Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20.819
Filtrar
1.
Biochemistry (Mosc) ; 84(10): 1186-1196, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31694514

RESUMO

Studies of interactions between natural killer (NK) cells and trophoblasts and identification of conditions for the NK cells to perform their cytotoxic function are of fundamental and practical importance for understanding their role in the development of pathological processes and complications during pregnancy. In this study, we examined changes in the content of caspases and studied activation of these enzymes in Jeg-3 trophoblasts in various models of their coculturing with NK-92 cells and demonstrated the necessity of direct contact between these cell populations for the activation of caspase-8 and caspase-3 in the trophoblasts. Contact coculturing of the two cell lines resulted in the appearance of the cytotoxic protein granzyme B in Jeg-3 cells that was accompanied by a decrease in the content of this enzyme in NK-92 cells. Distant coculturing of NK-92 and Jeg-3 cells did not trigger initiator and effector caspases characteristic for the apoptosis development in Jeg-3 cells. The observed decrease in the content of procaspases in the trophoblasts may be associated with alternative non-apoptotic functions of these enzymes.


Assuntos
Caspases/metabolismo , Técnicas de Cocultura , Células Matadoras Naturais/metabolismo , Modelos Biológicos , Trofoblastos/metabolismo , Linhagem Celular Tumoral , Humanos
2.
Adv Exp Med Biol ; 1209: 109-123, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31728867

RESUMO

Inflammasome is a molecular platform that mediates the activation of caspases, maturation of interleukin-1 (IL-1) family members, and leads to inflammatory cell death called pyroptosis. It is vital for innate immune responses, providing protection against infectious agents, sterile environmental insults, and host cell damages. Aberrant activation of inflammasome is closely correlated with numerous hereditary and acquired inflammatory disorders. Therefore, a better understanding of how inflammasome is regulated may provide more promising therapeutics for controlling inflammasome-associated diseases. In recent years, it becomes apparent that autophagy, a cellular machinery essential for the recycling of intracellular components and maintenance of cellular homeostasis, acts as a key player in the activation and regulation of inflammasome, and ameliorates symptoms of inflammasome-related diseases. This review will discuss the recent insights into inflammasome activation and regulation mediated by autophagy.


Assuntos
Autofagia , Inflamassomos , Autofagia/imunologia , Caspases/metabolismo , Ativação Enzimática , Humanos , Imunidade Inata/imunologia , Inflamassomos/imunologia , Interleucina-1/imunologia , Piroptose/imunologia
3.
Adv Exp Med Biol ; 1172: 189-205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628657

RESUMO

Gasdermin is a recently identified family of pore-forming proteins consisting of Gasdermin A (GSDMA), Gasdermin B (GSDMB), Gasdermin C (GSDMC), Gasdermin D (GSDMD), Gasdermin E (GSDME), and DFNB59. Gasdermin D (GSDMD) is a downstream effector of inflammasomes, which are supramolecular complexes that activate inflammatory caspases (-1, -4, and -5 in human and -1 and -11 in mouse). GSDMD contains a functionally important N-terminal domain (GSDMD-N), a C-terminal domain, and a linker in between that is recognized and cleaved by the activated inflammatory caspases. Upon cleavage, the GSDMD-N fragments translocate on the membrane and oligomerize to form membrane-embedded pores after specifically binding to acidic lipids such as phosphatidylinositol phosphates (PIPs), phosphatidic acid (PA), phosphatidylserine (PS), and cardiolipin. The pore exhibits strong membrane-disrupting cytotoxicity in mammalian cells by disrupting the osmotic potential and also serves as a gate for extracellular release of mature IL-1ß and IL-18 during pyroptosis. In this chapter, we review our current understanding of GSDM proteins in physiological and pathological cell death, with more focused discussions on its structural basis for GSDM activation and pore formation.


Assuntos
Proteínas de Neoplasias , Piroptose , Animais , Caspases/metabolismo , Ativação Enzimática , Humanos , Inflamassomos , Camundongos , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Relação Estrutura-Atividade
4.
J Agric Food Chem ; 67(41): 11474-11480, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31537057

RESUMO

Patulin (PAT) is the most common food-borne mycotoxin found in fruits and fruit-derived products, while chlorpyrifos (CPF) is a widely used pesticide on fruit and other crops. On the basis of the residue data, certain types of fruits can be contaminated simultaneously by patulin and chlorpyrifos. However, there are no available data about the combined toxicity. Since liver is a possible toxic target of both patulin and chlorpyrifos, we tested whether the combination exposure can cause enhanced hepatotoxicity using both cell culture and animal models. Results showed that the combination resulted in synergistic cytotoxicity in vitro and significantly enhanced liver toxicity in vivo. Mechanistically, PAT inhibited catalase activity via PIG3 induction, while CPF decreased catalase expression. These two mechanisms were converged in response to the combination, leading to enhanced inactivating catalase and boosted reactive oxygen species generation. The finding implicated that it is necessary to consider the combined toxicity in safety assessment of these food-borne contaminants.


Assuntos
Inibidores de Caspase/toxicidade , Clorpirifos/toxicidade , Hepatopatias/etiologia , Patulina/toxicidade , Praguicidas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Animais , Caspases/metabolismo , Catalase/antagonistas & inibidores , Catalase/metabolismo , Sinergismo Farmacológico , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos
5.
J Photochem Photobiol B ; 198: 111586, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31437760

RESUMO

Metronomic photodynamic therapy (mPDT) has emerged as an attractive treatment for the selective destruction of tumor cells by induction of apoptosis. Here, we compared the effects of mPDT and acute photodynamic therapy (aPDT) on human SW837 colorectal cancer (CRC) cells. CRC cells were subjected to mPDT using various exposure durations, concentrations of 5-aminolevulinic acid (ALA), fluence rates and energy densities. The effects were compared with those induced by aPDT. We found that apoptosis and autophagy were earlier induced to a greater extent by mPDT than by the same dose applied as aPDT. The survival rates for mPDT vs. aPDT were 35.2%, 32.4%,27.6%,31.6% vs. 85.7%, 71.1%, 67.8%, 42.1% after 3, 6, 12, and 24 h PDT, respectively. For the same time points, the apoptotic rates for mPDT vs. aPDT were 43.2%, 47.3%, 54.7%, and 50.3% vs. 14.6%, 17.6%, 27.1%, and 53.2%, respectively. mPDT induced a peak rate of autophagy of 20.0% at 3 h, whereas aPDT induced two smaller peaks at 3 h (14.1%) and 12 h (15.8%). Advanced autophagosomes were more abundant in mPDT- than aPDT-treated cells and appeared earlier after mPDT (3 h) than after aPDT (3-12 h). Western Bloting results showed that the ratio of LC3B-II/ß - actin at 3 h was higher (1.04 times) after mPDT than aPDT. Collectively, these datas indicated that ALA-mPDT was more effective than the same dose of ALA-aPDT at inducing SW837 CRC cell death via apoptosis and autophagy. Thus, mPDT may be a superior choice than aPDT for the treatment of human CRC.


Assuntos
Ácido Aminolevulínico/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Caspases/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo
6.
J Agric Food Chem ; 67(39): 10832-10843, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31464433

RESUMO

Excessive fluoride mainly causes skeletal lesions. Recently, it has been reported that an appropriate level of calcium can alleviate fluorosis. However, the appropriate concentration and mechanism of calcium addition is unclear. Hence, we evaluated the histopathology and ultrastructure, DNA fragmentation, hormonal imbalances, biomechanical levels, and expression of apoptosis-related genes after treating the rats with 150 mg/L NaF and different concentrations of CaCO3. Our results suggested that NaF induced the histopathological and ultrastructural injury, with a concomitant increase in the DNA fragmentation (P < 0.05) and serum OC (17.5 ± 0.89 pmoL/L) at 120 days. In addition, the qRT-PCR and western blotting results indicated that NaF exposure upregulated the mRNA and protein expression of Bax, Calpain, Caspase 12, Caspase 9, Caspase 7, Caspase 3, CAD, PARP, and AIF while downregulated Bcl-2 (P < 0.01) and decreased the bone ultimate load by 27.1%, the ultimate stress by 10.1%, and the ultimate deformity by 23.3% at 120 days. However, 1% CaCO3 supplementation decreased the serum OC (14.7 ± 0.65 pmoL/L), bone F content (P < 0.01), and fracture and breakage of collagen fibers and changed the expression of endoplasmic reticulum pathway-related genes and proteins at 120 days. Further, 1% CaCO3 supplementation increased the bone ultimate load by 20.9%, the ultimate stress by 4.89%, and the ultimate deformity by 21.6%. In summary, we conclude that 1% CaCO3 supplementation alleviated fluoride-induced bone damage by inhibiting endoplasmic reticulum stress and mitochondrial dysfunction.


Assuntos
Osso e Ossos/efeitos dos fármacos , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fluoretos/toxicidade , Mitocôndrias/efeitos dos fármacos , Animais , Osso e Ossos/metabolismo , Caspases/genética , Caspases/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley
7.
Nat Chem Biol ; 15(8): 786-794, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31320752

RESUMO

Protein-protein interactions between E3 ubiquitin ligases and protein termini help shape the proteome. These interactions are sensitive to proteolysis, which alters the ensemble of cellular N and C termini. Here we describe a mechanism wherein caspase activity reveals latent C termini that are then recognized by the E3 ubiquitin ligase CHIP. Using expanded knowledge of CHIP's binding specificity, we predicted hundreds of putative interactions arising from caspase activity. Subsequent validation experiments confirmed that CHIP binds the latent C termini at tauD421 and caspase-6D179. CHIP binding to tauD421, but not tauFL, promoted its ubiquitination, while binding to caspase-6D179 mediated ubiquitin-independent inhibition. Given that caspase activity generates tauD421 in Alzheimer's disease (AD), these results suggested a concise model for CHIP regulation of tau homeostasis. Indeed, we find that loss of CHIP expression in AD coincides with the accumulation of tauD421 and caspase-6D179. These results illustrate an unanticipated link between caspases and protein homeostasis.


Assuntos
Caspases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Caspases/genética , Linhagem Celular Tumoral , Cristalografia por Raios X , Escherichia coli/metabolismo , Regulação da Expressão Gênica , Humanos , Ligação Proteica , Ubiquitina/genética , Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Ubiquitinação
8.
BMC Cancer ; 19(1): 645, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262254

RESUMO

BACKGROUND: Ovarian cancer (OC) is the second most frequent gynecological cancer and is associated with a poor prognosis because OC progression is often asymptoma-tic and is detected at a late stage. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. As a nitric oxide prodrug, JS-K is reported highly cytotoxic to human cancer cells such as acute myeloid leukemia, multiple myeloma and breast cancer. This study is aim to investigate the influence of JS-K on proliferation and apoptosis in ovarian cancer cells and explored possible autophagy-related mechanisms, which will contribute to future ovarian cancer therapy and supply theory support that JS-K holds great promise as a novel therapeutic agent against ovarian cancer. METHODS: The cytotoxicity, extracellular ROS/RNS activity and apoptotic effect of JS-K and indicated inhibitors on ovarian cancer cells in vitro were evaluated by MTT assay, extracellular ROS/RNS assay, caspases activities assay and western blot. Further autophagy effect of JS-K and indicated inhibitors were examined by MTT assay, cell transfection, immunofluorescence analysis, transmission electron microscopy (TEM) analysis and western blot on ovarian cancer cells in vitro. In vivo, the BALB/c-nude female mice with SKOV3 ovarian cancer cells xenograft were used to examine the efficacy of JS-K treatment on tumor growth. PCNA and p62 proteins were analyzed by immunohistochemistry. RESULTS: In vitro, JS-K inhibited the proliferation of ovarian cancer cells, induced apoptosis and cell nucleus shrinkage, enhanced the enzymatic activity of caspase-3/7/8/9, and significantly increased the production of ROS/RNS in ovarian cancer A2780 and SKOV3 cells, these effects were attenuated by inhibition of NAC. In addition, JS-K induced autophagy-related proteins and autophagosomes changes in ovarian cancer A2780 and SKOV3 cells. In vivo, JS-K inhibited tumor growth, decreased p62 protein expression and increased the expression levels of PCNA in xenograft models which were established using SKOV3 ovarian cancer cells. CONCLUSION: Taken together, we demonstrated that ROS/RNS stress-mediated apoptosis and autophagy are mechanisms by which SKOV3 cells undergo cell death after treatment with JS-K in vitro. Moreover, JS-K inhibited SKOV3 tumor growth in vivo. An alternative therapeutic approach for triggering cell death in cancer cells could constitute a useful multimodal therapies for treating ovarian cancer, which is known for its resistance to apoptosis-inducing drugs.


Assuntos
Autofagia/efeitos dos fármacos , Compostos Azo/farmacologia , Doadores de Óxido Nítrico/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Piperazinas/farmacologia , Animais , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Espécies Reativas de Oxigênio , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Chem Biol Interact ; 310: 108734, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276661

RESUMO

This work aimed to evaluate the mechanisms involved in the apoptosis induction of isorhamnetin-3-O-glucosyl-pentoside (IGP) in metastatic human colon cancer cells (HT-29). To achieve this, we assessed phosphatidylserine (PS) exposure, cell membrane disruption, chromatin condensation, cell cycle alterations, mitochondrial damage, ROS production, and caspase-dependence on cell death. Our results showed that IGP induced cell death on HT-29 cells through PS exposure (48%) and membrane permeabilization (30%) as well as nuclear condensation (54%) compared with control cells. Moreover, IGP treatment induced cell cycle arrest in G2/M phase. Bax/Bcl-2 ratio increased and the loss of mitochondrial membrane potential (63%) was observed in IGP-treated cells. Finally, as apoptosis is a caspase-dependent cell death mechanism, we used a pancaspase-inhibitor (Q-VD-OPh) to demonstrate that the cell death induced by IGP was caspase-dependent. Overall these results indicated that IGP induced apoptosis through caspase-dependent mitochondrial damage in HT-29 colon cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Glicosídeos/farmacologia , Mitocôndrias/efeitos dos fármacos , Opuntia/química , Quercetina/análogos & derivados , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Flavonóis , Glicosídeos/isolamento & purificação , Glicosídeos/uso terapêutico , Células HT29 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/patologia , Extratos Vegetais/farmacologia , Quercetina/isolamento & purificação , Quercetina/farmacologia , Quercetina/uso terapêutico
10.
Chem Biol Interact ; 310: 108726, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255635

RESUMO

Tetrandrine (TET) and cepharanthine (CEP) are two bisbenzylisoquinoline alkaloids isolated from the traditional herbs. Recent molecular investigations firmly supported that TET or CEP would be a potential candidate for cancer chemotherapy. Prognosis of patients with glucocorticoid resistant T cell acute lymphoblastic leukemia (T-ALL) remains poor; here we examined the anti-T-ALL effects of TET and CEP and the underlying mechanism by using the glucocorticoid resistant human leukemia Jurkat T cell line in vitro. TET and CEP significantly inhibited cell viabilities and induced apoptosis in dose- and time-dependent manner. Further investigations showed that TET or CEP not only upregulated the expression of initiator caspases such as caspase-8 and 9, but also increased the expression of effector caspases such as caspase-3 and 6. As the important markers of apoptosis, p53 and Bax were both upregulated by the treatment of TET and CEP. However, TET and CEP paradoxically increased the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1, and activated the survival protein NF-κB, leading to high expression of p-NF-κB. Cell cycle arrest at S phase accompanied by increase in the amounts of cyclin A2 and cyclin B1, and decrease in cylcin D1 amount in cells treated with TET or CEP will be another possible mechanism. During the process of apoptosis in Jurkat T cells, treatment with TET or CEP also increased the phosphorylation of JNK and p38. The PI3K/Akt/mTOR signaling pathway modification appears to play significant role in the Jurkat T cell apoptosis induced by TET or CEP. Moreover, TET and CEP seemed to downregulate the expressions of p-PI3K and mTOR in an independent way from Akt, since these two drugs strongly stimulated the p-Akt expression. These results provide fundamental insights into the clinical application of TET or CEP for the treatment of patients with relapsed T-ALL.


Assuntos
Apoptose/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Benzilisoquinolinas/uso terapêutico , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Humanos , Células Jurkat , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
11.
Aquat Toxicol ; 213: 105229, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31255889

RESUMO

Although the global use of the 1,1,1-trichloro-2,2-bis (4-chlorophenyl) ethane (p,p'-DDT) has been prohibited, its persistence in the environment has caused long-lasting exposure on marine mammals. Our previous studies revealed exceedingly high residue levels of DDTs in Indo-Pacific humpback dolphins (Sousa chinensis) from the Pearl River Estuary region, China. However, the molecular mechanisms of p,p'-DDT toxicity on the dolphin are largely unknown. This study conducted the first cytotoxicity effect exploration of p,p'-DDT on the dolphin skin fibroblasts (ScSFs) to enhance the understanding of the cellular and molecular regulation impacts. ScSF cells were exposed to p,p'-DDT (28∼168 µM) for 24, 48 and 72 h. The exposure remarkably decreased viability of ScSF cells, possibly due to the synergetic effects of cell cycle arrest and apoptosis via DNA damage and mitochondria dysfunction. The DNA damage and mitochondria dysfunction were likely triggered by an increase of cellular reactive oxygen species (ROS), alteration in mitochondrial membrane potential, reduction in the cellular ATP levels, decreased expression of the genes CDK1, CDK4, cyclin B1, cyclin D1 and apoptosis regulator Bcl-2, release of cytochrome c, and activation of caspase-3, caspase-8 and caspase-9. Moreover, caspase inhibitor displayed protective activity against p,p'-DDT-induced apoptosis, indicating that caspases played a central role in p,p'-DDT-triggered apoptosis in the ScSF cells. We hypothesize apoptosis likely plays a minor role in cytocidal effects induced by p,p'-DDT exposure, but the mechanisms remain unclear. Overall, this research provides new evidence of the cytotoxic mechanisms underlying p,p'-DDT exposure on humpback dolphin skin cells, and suggests that p,p'-DDT contamination is one of key health concern issues for the protection of this marine mammal.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , DDT/toxicidade , Golfinhos/metabolismo , Exposição Ambiental , Fibroblastos/citologia , Mitocôndrias/metabolismo , Pele/citologia , Animais , Caspases/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Poluentes Químicos da Água/toxicidade
12.
BMC Complement Altern Med ; 19(1): 151, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242894

RESUMO

BACKGROUND: Costunolide, a sesquiterpene lactone extracted from Radix Aucklandiae, has the activity against multiple cancers. However, the effect of costunolide on gastric cancer (GC) have remained to be ambiguous. In this study, we investigated the underlying mechanisms of apoptosis induced by costunolide in human gastric adenocarcinoma BGC-823 cells in vitro and in vivo. METHODS: The viability of BGC-823 cells was detected by MTT assay. The apoptosis and mitochondrial membrane potential (ΔΨm) of BGC-823 cells induced by costunolide were analyzed by flow cytometry. The inhibiton of costunolide on human gastric adenocarcinoma was estimated in xenografts in nude mice. Apoptosis related proteins and genes were detected by Western blot and Q-PCR. RESULTS: Costunolide inhibited the viability of BGC-823 cells in a time and concentration dependent manner. Costunolide induced the apoptosis and lowered the ΔΨm of BGC-823 cells significantly. Costunolide increased the expression of Bax, cleaved caspase 9, cleaved caspase 7, cleaved caspase 3 and cleaved poly ADP ribose polymerase (PARP) proteins and decreased the expression of Bcl-2, pro-caspase 9, pro-caspase 7, pro-caspase 3 and PARP proteins. Costunolide upregulated the expression of puma, Bak1 and Bax mRNA and downregulated the expression of Bcl-2 mRNA. In addition, we demonstrated that costunolide inhibited the growth and induced apoptosis of BGC-823 cells xenografted in athymic nude mice. Costunolide increased the expression of cleaved caspase 9, cleaved caspase 3 and Bax proteins and decreased the expression of Bcl-2 protein in xenografted tumor. Costunolide upregulated the expression of puma and Bax mRNA and decreased the expression of Bcl-2 mRNA in xenografted tumor. CONCLUSIONS: Collectively, our results suggested that costunolide induced mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells and could be the candidate drug against GC in clinical practice.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sesquiterpenos/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatologia , Animais , Caspases/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/fisiopatologia
13.
Life Sci ; 231: 116593, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31228512

RESUMO

Inflammasomes are the major mechanistic complexes that include members of the NOD-like receptor (NLRs) or AIM2-like receptors (ALRs) families, which are affiliated with the innate immune system. Once NLRs or ALRs are activated by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), the caspase-1 or -11 is activated by binding with NLRs or ALRs via its own unique cytosolic domains. As a result, caspase-1 or -11 enhances the production of IL-1ß and IL-18, which results in inflammation via the recruitment of immune cells, such as macrophages, and the promotion of programmed cell death mechanisms such as pyroptosis. In addition, the consistent cascades of inflammasomes would precede both minor and severe autoimmune diseases and cancers. The clinical relevance of inflammasomes in multiple forms of cancer highlights their therapeutic promise as molecular targets. To closely analyze the physiological roles of inflammasomes in cancers, here, we describe the fundamental knowledge regarding the current issues of inflammasomes in relevant cancers, and discuss possible therapeutic values in targeting these inflammasomes for the prevention and treatment of cancer.


Assuntos
Inflamassomos/metabolismo , Inflamassomos/fisiologia , Neoplasias/terapia , Alarminas/metabolismo , Animais , Apoptose/fisiologia , Doenças Autoimunes/imunologia , Proteínas de Transporte/metabolismo , Caspase 1/metabolismo , Caspases/metabolismo , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Proteínas NLR/fisiologia , Padrões Moleculares Associados a Patógenos/metabolismo , Transdução de Sinais
14.
Immunity ; 50(6): 1352-1364, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216460

RESUMO

Caspases are an evolutionary conserved family of cysteine proteases that are centrally involved in cell death and inflammation responses. A wealth of foundational insight into the molecular mechanisms that control caspase activation has emerged in recent years. Important advancements include the identification of additional inflammasome platforms and pathways that regulate activation of inflammatory caspases; the discovery of gasdermin D as the effector of pyroptosis and interleukin (IL)-1 and IL-18 secretion; and the existence of substantial crosstalk between inflammatory and apoptotic initiator caspases. A better understanding of the mechanisms regulating caspase activation has supported initial efforts to modulate dysfunctional cell death and inflammation pathways in a suite of communicable, inflammatory, malignant, metabolic, and neurodegenerative diseases. Here, we review current understanding of caspase biology with a prime focus on the inflammatory caspases and outline important topics for future experimentation.


Assuntos
Caspases/metabolismo , Suscetibilidade a Doenças , Inflamação/etiologia , Inflamação/metabolismo , Animais , Apoptose , Biomarcadores , Caspases/química , Caspases/genética , Morte Celular/genética , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Terapia de Alvo Molecular , Piroptose , Transdução de Sinais/efeitos dos fármacos
15.
Artif Cells Nanomed Biotechnol ; 47(1): 2171-2178, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31159596

RESUMO

Nanomedicine is a rapidly emerging field and is reported to be a promising tool for treating various diseases. Green synthesized nanoparticles are documented to possess a potent anticancer effect. Rabdosia rubescens is a Chinese plant which is also one of the components of PC-SPES and used to treat prostate cancer. In the present study, we synthesized the gold nanoparticles from R. rubescens (RR-AuNP) and analyzed its anticancer activity against the lung carcinoma A549 cell lines. Since lung cancer is reported to be with increased morbidity and decreased survival rate. The biosynthesized RR-AuNP were confirmed using UV-Visible spectrophotometer, size and shape of RR-AuNP were assessed by DLS, TEM and EDX. The biomolecules present in RR-AuNP and its topographical structure were detected using FTIR, SAED and AFM analysis. MTT assay was performed to detect the IC50 dose of RR-AuNP and its apoptotic effect was assessed by detecting the caspases activation, ROS generation. The anticancer effect of RR-AuNP was confirmed by DAPI staining, TUNEL assay and its molecular mechanism were confirmed by assessing the apoptotic signalling molecules protein expression. Our results illustrate that RR-AuNP showed a strong absorption peak at 550 nm and the RRAuNP were polydispersed nanospheres with size of 130 nm. RR-AuNP IC50 dose against A549 lung carcinoma cell line was detected to be at 25 µg/ml. The results of DAPI staining, TUNEL and immunoblotting analysis confirms both the 25 µg/ml and 50 µg/ml of RR-AuNP possess potent anticancer and apoptotic effect, suggesting that RR-AuNP that it may be a persuasive molecule to treat lung cancer.


Assuntos
Ouro/química , Ouro/farmacologia , Isodon/química , Neoplasias Pulmonares/patologia , Nanopartículas Metálicas/química , Extratos Vegetais/química , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Química Verde , Humanos , Folhas de Planta/química , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Immunity ; 50(6): 1401-1411.e4, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31076358

RESUMO

Inflammasome activation and subsequent pyroptosis are critical defense mechanisms against microbes. However, overactivation of inflammasome leads to death of the host. Although recent studies have uncovered the mechanism of pyroptosis following inflammasome activation, how pyroptotic cell death drives pathogenesis, eventually leading to death of the host, is unknown. Here, we identified inflammasome activation as a trigger for blood clotting through pyroptosis. We have shown that canonical inflammasome activation by the conserved type III secretion system (T3SS) rod proteins from Gram-negative bacteria or noncanonical inflammasome activation by lipopolysaccharide (LPS) induced systemic blood clotting and massive thrombosis in tissues. Following inflammasome activation, pyroptotic macrophages released tissue factor (TF), an essential initiator of coagulation cascades. Genetic or pharmacological inhibition of TF abolishes inflammasome-mediated blood clotting and protects against death. Our data reveal that blood clotting is the major cause of host death following inflammasome activation and demonstrate that inflammasome bridges inflammation with thrombosis.


Assuntos
Coagulação Sanguínea , Inflamassomos/metabolismo , Piroptose , Trombose/etiologia , Trombose/metabolismo , Animais , Infecções Bacterianas/complicações , Infecções Bacterianas/microbiologia , Biomarcadores , Caspases/metabolismo , Micropartículas Derivadas de Células/imunologia , Micropartículas Derivadas de Células/metabolismo , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Transdução de Sinais , Tromboplastina/metabolismo , Trombose/sangue , Trombose/mortalidade
17.
Asian Pac J Cancer Prev ; 20(5): 1457-1462, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31127908

RESUMO

Objectives: Hepatocellular carcinoma is one of the most frequent cancers worldwide, for the treatment of which various therapy protocols and drugs have been introduced; however, none of them has suppressed cancer tissues completely. New research programs have been developed on cancer and the accompanied effects of novel synthesized compounds on cancer cell lines. Our latest reports on the molecular basis of cancer revealed a pattern of changes in gene expression triggered in the cancer pathway. Methods: HepG2 cell lines were cultured under similar conditions in both test and control groups. The IC50 concentration of the (2R, 4S)-N-(2, 5-difluorophenyl)-4-hydroxy-1-(2, 2, 2-trifluoroacetyl) pyrrolidine-2-carboxamide compound was used in the treatment group. After 48 hours from the culture, the expressional profiles of apoptosis pathway genes (84 genes) were studied using the PCR array method. Results: The findings demonstrated that the expression of some apoptosis-related genes pertaining to TNF, BCL2, IAP, and caspase families was regulated by (2R, 4S)-N-(2, 5-difluorophenyl)-4-Hydroxy-1-(2, 2, 2-Trifluoroacetyl) Pyrrolidine-2-Carboxamide. In the same vein, an alteration was observed in the expression of both pro-apoptotic and anti-apoptotic genes associated with the extrinsic and intrinsic apoptosis signaling pathways. Conclusions: According to the data obtained, the pyrrolidine-2-carboxamide compound was demonstrated to be able to regulate the apoptotic activities of HepG2 cells by affecting both pro-apoptotic and anti-apoptotic relevant genes.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pirrolidinas/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Necrose Tumoral/metabolismo
18.
Braz J Med Biol Res ; 52(5): e8499, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31116315

RESUMO

Two new coordination polymers [Zn (bdc)(bpybzimH2)](DMF)0.5 (1, H2bdc=1,4-dicarboxybenzene, bpybzimH2=6,6'-bis-(1H-benzoimidazol-2-yl)-2,2'-bipyridine, DMF=N,N-dimethylformamide) and [Co (bpybzimH2)(sbc)]H2O (2, H2sbc=4-mercaptobenzoic acid) have been successfully prepared under solvothermal conditions using the multi-N chelating organic ligand bpybzimH2 as the foundational building block. In addition, the Cell Counting Kit-8 assay was conducted to evaluate the anti-proliferation activity of compounds 1 and 2 against human spinal tumor cells OPM-2. The cell viability curves showed that the two compounds have anti-proliferation activity on spinal tumor cells, and the activity of compound 1 is higher than compound 2. The annexin V-FITC/PI assay and western blot were used to detect the apoptotic percentage of OPM-2 cells incubated with compounds 1 and 2. The YAP protein expression and its role in cell apoptosis were further studied with qRT-PCR, immunoblotting, and flow cytometer.


Assuntos
Apoptose/efeitos dos fármacos , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ligantes , Polímeros/química , Neoplasias da Coluna Vertebral/enzimologia , Linhagem Celular Tumoral , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Coluna Vertebral/patologia , Transfecção
19.
Environ Toxicol ; 34(8): 928-940, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31067004

RESUMO

Bioactive components of dietary phytochemicals have been reported to possess antitumor activities. Evidences suggested key role of stress responsive p38MAPK in the induction of nutraceuticals mediated apoptosis in hepatocellular carcinoma (HCC). Current study demonstrated detailed molecular bagatelle associated with p38 MAPK mediated effective suppression of cell growth both in HepG2 and chemically induced liver carcinoma after S-allyl cysteine (SAC) treatment. SAC promoted p38MAPK activity responsible for p53 phosphorylation, its stabilization followed by nuclear translocation leading to induction in expression and oligomerization of Fas protein. Distinctive p38MAPK-p53 axis dependent Fas-FasL-FADD mediated caspase activities along with perturbed cell cycling became normalized with continuation of SAC treatment for another month to diethylnitrosamine induced liver carcinoma. Co-treatment with SB203580, the p38MAPK inhibitor, prevented pro-apoptotic effect of SAC by altering p53 phosphorylation and death inducing signaling complex conformation in HepG2 and induced HCC. Collectively study suggested significant contribution of p38MAPK-p53-DISC-Caspase pathway in the regulation of anti-neoplastic activity of SAC against HCC.


Assuntos
Antineoplásicos/farmacologia , Cisteína/análogos & derivados , Neoplasias Hepáticas Experimentais/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Antineoplásicos/uso terapêutico , Caspases/metabolismo , Cisteína/farmacologia , Cisteína/uso terapêutico , Proteína Ligante Fas/metabolismo , Células Hep G2 , Humanos , Imidazóis/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/enzimologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Receptor fas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
20.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096565

RESUMO

Many medicinal plant species are currently threatened in their natural habitats because of the growing demand for phytochemicals worldwide. A sustainable alternative for the production of bioactive plant compounds are plant biofactories based on cell cultures and organs. In addition, plant extracts from biofactories have significant advantages over those obtained from plants, since they are free of contamination by microorganisms, herbicides and pesticides, and they provide more stable levels of active ingredients. In this context, we report the establishment of Satureja khuzistanica cell cultures able to produce high amounts of rosmarinic acid (RA). The production of this phytopharmaceutical was increased when the cultures were elicited with coronatine and scaled up to a benchtop bioreactor. S. khuzistanica extracts enriched in RA were found to reduce the viability of cancer cell lines, increasing the sub-G0/G1 cell population and the activity of caspase-8 in MCF-7 cells, which suggest that S. khuzistanica extracts can induce apoptosis of MCF-7 cells through activation of the extrinsic pathway. In addition, our findings indicate that other compounds in S. khuzistanica extracts may act synergistically to potentiate the anticancer activity of RA.


Assuntos
Aziridinas/farmacologia , Cinamatos/metabolismo , Cinamatos/farmacologia , Cicloexenos/farmacologia , Depsídeos/metabolismo , Depsídeos/farmacologia , Espécies em Perigo de Extinção , Extratos Vegetais/farmacologia , Satureja/metabolismo , Adenocarcinoma/tratamento farmacológico , Reatores Biológicos , Caspase 8/metabolismo , Caspases/metabolismo , Técnicas de Cultura de Células , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2/efeitos dos fármacos , Humanos , Células MCF-7 , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Satureja/crescimento & desenvolvimento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA