmio , Ferroptose , Animais , Camundongos , Cádmio/toxicidade , Microplásticos , Poliestirenos/toxicidade , Mitofagia , Estresse Oxidativo , Rim , MamíferosRESUMO
The development of acute liver injury can result in liver cirrhosis, liver failure, and even liver cancer, yet there is currently no effective therapy for it. The purpose of this study was to investigate the protective effect and therapeutic mechanism of Lyciumbarbarum polysaccharides (LBPs) on acute liver injury induced by carbon tetrachloride (CCl4). To create a model of acute liver injury, experimental canines received an intraperitoneal injection of 1 mL/kg of CCl4 solution. The experimental canines in the therapy group were then fed LBPs (20 mg/kg). CCl4-induced liver structural damage, excessive fibrosis, and reduced mitochondrial density were all improved by LBPs, according to microstructure data. By suppressing Kelch-like epichlorohydrin (ECH)-associated protein 1 (Keap1), promoting the production of sequestosome 1 (SQSTM1)/p62, nuclear factor erythroid 2-related factor 2 (Nrf2), and phase II detoxification genes and proteins downstream of Nrf2, and restoring the activity of anti-oxidant enzymes like catalase (CAT), LBPs can restore and increase the antioxidant capacity of liver. To lessen mitochondrial damage, LBPs can also enhance mitochondrial respiration, raise tissue adenosine triphosphate (ATP) levels, and reactivate the respiratory chain complexes IâV. According to serum metabolomics, the therapeutic impact of LBPs on acute liver damage is accomplished mostly by controlling the pathways to lipid metabolism. 9-Hydroxyoctadecadienoic acid (9-HODE), lysophosphatidylcholine (LysoPC/LPC), and phosphatidylethanolamine (PE) may be potential indicators of acute liver injury. This study confirmed that LBPs, an effective hepatoprotective drug, may cure acute liver injury by lowering oxidative stress, repairing mitochondrial damage, and regulating metabolic pathways.
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Doença Hepática Induzida por Substâncias e Drogas , Mitocôndrias , Estresse Oxidativo , Polissacarídeos , Animais , Cães , Antioxidantes/metabolismo , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fígado , Redes e Vias Metabólicas , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Polissacarídeos/farmacologia , Lycium/químicaRESUMO
Recurrence and distant metastasis after paclitaxel (PTX)-based chemotherapy in ovarian cancer (OC) patients remains a clinical obstacle. Flavokawain A (FKA) is a novel chalcone from kava plant that can induce G2/M arrest and inhibit invasion and metastasis in different tumor cells. In this study, we examined the effects and the molecular mechanism of sodium aescinate (Aes)-stabilized nanoparticles FKA-A NPs in enhancing the efficacy of PTX-A NPs in vitro and in vivo. We showed that FKA-A NPs combined with PTX-A NPs notably inhibited the proliferation and migration and reduced the expression of EMT-related markers in OCs. YAP nuclear translocation and its downstream signaling pathway were remarkably activated after PTX-A NPs treatment in OCs. FKA-A NPs obviously inhibited YAP nuclear translocation and reduced the transcriptional activity of YAP target genes. Simultaneously, FKA-A NPs dose and time dependently inhibited Skp2 expression in A2780 and Skov3 cells. In contrast, overexpression of Skp2 significantly attenuated the inhibition of FKA-A NPs on YAP nuclear translocation. In OC homograft mice, treatment with FKA-A NPs and PTX-A NPs significantly suppressed the growth of homograft tumor compared with PTX-A NPs but did not decrease mice's body weight. In summary, we demonstrate that FKA-A NPs enhance the efficacy of PTX-A NPs against OCs in vitro and in vivo via reducing Skp2 expression, thus suppressing YAP nuclear translocation and activity of its target genes.
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Nanopartículas , Neoplasias Ovarianas , Humanos , Camundongos , Animais , Feminino , Paclitaxel/farmacologia , Linhagem Celular Tumoral , Neoplasias Ovarianas/tratamento farmacológico , Apoptose , Pontos de Checagem da Fase G2 do Ciclo CelularRESUMO
Asiatic acid (AA), a triterpenoid compound isolated from Centella asiatica, has anti-inflammatory, antioxidant and anticancer biological characteristics. To explore the effect of AA on LPS-induced acute kidney injury (AKI) in broilers, a total of 60 one-day-old broilers were randomly divided into 6 groups, including the normal group, AKI model group, AKI + AA 15 mg/kg group, AKI + AA 30 mg/kg group, AKI + AA 60 mg/kg group and normal + AA 60 mg/kg group. Hematoxylin-eosin staining was used to observe the histopathology in kidney tissue, and the mRNA and protein expressions related to oxidative stress and ferroptosis were tested by qPCR and western blotting respectively. AA mitigated vacuolar degeneration and enlarged glomerular space caused by LPS in kidney tissue. Additionally, AA significantly increased the mRNA levels of Nrf2, HO-1, NQO1, GCLC, GCLM, GPX4, SLC7A11 and FTH1, and decreased the mRNA levels of Keap1 and PTGS2 in LPS-induced AKI. Likewise, AA significantly upregulated the protein expressions of Nrf2, HO-1, NQO1, GPX4, SLC7A11 and FTH1, and downregulated the protein expressions of Keap1 and PTGS2 in LPS-induced AKI. These results suggested that AA alleviated LPS-induced AKI by inhibiting oxidative stress and ferroptosis through targeting regulation of the Nrf2 pathway in broilers.
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Injúria Renal Aguda , Ferroptose , Animais , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/efeitos adversos , Galinhas/metabolismo , Ciclo-Oxigenase 2/metabolismo , Estresse Oxidativo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: The purpose of the study is to identify off-pump patients who are at higher risk of mortality after re-exploration for bleeding or tamponade. METHODS: We analyzed the data of 3256 consecutive patients undergoing isolated off-pump coronary artery bypass grafting (OPCABG) in our heart center from 2013 through 2020. Fifty-eight patients underwent re-exploration after OPCABG. The 58 patients were divided into death group and survival group according to their discharge status. Propensity score matching (PSM) was performed to analysis the risk factors of death. 15 pairs of cases of two groups were matched well. RESULTS: The mortality rate of patients underwent re-exploration after OPCABG for bleeding or tamponade was 27.59% (16/58). In the raw data, we found the patients in death group had higher body mass index (BMI) (P = 0.030), higher cardiac troponin T (cTnT) (P = 0.028) and higher incidence of heart failure before OPCABG (P = 0.003). After PSM, the levels of lactic acid before and after re-exploration (P = 0.028 and P < 0.001) were higher in death group. And the levels of creatinine (P = 0.002) and cTnT (P = 0.017) were higher in the death group after re-exploration. The death group had longer reoperation time (P = 0.010). In addition, the perioperative utilization rate of intra-aortic ballon pump (IABP) (P = 0.027), continuous renal replacement therapy (CRRT) (P < 0.001) and platelet transfusion (P = 0.017) were higher than survival group. CONCLUSIONS: The mortality rate of patients undergoing re-exploration for bleeding or tamponade after isolated OPCABG is high. More attention should be paid to patients with above risk factors and appropriate measures should be taken in time.
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Tamponamento Cardíaco/cirurgia , Ponte de Artéria Coronária sem Circulação Extracorpórea/mortalidade , Doença da Artéria Coronariana/cirurgia , Hemorragia Pós-Operatória/cirurgia , Reoperação/mortalidade , Idoso , Tamponamento Cardíaco/diagnóstico por imagem , Tamponamento Cardíaco/etiologia , Tamponamento Cardíaco/mortalidade , Ponte de Artéria Coronária sem Circulação Extracorpórea/efeitos adversos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/diagnóstico por imagem , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/mortalidade , Reoperação/efeitos adversos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: 5-fluorouracil (5-FU) is a cytotoxic antimetabolite that interferes with nucleic acid metabolism in both normal and cancer cells. Capecitabine is a prodrug of 5-FU, and S-1 is an oral 5-FU derivative. Patients usually tolerate treatment with one fluorouracil drug well. However, simultaneous application of two or more fluorouracil drugs such as capecitabine and S-1 can lead to life-threatening toxicities. CASE REPORT: A 73-year-old male with gastric and rectal cancer was admitted to the emergency department because of severe oral mucositis, hand-foot syndrome, and fever after concurrently taking capecitabine (1.5 g twice a day) and S-1 (50 mg twice a day) for 3 days at home. He was immediately given recombinant human granulocyte colony-stimulating factor (200 mg SC once a day) and recombinant human thrombopoietin (15,000 IU SC once a day). Hemagglutinin (1 unit IM once a day) was administered. Anti-infection and mucosal care were started promptly. A few days later, he developed supraventricular premature beats and short flutter requiring cardioversion. After comprehensive treatment, the patient's infection was effectively controlled, and mucosal damage and cardiac toxicity were significantly alleviated. CONCLUSION: 5-FU overdose caused by the combination of capecitabine and S-1 can cause serious adverse reactions. Careful checking of the medical orders and extensive education of patients to recognize the symptoms of toxicity may reduce the occurrence of such adverse reactions.
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Antineoplásicos , Pró-Fármacos , Idoso , Capecitabina , Fluoruracila/efeitos adversos , Humanos , MasculinoRESUMO
BACKGROUND: The development of paclitaxel (PTX) resistance seriously restricts its clinical efficacy. An attractive option for combating resistance is inhibiting the expression of P-glycoprotein (P-gp) in tumor cells. We have reported that flavokawain A (FKA) inhibited P-gp protein expression in PTX-resistant A549 (A549/T) cells, indicating that FKA combined with PTX may reverse PTX resistance. However, due to the variable pharmacokinetics of FKA and PTX, the conventional cocktail combination in clinics may cause uncertainty of treatment efficacy in vivo. MATERIALS AND METHODS: To synergistically elevate the anti-cancer activity of PTX and FKA in vivo, the national medical products administration (NMPA) approved sodium aescinate (Aes) was utilized to stabilize hydrophobic PTX and FKA to form polymer-free twin like PTX-A nanoparticles (NPs) and FKA-A NPs. RESULTS: The resulting nanoparticles prepared simply by nanoprecipitation possessed similar particle size, good stability and ultrahigh drug loadings of up to 50%. With the aid of Aes, these two drugs accumulated in tumor tissue by passive targeting and were efficiently taken up by A549/T cells; this resulted in significant suppression of tumor growth in A549/T homograft mice at a low PTX dose (2.5 mg·kg-1). Synergistic effects and reversed PTX resistance were achieved by the combination of PTX-A NPs and FKA-A NPs by inhibiting P-gp expression in tumor cells. CONCLUSION: Using NMPA-approved Aes to prepare twin-like nanoparticles without introducing any new materials provides an efficient platform for combination chemotherapy and clinical translation.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanopartículas/química , Paclitaxel/farmacologia , Saponinas/química , Triterpenos/química , Células A549 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Linhagem Celular Tumoral , Chalcona/administração & dosagem , Chalcona/análogos & derivados , Chalcona/farmacocinética , Estabilidade de Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Nanopartículas/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Tamanho da Partícula , Polímeros/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Lung cancer is one of the most common cancers, which is the leading cause of cancer-related death among various cancers worldwide. Flavokawain A (FKA), a chalcone found in the kava plant, exerts potent anticancer activity. However, the activity and mechanisms of FKA in inhibiting the viability of paclitaxel (PTX)-resistant lung cancer A549 (A549/T) have not been investigated. In the present study, the effect of FKA on the viability of A549/T and hepatotoxicity in normal liver epithelial cells was detected by Cell Counting Kit-8 assay. Flow cytometry, western blot analysis and Annexin V-FITC/PI apoptosis detection kit were used to assess cell apoptosis. The effect of FKA on permeability-glycoprotein (P-gp) expression was measured by reverse transcription-PCR and western blot analysis. The results indicated that FKA dose-dependently inhibited cell proliferation and induced cell apoptosis in PTX-resistant A549/T cells, with an IC50 value of ~21 µM, while the IC50 value of A549/T cells to PTX was 34.64 µM. FKA had no hepatic toxicity in liver epithelial cells. P-gp, which contributes to the chemoresistant phenotype, was not expressed in A549 cells but was remarkably enhanced in A549/T cells. FKA (30 µM) decreased P-gp protein expression at 24 h by 3-fold. Furthermore, FKA downregulated P-gp expression by blocking the PI3K/Akt pathway. These findings suggest FKA as a potential candidate for the treatment of PTX-resistant lung cancer.
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Acquired docetaxel-resistance of prostate cancer (PCa) remains a clinical obstacle due to the lack of effective therapies. Acetyl-11-keto-ß-boswellic acid (AKBA) is a pentacyclic triterpenic acid isolated from the fragrant gum resin of the Boswellia serrata tree, which has shown intriguing antitumor activity against human cell lines established from PCa, colon cancer, malignant glioma, and leukemia. In this study, we examined the effects of AKBA against docetaxel-resistant PCa in vitro and in vivo as well as its anticancer mechanisms. We showed that AKBA dose-dependently inhibited cell proliferation and induced cell apoptosis in docetaxel-resistant PC3/Doc cells; its IC50 value in anti-proliferation was â¼17 µM. Furthermore, AKBA dose-dependently suppressed the chemoresistant stem cell-like properties of PC3/Doc cells, evidenced by significant decrease in the ability of mammosphere formation and down-regulated expression of a number of stemness-associated genes. The activation of Akt and Stat3 signaling pathways was remarkably enhanced in PC3/Doc cells, which contributed to their chemoresistant stem-like phenotype. AKBA (10-30 µM) dose-dependently suppressed the activation of Akt and Stat3 signaling pathways in PC3/Doc cells. In contrast, overexpression of Akt and Stat3 significantly attenuated the inhibition of AKBA on PC3/Doc cell proliferation. In docetaxel-resistant PCa homograft mice, treatment with AKBA significantly suppresses the growth of homograft RM-1/Doc, equivalent to its human PC3/Doc, but did not decrease their body weight. In summary, we demonstrate that AKBA inhibits the growth inhibition of docetaxel-resistant PCa cells in vitro and in vivo via blocking Akt and Stat3 signaling, thus suppressing their cancer stem cell-like properties.
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Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Docetaxel/farmacologia , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neoplásicas/efeitos dos fármacos , Triterpenos/farmacologiaRESUMO
Colorectal cancer (CRC) is a major cause of mortality and morbidity. Chronic inflammation is closely associated with the development, progression and prognosis of the majority of intestinal malignancies. In recent years, targeting the nuclear factor (NF)κB signaling pathway for CRC therapy has become an attractive strategy. Riccardin D, a novel macrocyclicbis (bibenzyl) compound, was isolated from the Chinese liverwort plant. Previous studies have suggested that Riccardin D exerted chemopreventative effects against the intestinal malignancy formation. In the present study, cell counting kit8, Hochest 33258 staining, mitochondria membrane permeability assay, western blotting analysis, reverse transcriptionpolymerase chain reaction, luciferase reporter gene assay and molecular modeling analysis were performed to detect the effect and mechanisms of Riccardin D on human colon cancer cells. The results demonstrated that Riccardin D significantly inhibited the growth of HT29 cells. In addition, the cDNA expression of cyclooxygenase2, and the protein expression and activity of NFκB and tumor necrosis factorα were downregulated; however, the protein expression of cleaved caspase3 and 9, and cleaved poly (adenosine diphosphateribose) polymerase, and the Bcell lymphoma (Bcl)2: Bcl2associated X protein ratio were upregulated. Furthermore, Auto Dock analysis identified binding sites between Riccardin D and NFκB. These results indicated that Riccardin D may inhibit cell proliferation and induce apoptosis in HT29 cells, which may be associated with the blocking of the NFκB signaling pathway. Thus, Riccardin D should be investigated as an NFκB inhibitor in cancer therapy.
Assuntos
Produtos Biológicos/farmacologia , Neoplasias do Colo/metabolismo , Hepatófitas/química , NF-kappa B/metabolismo , Éteres Fenílicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Apoptose/efeitos dos fármacos , Produtos Biológicos/química , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Expressão Gênica , Genes Reporter , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Moleculares , Conformação Molecular , NF-kappa B/química , NF-kappa B/genética , Éteres Fenílicos/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ligação Proteica , Estilbenos/química , Relação Estrutura-AtividadeRESUMO
Retigeric acid B (RAB), a natural compound isolated from lichen, has been demonstrated to inhibit cell growth and promote apoptosis in prostate cancer (PCa) cells. The present study evaluated the function of RAB combined with clinical chemotherapeutic drugs in PCa cell lines by MTT assay, reverse transcription quantitative polymerase chain reaction and western blot analysis, and identified that RAB at low doses produced significant synergistic cytotoxicity in combination with cisplatin (CDDP); however, no marked synergism between RAB and the other chemotherapeutics was observed. Additional studies revealed that RAB exerted an inhibitory effect on DNA damage repair pathways, including the nucleotide excision repair and mismatch repair pathways, which are involved in the sensitivity to CDDP-based chemotherapy, as suggested by the significantly downregulated expression of certain associated repair proteins. Notably, Excision repair cross-complementing 1, a critical gene in the nucleotide excision repair pathway, exhibited the most significant decrease. When combined with CDDP, RAB-mediated impairment of DNA repair resulted in prolonged DNA damage, as demonstrated by the long-lasting appearance of phosphorylation of histone H2AX at Ser139, which potentially enhanced the chemosensitivity to CDDP. Concurrently, the proapoptotic protein death receptor 5 (DR5) was activated by RAB, which also enhanced the chemotherapeutic response of CDDP. Knockdown of DR5 partially blocked RAB-CDDP synergism, suggesting the crucial involvement of DR5 in this event. The results of the present study identified that RAB functioned synergistically with CDDP to increase the efficacy of CDDP by inhibiting DNA damage repair and activating DR5, suggesting the mechanistic basis for the antitumor effect of RAB in combination with current chemotherapeutics.
RESUMO
Despite the fact that many therapeutic strategies have been adopted to delay the development of sepsis, sepsis remains one of the leading causes of death in noncoronary intensive care units. Recently, sepsis-3 was defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Here, we report that swiprosin-1 (also known as EFhd2) plays an important role in the macrophage immune response to LPS-induced or cecal ligation and puncture-induced (CLP-induced) sepsis in mice. Swiprosin-1 depletion causes higher mortality, more severe organ dysfunction, restrained macrophage recruitment in the lung and kidney, and attenuated inflammatory cytokine production (including IL-1ß, IL-6, TNF-α, IL-10, and IFN-γ). The immunosuppression caused by swiprosin-1 deficiency is manifested by impaired bactericidal capacity and decreased HLA-DR expression in macrophages. Swiprosin-1 affects the activation of the JAK2/STAT1/STAT3 pathway by regulating the expression of IFN-γ receptors in macrophages. Our findings provide a potential target for the regulation of the macrophage immune response in sepsis.
Assuntos
Proteínas de Ligação ao Cálcio/deficiência , Macrófagos/imunologia , Sepse/imunologia , Transdução de Sinais/imunologia , Animais , Proteínas de Ligação ao Cálcio/genética , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Escherichia coli , Humanos , Rim/citologia , Rim/imunologia , Lipopolissacarídeos/toxicidade , Pulmão/citologia , Pulmão/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7 , Sepse/microbiologia , Sepse/mortalidadeRESUMO
Doxorubicin (DOX) is one of the most effective cytotoxic anticancer drugs and has been successfully applied in clinics to treat haematological malignancies and a broad range of solid tumours. However, the clinical applications of DOX have long been limited due to severe dose-dependent toxicities. Recent advances in the development of DOX delivery vehicles have addressed some of the non-specific toxicity challenges associated with DOX. These DOX-loaded vehicles are designed to release DOX in cancer cells effectively by cutting off linkers between DOX and carriers response to stimuli. This article focuses on various strategies that serve as potential tools to release DOX from DOX-loaded vehicles efficiently to achieve a higher DOX concentration in tumour tissue and a lower concentration in normal tissue. With a deeper understanding of the differences between normal and tumour tissues, it might be possible to design ever more promising prodrug systems for DOX delivery and cancer therapy in the near future.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Antineoplásicos/química , Doxorrubicina/química , Portadores de Fármacos , Sistemas de Liberação de Medicamentos/efeitos adversos , HumanosRESUMO
Macrophage motility is vital in innate immunity, which contributes strategically to the defensive inflammation process. During bacterial infection, lipopolysaccharide (LPS) potently activates the migration of macrophages via the NF-κB/iNOS/c-Src signaling pathway. However, the downstream region of c-Src that participates in macrophage migration is unclear. EFhd2, a novel actin bundling protein, was evaluated for its role in LPS-stimulated macrophage migration in this study. We found that LPS stimulated the up-regulation, tyrosine phosphorylation and membrane translocation of EFhd2 in macrophages. The absence of EFhd2 inhibited the recruitment of macrophages in the lungs of LPS-induced septic mice. LPS-induced macrophage migration was neutralized by the deletion of EFhd2. EFhd2-mediated up-regulation of NFPs (including Rac1/Cdc42, N-WASP/WAVE2 and Arp2/3 complex) induced by LPS could be used to explain the role of EFhd2 in promoting actin polymerization. Furthermore, the purified EFhd2 could directly promote actin polymerization in vitro. Dasatinib, a c-Src specific inhibitor, inhibited the up-regulation of EFhd2 stimulated by LPS. Therefore, our study demonstrated that EFhd2 might be involved in LPS-stimulated macrophage migration, which provides a potential target for LPS-activated c-Src during macrophage mobilization.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Membrana Celular/metabolismo , Pulmão/imunologia , Macrófagos/imunologia , Sepse/imunologia , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Actinas/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Movimento Celular , Dasatinibe/farmacologia , Imunidade Inata , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polimerização , Ligação Proteica , Transporte Proteico , Células RAW 264.7 , Transdução de SinaisRESUMO
Berberine has demonstrated efficacy in alleviating experimental colitis in vivo and in vitro. However, the anti-colitis mechanisms of berberine that enable it to promote intestinal barrier function in vivo remain unclear. The present study aimed to evaluate the effect of berberine on intestinal epithelial barrier function, expression of tight junction proteins and the levels of inflammatory and oxidative stress factors in the intestinal mucosa of dextran sulfate sodium (DSS)-induced colitis mice. Berberine (100 mg/kg) was administered for five days to mice with established colitis, induced by administration of DSS (3% w/v) for six days. Intestinal barrier function and the presence of proinflammatory factors, oxidative stress and active signaling pathways in the colon were determined principally by western blotting and reverse transcription-quantitative polymerase chain reaction. It was observed that berberine reduced weight loss, shortening of the colon and colon damage in DSS-colitis mice. In addition, berberine significantly inhibited the increase of fluorescein isothiocyanate-dextran in serum and the decrease of zonula occluden-1 (also known as tight junction protein-1), occludin and epithelial cadherin expression in colonic tissue, relative to a DSS-treated control group. Berberine also significantly inhibited the expression of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α mRNA and phosphorylation of signal transducer and activator of transcription 3. Furthermore, berberine reduced the levels of myeloperoxidase and increased the levels of superoxide dismutase and catalase in colon and serum samples relative to the control group. The expression of cluster of differentiation 68 in the colon of colitis mice was also reduced by berberine. Collectively, these data suggest that berberine alleviates colitis principally by improving intestinal barrier function and promoting anti-inflammatory and antioxidative stress responses. In turn these effects inhibit macrophage infiltration into the colon and thus may be central to the anti-colitis activity of berberine.
RESUMO
Multidrug resistance (MDR) represents a clinical obstacle to cancer chemotherapy since it causes cancer recurrence and metastasis. Acetyl-11-keto-ß-boswellic acid (AKBA), an active ingredient derived from the plant Boswellia serrata, has been found to inhibit the growth of a wide variety of tumor cells, including glioma, colorectal cancer, leukemia, human melanoma, hepatocellular carcinoma, and prostate cancer cells. However, the actions of AKBA in multidrug-resistant cancer cells have not been fully elucidated. The current study examined the reversal of MDR by AKBA in a human ileocecal adenocarcinoma cell line with vincristine-induced resistance, HCT-8/VCR. A 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay indicated that cytotoxicity increased drastically and the IC50 of VCR in HCT-8/VCR cells decreased in the presence of AKBA. AKBA had a maximum "fold reversal" of MDR (FR) of 9.19-fold. In addition, HCT-8/VCR cells treated with AKBA and VCR exhibited a higher percentage of apoptotic tumor cells according to flow cytometry. The reversal of MDR by AKBA was evident in an intracellular increase in Rhodamine (Rh123), indicating that the activity of P-glycoprotein (P-gp) was blocked. Furthermore, AKBA inhibited the expression of P-gp and decreased levels of expression of multidrug resistance gene 1 in HCT-8/VCR cells. The current results indicated that AKBA might be a potential agent to reverse MDR in human ileocecal adenocarcinoma.