RESUMO
Indoxyl sulfate (IS) and p-cresyl sulfate (PCS), protein-bound uremic toxins, can induce oxidative stress and cause renal disease progression. However, the different cytotoxic effects on renal cells between IS and PCS are not stated. Due to uremic toxins are generally found in CKD patients, the mechanisms of uremic toxins-induced renal injury are required to study. Curcumin has anti-oxidant, anti-inflammatory and anti-apoptotic effects which may be potential used to protect against renal damage. In contrast, curcumin also exert cytotoxic effects on various cells. In addition, curcumin may reduce or enhance cytotoxicity combined with different chemicals treatments. However, whether curcumin may influence uremic toxins-induced renal injury is unclear. The goal of this study is to compare the different cytotoxic effects on renal cells between IS and PCS treatment, as well as the synergistic or antagonistic effects by combination treatments with curcumin and PCS. Our experimental result shows the PCS exerts a stronger antiproliferative effect on renal tubular cells than IS treatment. In addition, our study firstly demonstrates that curcumin enhances PCS-induced cell cytotoxicity through caspase-dependent apoptotic pathway and cell cycle alteration.
Assuntos
Curcumina , Insuficiência Renal Crônica , Cresóis/metabolismo , Curcumina/farmacologia , Curcumina/uso terapêutico , Humanos , Indicã/metabolismo , Indicã/toxicidade , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , Sulfatos , Ésteres do Ácido Sulfúrico/metabolismo , Ésteres do Ácido Sulfúrico/toxicidadeRESUMO
Guava extracts purified from leaf and bark have many bio-active molecules with anti-cancer activities. In addition, lycopene-rich extracts obtained from red guava fruit can induce apoptosis in estrogen receptor-positive breast cancers. Triple-negative breast cancer (TNBC) lacks estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2) and, therefore, hormone therapy and targeted therapy are not used in the clinic. The purpose of this study was to determine whether red guava fruit extracts can affect the proliferation of TNBC cells. In this study, cell viability was determined by using the MTT assay. Apoptosis and necrosis were analyzed using flow cytometry. Cleaved caspase-3 and PARP were analyzed by western blotting. We found that red guava extracts can, through caspase-3 activation and PARP cleavage signaling, induce apoptotic and necrotic death in TNBC cells. Our results thus show the therapeutic benefit of red guava extracts as a potential cancer treatment for TNBC in combination with doxorubicin or targeted therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Doxorrubicina/farmacologia , Extratos Vegetais/farmacologia , Psidium/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Aim: Sulfasalazine (SSZ) displayed anti-cancer activities. Vitamin E succinate (VES) could inhibit cell growth in various cancer cells. However, chemical therapies were often not useful for triple-negative breast cancer cells (TNBCs) treatment. Here, this study investigated the anti-cancer effects and the mechanisms on TNBCs under combination treatment with SSZ and VES. Methods: Cell viability was analyzed by using the MTT assay. The H2O2 levels were determined by using lucigenin-amplified chemiluminescence method. In addition, caspase and MAPs signals were studied by using western blotting. Results: Low-dose VES antagonized the SSZ-induced cytotoxicity effects while high-dose VES promoted the SSZ-induced cytotoxicity effects on TNBCs. In addition, SSZ alone treatment activated both caspase-3 and ERK signals, however, VES alone treatment only activated JNK signals. On the other hand, activation of caspase-3, JNK, and ERK were found in SSZ plus VES-treated cells. Conclusion: Combined SSZ and VES has synergistic or antagonistic cytotoxic effects depending on VES concentration. In addition, different cytotoxic signals are induced on SSZ-treated, VES-treated and SSZ plus VES-treated cells.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sulfassalazina/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , alfa-Tocoferol/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Peróxido de Hidrogênio/isolamento & purificação , MAP Quinase Quinase 4/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
AIMS/HYPOTHESIS: Chronic inflammatory processes have been increasingly shown to be involved in the pathogenesis of diabetes and diabetic nephropathy. Recently, we demonstrated that a lectin-like domain of thrombomodulin (THBD), which is known as THBD domain 1 (THBDD1) and which acts independently of protein C activation, neutralised an inflammatory response in a mouse model of sepsis. Here, therapeutic effects of gene therapy with adeno-associated virus (AAV)-carried THBDD1 (AAV-THBDD1) were tested in a mouse model of type 2 diabetic nephropathy. METHODS: To assess the therapeutic potential of THBDD1 and the mechanisms involved, we delivered AAV-THBDD1 (10(11) genome copies) into db/db mice and tested the effects of recombinant THBDD1 on conditionally immortalised podocytes. RESULTS: A single dose of AAV-THBDD1 improved albuminuria, renal interstitial inflammation and glomerular sclerosis, as well as renal function in db/db mice. These effects were closely associated with: (1) inhibited activation of the nuclear factor κB (NF-κB) pathway and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome; (2) promotion of nuclear factor (erythroid-derived 2)-like 2 (NRF2) nuclear translocation; and (3) suppression of mitochondria-derived apoptosis in the kidney of treated mice. CONCLUSIONS/INTERPRETATION: AAV-THBDD1 gene therapy resulted in improvements in a model of diabetic nephropathy by suppressing the NF-κB-NLRP3 inflammasome-mediated inflammatory process, enhancing the NRF2 antioxidant pathway and inhibiting apoptosis in the kidney.
Assuntos
Antioxidantes/farmacologia , Proteínas de Transporte/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/metabolismo , Terapia Genética , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Trombomodulina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas de Transporte/antagonistas & inibidores , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/imunologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/imunologia , Terapia Genética/métodos , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLRRESUMO
Drug resistance frequently develops in tumors during chemotherapy. Therefore, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Here, we show that isochaihulactone (K8) enhanced paclitaxel-induced apoptotic death in human lung cancer cells, and the enhancing effect was related to increased NSAID-activated gene-1 (NAG-1) expression. CalcuSyn software was used to evaluate the synergistic interaction of K8 and paclitaxel on human lung cancer cells; the synergistic effect of K8 in combination with paclitaxel was increased more than either of these drugs alone. Furthermore, the activity of ERK1/2 was enhanced by the combination of K8 and paclitaxel, and an ERK1/2 inhibitor dramatically inhibited NAG-1 expression in human lung cancer cells. Therefore, this synergistic apoptotic effect in human lung cancer cells may be directly associated with K8-induced NAG-1 expression through ERK1/2 activation. Moreover, over-expression of NAG-1 enhanced K8/paclitaxel-induced apoptosis in human lung cancer cells. In addition, treatment of nude mice with K8 combined with paclitaxel induced phospho-ERK1/2 and NAG-1 expression in vivo. Targeting of NAG-1 signaling could enhance therapeutic efficacy in lung cancer. Our results reveal that activation of NAG-1 by K8 enhanced the therapeutic efficacy of paclitaxel in human lung cancer cells via the ERK1/2 signaling pathway.
Assuntos
4-Butirolactona/análogos & derivados , Adenocarcinoma/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzodioxóis/farmacologia , Neoplasias Pulmonares/metabolismo , Paclitaxel/farmacologia , 4-Butirolactona/farmacologia , Adenocarcinoma/patologia , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologiaRESUMO
Vitamin C and vitamin E are well-known antioxidant vitamins, both of which are also applied as adjunct treatments for cancer therapy. Methotrexate (MTX) is a clinical drug that is used widely for rheumatoid arthritis and cancer treatment. Human glioblastoma multiforme (GBM) is an aggressive malignant brain tumor; the mean survival time for GBM patients is <2 years with traditional therapies. Developing and investigating novel treatments are important for clinical GBM therapy. Therefore, the aim of this study was to investigate whether combined treatment with vitamin C/E and MTX can display anticancer activities on GBM. Our studies showed that MTX displays anticancer effects on GBM in a dose-dependent manner, while vitamins C and E are not cytotoxic to glioblastoma. Importantly, this study showed that vitamins C and E can promote anticancer effects on low-concentration methotrexate-treated glioblastoma. Additionally, this study suggested that MTX alone or combined with vitamins C/E inhibits GBM cell growth via the caspase-3 death pathway.
RESUMO
Renal tubulointerstitial lesions (TILs), a common pathologic hallmark of chronic kidney disease that evolves to end-stage renal disease, is characterized by progressive inflammation and pronounced fibrosis of the kidney. However, current therapeutic approaches to treat these lesions remain largely ineffectual. Previously, we demonstrated that elevated IL-36α levels in human renal tissue and urine are implicated in impaired renal function, and IL-36 signaling enhances activation of NLRP3 inflammasome in a mouse model of TILs. Recently, we synthesized NSC828779, a salicylanilide derivative (protected by U.S. patents with US 8975255 B2 and US 9162993 B2), which inhibits activation of NF-κB signaling with high immunomodulatory potency and low IC50, and we hypothesized that it would be a potential drug candidate for renal TILs. The current study validated the therapeutic effects of NSC828779 on TILs using a mouse model of unilateral ureteral obstruction (UUO) and relevant cell models, including renal tubular epithelial cells under mechanically induced constant pressure. Treatment with NSC828779 improved renal lesions, as demonstrated by dramatically reduced severity of renal inflammation and fibrosis and decreased urinary cytokine levels in UUO mice. This small molecule specifically inhibits the IL-36α/NLRP3 inflammasome pathway. Based on these results, the beneficial outcome represents synergistic suppression of both the IL-36α-activated MAPK/NLRP3 inflammasome and STAT3- and Smad2/3-dependent fibrogenic signaling. NSC828779 appears justified as a new drug candidate to treat renal progressive inflammation and fibrosis.
Assuntos
Interleucina-1/metabolismo , Nefrite Intersticial/metabolismo , Salicilanilidas/farmacologia , Transdução de Sinais , Animais , Linhagem Celular , Citocinas/urina , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Peróxido de Hidrogênio , Inflamassomos/metabolismo , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nefrite Intersticial/complicações , Nefrite Intersticial/patologia , Nefrite Intersticial/urina , Fator de Transcrição STAT3/metabolismo , Obstrução Ureteral/complicaçõesRESUMO
Human interleukin-15 (hIL15) has anti-tumor activities, but it is not convenient for tumor treatment because of its short half-life. A gene therapy for mouse lung cancer using an adenovirus vector expressing IL15 has been reported. However, adenovirus vector-mediated gene therapy can provoke cellular toxicity and inflammatory reactions. The recombinant adenovirus-associated vector 2 (rAAV2) is safer due to minimal cellular toxicity and immune response. In order to demonstrate that gene therapy can be used safely and successfully for human cancer treatment, the rAAV2 expressing hIL15 gene (rAAV2-hIL15) is applied for human cervical cancer, HeLa cell, in this study. This study successfully demonstrates that rAAV2-hIL15 can express IL15 with bioactivities in vitro and in vivo. In conclusion, our studies show that human cervical cancers are inhibited on animal model with rAAV2-hIL15 treatment and provide a safer and important reference for human cancer gene therapy.
Assuntos
Dependovirus/genética , Vetores Genéticos/genética , Interleucina-15/genética , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Dependovirus/metabolismo , Feminino , Terapia Genética , Células HeLa , Humanos , Imunoterapia , Interleucina-15/metabolismo , Camundongos , Camundongos Nus , Neoplasias/metabolismoRESUMO
AIM: To investigate the role of hTERT gene expression and AP-2alpha in n-butylidenephthalide (n-BP)-induced apoptosis in A549 lung cancer cells. METHODS: Viability of A549 cells was measured by MTT assay. Protein expression was determined by Western blot. Telomerase activity was measured using the modified telomere repeat amplification protocol (TRAP) assay. Xenograft mice were used as a model system to study the cytotoxic effect of n-BP in vivo. The morphology of tumor was examined by immunohistochemical staining. RESULTS: The growth of A549 lung cancer cells treated with n-BP was significantly inhibited. Telomerase activity and hTERT mRNA expression were determined by telomeric repeat amplification protocol and reverse transcription-polymerase chain reaction, respectively. n-BP inhibited telomerase activity and hTERT mRNA expression in A549 cells while overexpression of hTERT could abolish BP-induced growth inhibition in the A549 cells. We also showed that hTERT promoter activity in the presence of n-BP was mediated via AP-2alpha. We saw an inhibition of tumor growth when nude mice carrying A549 subcutaneous xenograft tumors were treated with n-BP. Immunohistochemistry of this tumor tissue also showed a decrease in the expression of hTERT. CONCLUSION: The antiproliferative effects of n-BP on A549 cells in vitro and in vivo suggest a novel clinical application of this compound in the treatment of lung cancers.
Assuntos
Adenocarcinoma/genética , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/genética , Anidridos Ftálicos/farmacologia , Telomerase/metabolismo , Fator de Transcrição AP-2/efeitos dos fármacos , Adenocarcinoma/enzimologia , Animais , Western Blotting , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/enzimologia , Camundongos , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telomerase/efeitos dos fármacos , Telomerase/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
p-Cresyl sulfate (pCS), a uremic toxin, can cause renal damage and dysfunction. Studies suggest that renal dysfunction increases the prevalence of renal cancer. However, the effect of pCS on the proliferation and migration of renal cancer is unclear. Clear cell renal cell carcinoma (ccRCC) expresses mutant von Hippel-Lindau gene and is difficult to treat. Hypoxia-inducible factor-1α and 2-α (HIF-1α and HIF-2α) as well as microRNA-21 (miR-21) can regulate the proliferation and migration of ccRCC cells. However, the association between HIF-α and miR-21 in ccRCC remains unclear. Therefore, the effects of pCS on ccRCC cells were investigated for HIF-α and miR-21 signals. Our results showed that pCS induced overexpression of HIF-1α and promoted the proliferation and regulated epithelial-mesenchymal transition-related proteins, including E-cadherin, fibronectin, twist and vimentin in ccRCC cells. pCS treatment increased miR-21 expression. Specifically, inhibition of miR-21 blocked pCS-induced proliferation and migration. Taken together, the present results demonstrate that pCS directly induced the proliferation and migration of ccRCC cells through mechanisms involving miR-21/HIF-1α signaling pathways.
Assuntos
Carcinoma de Células Renais/patologia , Movimento Celular/efeitos dos fármacos , Cresóis/toxicidade , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/patologia , MicroRNAs/metabolismo , Transdução de Sinais , Ésteres do Ácido Sulfúrico/toxicidade , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Renais/genética , MicroRNAs/genética , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Tempo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismoRESUMO
Triplenegative breast cancers (TNBCs) lack the estrogen receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Therefore, hormone or targeted therapies are not effective in the treatment of TNBC and thus the development of novel therapeutic strategies is crucial. Methotrexate (MTX), a folate antagonist, has been used in the treatment of various types of cancer; however, the anticancer effects of MTX treatment on breast cancer have thus far been ineffective. Vitamin E variants and derivatives have been applied for cancer therapy. Previous studies have indicated that vitamin E variants and derivatives exert distinct anticancer effects on different types of cancer. However, whether MTX plus vitamin E variants or its derivatives can inhibit TNBC remains unclear. The aim of the present study was to examine the anticancer effects and mechanisms of action of MTX in combination with vitamin E variants (αtocopherol) and derivatives (αtocopherol succinate) on TNBC. In the present study, MTT assay and western blot analysis were used to determine the cell survival rates and protein levels. The results demonstrated that combination treatment with MTX and αtocopherol suppressed TNBC cell proliferation. In addition, various concentrations of MTX exerted distinct cytotoxic effects on αtocopherol succinatetreated cells. Furthermore, highdose MTX enhanced αtocopherol succinateinduced anticancer activity; however, lowdose MTX inhibited αtocopherol succinateinduced anticancer activity. The present study also demonstrated that caspase3 activation and poly(adenosine diphosphateribose) polymerase cleavage were observed in the αtocopherol succinate/MTXtreated cells. In conclusion, the findings of the present study demonstrated that highdose MTX enhanced anticancer activity in αTOStreated TNBC, while lowdose MTX reduced anticancer activity in αTOStreated TNBC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Metotrexato/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , alfa-Tocoferol/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Metotrexato/uso terapêutico , alfa-Tocoferol/uso terapêuticoRESUMO
Many studies have indicated that differentiated cells inhibit drug-induced cytotoxicity but undifferentiated cells do not, though the mechanisms are unclear. Currently, HL-60 cells are induced to differentiate into macrophage-like cells with Phorbol-12-myristate-13-acetate (TPA) treatment (TPA-differentiated cells). Our study shows that caspase-9/-3-mediated cytotoxicity can be induced in undifferentiated HL-60 cells but not in TPA-differentiated HL-60 cells. However, caspase-9/-3-mediated cytotoxicity can be induced in TPA-differentiated cells if they are pretreated with a protein kinase C (PKC) or a mitogen activated protein kinase (MEK) inhibitor. Taken together, this study demonstrates that TPA-differentiated HL-60 cells inhibit caspases-9/-3-mediated cytotoxicity through the PKC and MEK signaling pathways.
Assuntos
Inibidores de Caspase , Diferenciação Celular , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteína Quinase C/metabolismo , Apoptose , Caspase 3/metabolismo , Caspase 9/metabolismo , Ativação Enzimática , Células HL-60 , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Aristolochic acid (AA) is a component identified in traditional Chinese remedies for the treatment of arthritic pain, coughs and gastrointestinal symptoms. However, previous studies have indicated that AA can induce oxidative stress in renal cells leading to nephropathy. αtocopherol exists in numerous types of food, such as nuts, and belongs to the vitamin E isoform family. It possesses antioxidant activities and has been used previously for clinical applications. Therefore, the aim of the present study was to determine whether αtocopherol could reduce AAinduced oxidative stress and renal cell cytotoxicity, determined by cell survival rate, reactive oxygen species detection and apoptotic features. The results indicated that AA markedly induced H2O2 levels and caspase3 activity in renal tubular epithelial cells. Notably, the presence of αtocopherol inhibited AAinduced H2O2 and caspase3 activity. The present study demonstrated that antioxidant mechanisms of αtocopherol may be involved in the increased survival rates from AAinduced cell injury.
Assuntos
Apoptose/efeitos dos fármacos , Ácidos Aristolóquicos/efeitos adversos , Caspase 3/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Túbulos Renais/citologia , Estresse Oxidativo/efeitos dos fármacos , Vitamina E/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , alfa-Tocoferol/farmacologiaRESUMO
Acetaminophen (APAP) is an analgesic and antipyretic agent primarily used in the clinical setting. However, high doses of APAP can cause oxidative stress. Guavas have been reported to provide antiinflammatory, antimicrobial, antioxidative and antidiarrheal functions. In addition, guavas have been reported to prevent renal damage due to progression of diabetes mellitus. Therefore, the aim of the present study was to investigate whether guavas can reduce APAPinduced renal cell damage. In the present study, extracts from guavas were obtained and added to APAPtreated renal tubular endothelial cells. The present results demonstrated that APAP induces cytotoxicity in renal tubular endothelial cells, while guava extracts inhibited this cytotoxicity. In addition, the study demonstrated that the protective effects of guava extracts against APAPinduced cytotoxicity may be associated with inhibition of oxidative stress and caspase3 activation.
Assuntos
Acetaminofen/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Frutas/química , Túbulos Renais/citologia , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Psidium/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/metabolismo , RatosRESUMO
Methotrexate (MTX) is widely used as both an anticancer and anti-rheumatoid arthritis drug. Although MTX has been used to inhibit the growth of many cancer cells, it cannot effectively inhibit growth of triple-negative breast cancer cells (TNBC cells). Vitamin C is an antioxidant that can prevent oxidative stress. In addition, vitamin C has been applied as adjunct treatment for growth inhibition of cancer cells. Recent studies indicated that combined treatment with vitamin C and MTX may inhibit MCF-7 and MDA-MB-231 breast cancer cell growth through G2/M elongation. However, the mechanisms remain unknown. The aim of the present study was to determine whether combined treatment with low-dose vitamin C and MTX inhibits TNBC cell growth and to investigate the mechanisms of vitamin C/MTX-induced cytotoxicity. Neither low-dose vitamin C alone nor MTX alone inhibited TNBC cell growth. However, combined low-dose vitamin C and MTX had synergistic anti-proliferative/cytotoxic effects on TNBC cells. In addition, co-treatment increased H2O2 levels and activated both caspase-3 and p38 cell death pathways.
Assuntos
Ácido Ascórbico/farmacologia , Caspase 3/metabolismo , Peróxido de Hidrogênio/metabolismo , Metotrexato/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células MCF-7 , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
We have previously showed that IL-1ß is involved in the pathogenesis of both spontaneously occurring and passively induced IgA nephropathy (IgAN) models. However, the exact causal-relationship between NLRP3 inflammasome and the pathogenesis of IgAN remains unknown. In the present study, we showed that [1] IgA immune complexes (ICs) activated NLRP3 inflammasome in macrophages involving disruption of mitochondrial integrity and induction of mitochondrial ROS, bone marrow-derived dendritic cells (BMDCs) and renal intrinsic cells; [2] knockout of NLRP3 inhibited IgA ICs-mediated activation of BMDCs and T cells; and [3] knockout of NLRP3 or a kidney-targeting delivery of shRNA of NLRP3 improved renal function and renal injury in a mouse IgAN model. These results strongly suggest that NLRP3 inflammasome serves as a key player in the pathogenesis of IgAN partly through activation of T cells and mitochondrial ROS production and that a local, kidney-targeting suppression of NLRP3 be a therapeutic strategy for IgAN.
Assuntos
Glomerulonefrite por IGA/metabolismo , Inflamassomos/metabolismo , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Feminino , Glomerulonefrite por IGA/imunologia , Rim/imunologia , Rim/metabolismo , Camundongos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Bacillus amyloliquefaciens JN68, which has been discussed with regards to its antimicrobial activities, was successfully isolated from healthy chicken intestines in the present study. Using the spot-on-the-lawn antagonism method, the preliminary study indicated that a suspension culture of the B. amyloliquefaciens JN68 strain can inhibit the growth of Aspergillus niger and Penicillium pinophilum. Furthermore, the cyclic lipopeptides (CLPs) produced by the B. amyloliquefaciens JN68 strain were further purified through acid precipitation and Bond Elut®C18 chromatography, and their structures were identified using the liquid chromatographyelectrospray ionizationmass spectrometry (MS)/MS method. Purified CLPs exerted broad spectrum antimicrobial activities on various pathogenic and foodborne bacteria and fungi, as determined using the agar well diffusion method. Listeria monocytogenes can induce listeriosis, which is associated with a high mortality rate. Methicillinresistant Staphylococcus aureus (MRSA) is a major pathogenic bacteria that causes nosocomial infections. Therefore, L. monocytogenes and MRSA are currently of great concern. The present study aimed to determine whether B. amyloliquefaciens JN68 extracts could inhibit L. monocytogenes and MRSA. The results indicated that extracts of B. amyloliquefaciens JN68 have CLP components, and can successfully inhibit the growth of L. monocytogenes and MRSA.
Assuntos
Anti-Infecciosos/farmacologia , Bacillus amyloliquefaciens/metabolismo , Lipopeptídeos/farmacologia , Listeria monocytogenes/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Animais , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Anti-Infecciosos/isolamento & purificação , Antibiose , Bacillus amyloliquefaciens/isolamento & purificação , Galinhas , Intestinos/microbiologia , Lipopeptídeos/isolamento & purificação , Peptídeos Cíclicos/isolamento & purificaçãoRESUMO
Renal fibroblast proliferation is key in renal fibrosis and chronic kidney disease. Transforming growth factor-ß1 (TGF-ß1) has been demonstrated to be an important factor that induces cell proliferation in renal fibroblasts. Epidermal growth factor receptor (EGFR) is also recognized as a factor promoting renal fibroblast proliferation. In addition, mitogenactivated protein kinase signaling pathways are associated with TGFß1 and EGFRinduced cell proliferation. Gefitinib, an EGFR tyrosine kinase inhibitor, is predominantly used as an antitumor therapeutic agent in clinical therapeutic strategies. However, gefitinib has been suggested to exert antiproliferative effects on renal fibroblasts, however, highdose gefitinib may result in serious side effects. The present study aims to determine whether lowdose gefitinib reduces gefitinibinduced side effects and maintains the antiproliferative effects on renal fibroblasts. TGFß1 promotes cell proliferation in renal fibroblasts, and the current study demonstrates that lowdose gefitinib treatment exhibits antiproliferative effects similar to those of highdose gefitinib treatment. Thus, although highdose gefitinib is a conventional antitumor drug, lowdose gefitinib may be of use in renal fibrosis treatment. Furthermore, the present study demonstrates that a combined treatment with low-dose gefitinib and vitamin E has synergistic effects that reduce TGFß1induced fibroblast proliferation, cell-cycle arrest and the ERK phosphorylation pathway.
Assuntos
Proliferação de Células/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/metabolismo , Quinazolinas/farmacologia , Fator de Crescimento Transformador beta1/biossíntese , Vitamina E/farmacologia , Animais , Linhagem Celular , Sinergismo Farmacológico , Fibroblastos/citologia , Gefitinibe , Rim/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinazolinas/agonistas , Ratos , Vitamina E/agonistasRESUMO
Rana catesbeiana ribonuclease (RC-RNase) possesses tumor-specific cytotoxicity, which can be synergized by IFN-gamma. However, it is unclear how RC-RNase and RC-RNase/IFN-gamma induce cell death. In this study, we use substrate cleavage assays to systematically investigate RC-RNase- and RC-RNase/IFN-gamma-induced caspase activation in HL-60, MCF-7, and SK-Hep-1 cells. We find that RC-RNase and RC-RNase/IFN-gamma induce mitochondria-mediated caspase activation in HL-60 and MCF-7 cells but not in SK-Hep-1 cells, although death of SK-Hep-1 cells is closely related to mitochondrial disruptions. Our findings provide evidence that RC-RNase and RC-RNase/IFN-gamma can kill different cancer cells by distinct mechanisms. Compared with onconase, RC-RNase seems to harbor a more specific anti-cancer activity.
Assuntos
Proteínas de Anfíbios/farmacologia , Antineoplásicos/farmacologia , Caspases/metabolismo , Endorribonucleases/farmacologia , Interferon gama/farmacologia , Neoplasias/enzimologia , Proteínas de Anfíbios/toxicidade , Animais , Antineoplásicos/toxicidade , Morte Celular , Linhagem Celular Tumoral , Sinergismo Farmacológico , Endorribonucleases/toxicidade , Interferon gama/toxicidade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Poli(ADP-Ribose) Polimerases/metabolismoRESUMO
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. Generally, the therapeutic dose of APAP is clinically safe, however, high doses of APAP can cause acute liver and kidney injury. Therefore, the majority of previous studies have focussed on elucidating the mechanisms of APAP-induced hepatotoxicity and nephrotoxicity, in addition to examining ways to treat these conditions in clinical cases. However, few studies have reported APAP-induced intoxication in human stem cells. Stem cells are important in cell proliferation, differentiation and repair during human development, particularly during fetal and child development. At present, whether APAP causes cytotoxic effects in human stem cells remains to be elucidated, therefore, the present study aimed to investigate the cellular effects of APAP treatment in human stem cells. The results of the present study revealed that high-dose APAP induced more marked cytotoxic effects in human mesenchymal stem cells (hMSCs) than in renal tubular cells. In addition, increased levels of hydrogen peroxide (H2O2), phosphorylation of c-Jun N-terminal kinase and p38, and activation of caspase-9/-3 cascade were observed in the APAP-treated hMSCs. By contrast, antioxidants, including vitamin C reduced APAP-induced augmentations in H2O2 levels, but did not inhibit the APAP-induced cytotoxic effects in the hMSCs. These results suggested that high doses of APAP may cause serious damage towards hMSCs.