RESUMO
Triple-negative breast cancer (TNBC) is the most aggressive and fatal breast cancer subtype. Nowadays, chemotherapy remains the standard treatment of TNBC, and immunotherapy has emerged as an important alternative. However, the high rate of TNBC recurrence suggests that new treatment is desperately needed. Schisandrin B (Sch B) has recently revealed its anti-tumor effects in cancers such as cholangiocarcinoma, hepatoma, glioma, and multi-drug-resistant breast cancer. However, there is still a need to investigate using Sch B in TNBC treatment. Interleukin (IL)-1ß, an inflammatory cytokine that can be expressed and produced by the cancer cell itself, has been suggested to promote BC proliferation and progression. In the current study, we present evidence that Sch B can significantly suppress the growth, migration, and invasion of TNBC cell lines and patient-derived TNBC cells. Through inhibition of inflammasome activation, Sch B inhibits interleukin (IL)-1ß production of TNBC cells, hindering its progression. This was confirmed using an NLRP3 inhibitor, OLT1177, which revealed a similar beneficial effect in combating TNBC progression. Sch B treatment also inhibits IL-1ß-induced EMT expression of TNBC cells, which may contribute to the anti-tumor response.
Assuntos
Neoplasias dos Ductos Biliares , Lignanas , Compostos Policíclicos , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR , Interleucina-1beta , Ductos Biliares Intra-Hepáticos , Ciclo-OctanosRESUMO
Excessive alcohol consumption can lead to serious health complications, with liver and neurological complications being the most important. In Western nations, alcoholic liver disease accounts for 50% of mortality from end-stage liver disease and is the second most common cause of liver transplants. In addition to direct damage, hepatic encephalopathy may also arise from alcohol consumption. However, effective treatment for liver disease, as well as neurological injury, is still lacking today; therefore, finding an efficacious alternative is urgently needed. In the current study, the preventive and therapeutic effects of Schisandrin B (Sch B) against ethanol-induced liver and brain injuries were investigated. By using two treatment models, our findings indicated that Sch B can effectively prevent and ameliorate alcoholic liver diseases, such as resolving liver injuries, lipid deposition, inflammasome activation, and fibrosis. Moreover, Sch B reverses brain damage and improves the neurological function of ethanol-treated mice. Therefore, Sch B may serve as a potential treatment option for liver diseases, as well as subsequential brain injuries. Furthermore, Sch B may be useful in preventive drug therapy against alcohol-related diseases.
Assuntos
Lesões Encefálicas , Lignanas , Camundongos , Animais , Etanol/efeitos adversos , Fígado , Lignanas/farmacologiaRESUMO
BACKGROUND: In most developing or undeveloped countries, patients are often co-infected with multiple pathogens rather than a single pathogen. While different pathogens have their impact on morbidity and mortality, co-infection of more than one pathogen usually made the disease outcome different. Many studies reported the co-infection of Schistosoma with Salmonella in pandemic areas. However, the link or the underlying mechanism in the pathogenesis caused by Schistosoma-Salmonella co-infection is still unknown. METHODS: In this study, Salmonella typhimurium (S. typhimurium) was challenged to Schistosoma mansoni (S. mansoni)-infected mice. Further experiments such as bacterial culture, histopathological examination, western blotting, and flow cytometry were performed to evaluate the outcomes of the infection. Cytokine responses of the mice were also determined by ELISA and real-time quantitative PCR. RESULTS: Our results demonstrated that co-infected mice resulted in higher bacterial excretion in the acute phase but higher bacterial colonization in the chronic phase. Lesser egg burden was also observed during chronic schistosomiasis. Infection with S. typhimurium during schistosomiasis induces activation of the inflammasome and apoptosis, thereby leading to more drastic tissue damage. Interestingly, co-infected mice showed a lower fibrotic response in the liver and spleen. Further, co-infection alters the immunological functioning of the mice, possibly the reason for the observed pathological outcomes. CONCLUSION: Collectively, our findings here demonstrated that S. mansoni-infected mice challenged with S. typhimurium altered their immunological responses, thereby leading to different pathological outcomes.
Assuntos
Coinfecção , Infecções por Salmonella , Esquistossomose mansoni , Esquistossomose , Animais , Camundongos , Esquistossomose mansoni/complicações , Esquistossomose mansoni/patologia , Salmonella typhimurium , Baço/patologia , Coinfecção/microbiologia , Fígado/patologia , Schistosoma mansoni/fisiologia , Infecções por Salmonella/patologia , FibroseRESUMO
BACKGROUND/PURPOSE: Schistosomiasis is an important tropical disease caused by Schistosoma. Although the pathogenesis of liver fibrosis has been intensively studied, the choice of effective treatment is still inadequate. In this study, we aimed to investigate the potential of using Casticin to treat Schistosoma mansoni-induced liver fibrosis. METHODS: BALB/c mice were divided into three groups - control, infection, and treatment group. The infection and treatment group were percutaneously infected with 100-120 cercariae. Mice from the treatment group were treated with 20 mg/kg/day Casticin for 14 consecutive days to investigate the potential protective effects of Casticin. Mice were sacrificed and were used for histological, RNA, protein, and parasite burden analysis. RESULTS: Our results showed that hepatic fibrosis was significantly attenuated, as indicated by histology and reduction of fibrotic markers such as collagen AI, transforming growth factor ß (TGF-ß), and α-smooth muscle actin (α-SMA). Furthermore, Casticin treatment significantly reduced worm burden. Anthelmintic effect of Casticin was also observed by scanning electron microscopy. CONCLUSION: Collectively, our study suggested that Casticin may be a beneficial candidate in treating S. mansoni infection.
Assuntos
Anti-Helmínticos , Anti-Infecciosos , Esquistossomose mansoni , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Anti-Infecciosos/farmacologia , Flavonoides , Humanos , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Camundongos , Camundongos Endogâmicos BALB C , Praziquantel/farmacologia , Praziquantel/uso terapêutico , Schistosoma mansoni , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/parasitologia , Esquistossomose mansoni/patologiaRESUMO
After many years of the excessive use of praziquantel against Schistosoma mansoni (S. mansoni), it has already led to the development of drug resistance. While schistosomiasis is still affecting millions of people every year, vaccination may be one realistic alternative way to control the disease. Currently, S. mansoni 14-kDa fatty acid-binding protein (Sm14) has shown promising results as a vaccine antigen. Yet, the use of an adjuvant may be necessary to further increase the effectiveness of the vaccine. Herein, we investigated the potential of using heat-killed Cutibacterium acnes (C. acnes) as an adjuvant for recombinant Sm14 (rSm14). Immunization of mice with C. acnes-adjuvanted rSm14 showed increased humoral immune responses, compared with mice immunized with rSm14 alone. Additionally, C. acnes-adjuvanted rSm14 vaccination provided higher protection to mice against S. mansoni infection and liver injuries. These results suggest that C. acnes increases the immunogenicity of rSm14, which leads to better protection against S. mansoni infection. Therefore, heat-killed C. acnes may be a promising adjuvant to use with rSm14.
Assuntos
Proteínas de Transporte de Ácido Graxo/imunologia , Proteínas de Helminto/imunologia , Imunogenicidade da Vacina , Propionibacteriaceae/química , Schistosoma mansoni/imunologia , Esquistossomose mansoni/prevenção & controle , Vacinas/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Sm28GST is one of the candidate antigens for Schistosoma mansoni vaccine. Already Sm28GST vaccine formulations have shown to be protective against S. mansoni infection. Currently, efforts have been put into finding an adjuvant to enhance the immunity induced by Sm28GST. In the present work, we investigated whether heat-killed Propionibacterium acnes can be served as a potential adjuvant for recombinant Sm28GST (rSm28GST) antigen. As the results showed, P. acnes successfully modulated the Th1 humoral immune response induced by rSm28GST. Stronger Th1 cytokines responses were also observed in mice immunized with P. acnes-adjuvanted rSm28GST. Immunization of mice with P. acnes-adjuvanted rSm28GST was able to reduce worm burden and hepatic egg burden by 54.20 and 73.61%. Reduced granuloma size and count, as well as improved liver histology, were seen in P. acnes-adjuvanted rSm28GST immunized mice. These data suggest that P. acnes may evoke a stronger rSm28GST-induced immune response, higher resistance to S. mansoni infection, and more profound protection against S. mansoni-induced liver damages.
Assuntos
Antígenos de Helmintos/imunologia , Glutationa Transferase/imunologia , Propionibacterium acnes , Esquistossomose mansoni , Vacinas/imunologia , Adjuvantes Imunológicos , Animais , Anticorpos Anti-Helmínticos , Temperatura Alta , Camundongos , Schistosoma mansoni/imunologia , Esquistossomose mansoni/prevenção & controle , Células Th1/imunologiaRESUMO
Schistosomiasis is second only to malaria as the most devastating parasitic disease in the world. It is caused by the helminths Schistosoma mansoni (S. mansoni), S. haematobium, or S. japonicum. Typically, patients with schistosomiasis suffer from symptoms of liver fibrosis and hepatosplenomegaly. Currently, patients were treated with praziquantel. Although praziquantel effectively kills the worm, it cannot prevent re-infection or resolve liver fibrosis. Also, current treatment options are not ample to completely cure liver fibrosis and splenic damages. Moreover, resistance of praziquantel has been reported in vivo and in vitro studies. Therefore, finding new effective treatment agents is urgently needed. Schisandrin B (Sch B) of Schisandra chinensis has been shown to protect against different liver injuries including fatty liver disease, hepatotoxicity, fibrosis, and hepatoma. We herein investigate the potential of using Sch B to treat S. mansoni-induced liver fibrosis. Results from the present study demonstrate that Sch B is beneficial in treating S. mansoni-induced liver fibrosis and splenic damages, through inhibition of inflammasome activation and apoptosis; and aside from that regulates host immune responses. Besides, Sch B treatment damages male adult worm in the mice, consequently helps to reduce egg production and lessen the parasite burden.
Assuntos
Anti-Inflamatórios/farmacologia , Lignanas/farmacologia , Cirrose Hepática/tratamento farmacológico , Compostos Policíclicos/farmacologia , Esquistossomose mansoni/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Inflamassomos/efeitos dos fármacos , Cirrose Hepática/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Schistosoma mansoni/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/parasitologiaRESUMO
Currently, there are no effective treatments for liver diseases. Treatment usually involves controlling complications and supportive care. As liver injuries also affect other organs such as the spleen, kidney, and brain due to their anatomical and physiological relationships, finding an effective treatment is urgently needed. This research aimed to evaluate the therapeutic effect of Schisandrin B (Sch B) in the liver and other organs in thioacetamide (TAA)-intoxicated mice. In this study, mice were exposed to a single intraperitoneal injection of 200 mg/kg TAA to induce hepatitis. Following Sch B (20 mg/kg/day, 28 consecutive days) treatment, biochemistry analysis and histopathological examination of different organs were performed, in addition to western blotting and flow cytometry to evaluate the involvement of inflammasomes and apoptotic proteins. Our results showed that administration of Sch B protected against TAA-induced damages, and it disparately affected inflammasome activation and apoptosis in different organs. Furthermore, Sch B treatment improved organ function, as indicated by the improvement of serum biochemical parameters. Collectively, our findings reveal a beneficial effect of Sch B on different organ damages in mice intoxicated with TAA.
RESUMO
Angiostrongylus cantonensis is one of the most widespread parasites causing central nervous system (CNS) diseases in mammals. Since the mitochondrion is an essential cell organelle responsible for both physiological and pathological processes, its dysfunction might lead to inflammation and multiple disorders. In this study we aimed to investigate the changes in mitochondrial dynamics that occur in the mouse brain upon infection with A. cantonensis, using molecular biology techniques such as polymerase chain reaction (PCR), western blot analysis, transmission electron microscopy (TEM), and different staining methods. Here, we show that mouse brain infected with A. cantonensis exhibits altered mitochondrial dynamics, including fission, fusion, and biogenesis. Additionally, we demonstrate that caspases and B-cell lymphoma 2 (BCL-2) were significantly upregulated in A. cantonensis-infected brain. These results are indicative of the occurrence of apoptosis during A. cantonensis infection, which was further confirmed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. These findings suggest the change in mitochondrial dynamics in A. cantonensis-infected brain, providing another point of view on the pathogenesis of meningoencephalitis caused by A. cantonensis infection.
Assuntos
Angiostrongylus cantonensis/fisiologia , Encéfalo/parasitologia , Dinâmica Mitocondrial , Infecções por Strongylida/fisiopatologia , Angiostrongylus cantonensis/crescimento & desenvolvimento , Animais , Apoptose , Western Blotting , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Encéfalo/ultraestrutura , Larva/crescimento & desenvolvimento , Larva/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Reação em Cadeia da Polimerase em Tempo Real , Coloração e Rotulagem/métodos , Infecções por Strongylida/parasitologia , Regulação para CimaRESUMO
Abstract: Currently, Angiostrongylus cantonensis infections are predominantly treated with albendazole. However, the use of albendazole can provoke certain neurological symptoms as a result of the immune response triggered by the dead worms. Therefore, treatment usually involves co-administration of corticosteroids to limit the inflammatory reaction. Corticosteroids play a useful role in suppressing inflammation in the brain; however, long-term usage or high dosage may make it problematic.Schisandrin B, an active ingredient from Schisandra chinensis, has been shown to have anti-inflammatory effects on the brain. This study aimed to investigate the effects and potential of schisandrin B in combination with albendazole to treat Angiostrongylus-induced meningoencephalitis. Here, we show that albendazole-schisandrin B co-treatment suppressed neuroinflammation in Angiostrongylus-infected mice and increased the survival of the mice. Accordingly, albendazole-schisandrin B co-treatment significantly inhibited inflammasome activation, pyroptosis, and apoptosis. The sensorimotor functions of the mice were also repaired after albendazole-schisandrin B treatment. Immune response was shown to shift from Th2 to Th1, which reduces inflammation and enhances immunity against A. cantonensis. Collectively, our study showed that albendazole-schisandrin B co-therapy may be used as an encouraging treatment for Angiostrongylus-induced meningoencephalitis.