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1.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199295

RESUMO

Spinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (ATXN3). The toxic fragments processed from mutant ATXN3 can induce neuronal death, leading to the muscular incoordination of the human body. Some treatment strategies of SCA3 are preferentially focused on depleting the abnormal aggregates, which led to the discovery of small molecule n-butylidenephthalide (n-BP). n-BP-promoted autophagy protected the loss of Purkinje cell in the cerebellum that regulates the network associated with motor functions. We report that the n-BP treatment may be effective in treating SCA3 disease. n-BP treatment led to the depletion of mutant ATXN3 with the expanded polyQ chain and the toxic fragments resulting in increased metabolic activity and alleviated atrophy of SCA3 murine cerebellum. Furthermore, n-BP treated animal and HEK-293GFP-ATXN3-84Q cell models could consistently show the depletion of aggregates through mTOR inhibition. With its unique mechanism, the two autophagic inhibitors Bafilomycin A1 and wortmannin could halt the n-BP-induced elimination of aggregates. Collectively, n-BP shows promising results for the treatment of SCA3.


Assuntos
Autofagia , Doença de Machado-Joseph/tratamento farmacológico , Doença de Machado-Joseph/patologia , Anidridos Ftálicos/uso terapêutico , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Adenilato Quinase/metabolismo , Animais , Ataxina-3/genética , Autofagia/efeitos dos fármacos , Cerebelo/patologia , Feminino , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Doença de Machado-Joseph/fisiopatologia , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Mutação/genética , Anidridos Ftálicos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/patologia , Transdução de Sinais/efeitos dos fármacos
2.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: covidwho-1259507

RESUMO

The COVID-19 pandemic is caused by the 2019-nCoV/SARS-CoV-2 virus. This severe acute respiratory syndrome is currently a global health emergency and needs much effort to generate an urgent practical treatment to reduce COVID-19 complications and mortality in humans. Viral infection activates various cellular responses in infected cells, including cellular stress responses such as unfolded protein response (UPR) and autophagy, following the inhibition of mTOR. Both UPR and autophagy mechanisms are involved in cellular and tissue homeostasis, apoptosis, innate immunity modulation, and clearance of pathogens such as viral particles. However, during an evolutionary arms race, viruses gain the ability to subvert autophagy and UPR for their benefit. SARS-CoV-2 can enter host cells through binding to cell surface receptors, including angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1). ACE2 blockage increases autophagy through mTOR inhibition, leading to gastrointestinal complications during SARS-CoV-2 virus infection. NRP1 is also regulated by the mTOR pathway. An increased NRP1 can enhance the susceptibility of immune system dendritic cells (DCs) to SARS-CoV-2 and induce cytokine storm, which is related to high COVID-19 mortality. Therefore, signaling pathways such as mTOR, UPR, and autophagy may be potential therapeutic targets for COVID-19. Hence, extensive investigations are required to confirm these potentials. Since there is currently no specific treatment for COVID-19 infection, we sought to review and discuss the important roles of autophagy, UPR, and mTOR mechanisms in the regulation of cellular responses to coronavirus infection to help identify new antiviral modalities against SARS-CoV-2 virus.


Assuntos
Autofagia , COVID-19/patologia , Neuropilina-1/metabolismo , Resposta a Proteínas não Dobradas , Antivirais/farmacologia , Autofagia/efeitos dos fármacos , COVID-19/virologia , Humanos , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo
3.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206057

RESUMO

The COVID-19 pandemic is caused by the 2019-nCoV/SARS-CoV-2 virus. This severe acute respiratory syndrome is currently a global health emergency and needs much effort to generate an urgent practical treatment to reduce COVID-19 complications and mortality in humans. Viral infection activates various cellular responses in infected cells, including cellular stress responses such as unfolded protein response (UPR) and autophagy, following the inhibition of mTOR. Both UPR and autophagy mechanisms are involved in cellular and tissue homeostasis, apoptosis, innate immunity modulation, and clearance of pathogens such as viral particles. However, during an evolutionary arms race, viruses gain the ability to subvert autophagy and UPR for their benefit. SARS-CoV-2 can enter host cells through binding to cell surface receptors, including angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1). ACE2 blockage increases autophagy through mTOR inhibition, leading to gastrointestinal complications during SARS-CoV-2 virus infection. NRP1 is also regulated by the mTOR pathway. An increased NRP1 can enhance the susceptibility of immune system dendritic cells (DCs) to SARS-CoV-2 and induce cytokine storm, which is related to high COVID-19 mortality. Therefore, signaling pathways such as mTOR, UPR, and autophagy may be potential therapeutic targets for COVID-19. Hence, extensive investigations are required to confirm these potentials. Since there is currently no specific treatment for COVID-19 infection, we sought to review and discuss the important roles of autophagy, UPR, and mTOR mechanisms in the regulation of cellular responses to coronavirus infection to help identify new antiviral modalities against SARS-CoV-2 virus.


Assuntos
Autofagia , COVID-19/patologia , Neuropilina-1/metabolismo , Resposta a Proteínas não Dobradas , Antivirais/farmacologia , Autofagia/efeitos dos fármacos , COVID-19/virologia , Humanos , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo
4.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200718

RESUMO

Euterpe oleracea Mart. (açai) is a native palm from the Amazon region. There are various chemical constituents of açai with bioactive properties. This study aimed to evaluate the chemical composition and cytotoxic effects of açai seed extract on breast cancer cell line (MCF-7). Global Natural Products Social Molecular Networking (GNPS) was applied to identify chemical compounds present in açai seed extract. LC-MS/MS and molecular networking were employed to detect the phenolic compounds of açai. The antioxidant activity of açai seed extract was measured by DPPH assay. MCF-7 breast cancer cell line viability was evaluated by MTT assay. Cell death was evaluated by flow cytometry and time-lapse microscopy. Autophagy was evaluated by orange acridin immunofluorescence assay. Reactive oxygen species (ROS) production was evaluated by DAF assay. From the molecular networking, fifteen compounds were identified, mainly phenolic compounds. The açai seed extract showed cytotoxic effects against MCF-7, induced morphologic changes in the cell line by autophagy and increased the ROS production pathway. The present study suggests that açai seed extract has a high cytotoxic capacity and may induce autophagy by increasing ROS production in breast cancer. Apart from its antioxidant activity, flavonoids with high radical scavenging activity present in açai also generated NO (nitric oxide), contributing to its cytotoxic effect and autophagy induction.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Euterpe/química , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sementes/química , Antioxidantes/química , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Cromatografia Líquida/métodos , Feminino , Flavonoides/química , Flavonoides/farmacologia , Frutas/química , Humanos , Células MCF-7 , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química , Polifenóis/química , Polifenóis/farmacologia , Espectrometria de Massas em Tandem/métodos
5.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208589

RESUMO

There is mounting evidence that type 2 diabetes mellitus (T2DM) is related with increased risk for the development of cancer. Apart from shared common risk factors typical for both diseases, diabetes driven factors including hyperinsulinemia, insulin resistance, hyperglycemia and low grade chronic inflammation are of great importance. Recently, vitamin D deficiency was reported to be associated with the pathogenesis of numerous diseases, including T2DM and cancer. However, little is known whether vitamin D deficiency may be responsible for elevated cancer risk development in T2DM patients. Therefore, the aim of the current review is to identify the molecular mechanisms by which vitamin D deficiency may contribute to cancer development in T2DM patients. Vitamin D via alleviation of insulin resistance, hyperglycemia, oxidative stress and inflammation reduces diabetes driven cancer risk factors. Moreover, vitamin D strengthens the DNA repair process, and regulates apoptosis and autophagy of cancer cells as well as signaling pathways involved in tumorigenesis i.e., tumor growth factor ß (TGFß), insulin-like growth factor (IGF) and Wnt-ß-Cathenin. It should also be underlined that many types of cancer cells present alterations in vitamin D metabolism and action as a result of Vitamin D Receptor (VDR) and CYP27B1 expression dysregulation. Although, numerous studies revealed that adequate vitamin D concentration prevents or delays T2DM and cancer development, little is known how the vitamin affects cancer risk among T2DM patients. There is a pressing need for randomized clinical trials to clarify whether vitamin D deficiency may be a factor responsible for increased risk of cancer in T2DM patients, and whether the use of the vitamin by patients with diabetes and cancer may improve cancer prognosis and metabolic control of diabetes.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Neoplasias/etiologia , Deficiência de Vitamina D/complicações , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Redes e Vias Metabólicas , Neoplasias/epidemiologia , Neoplasias/prevenção & controle , Neoplasias/terapia , Prognóstico , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia , Deficiência de Vitamina D/metabolismo
6.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065350

RESUMO

Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of the present study consists of detailing an mTOR-dependent mitophagy occlusion, along with suppression of mitochondrial fission. These phenomena contribute to explain the increase in altered mitochondria reported here. Administration of the mTOR inhibitor rapamycin rescues mitochondrial alterations. In detail, rapamycin induces the expression of genes promoting mitophagy (PINK1, PARKIN, ULK1, AMBRA1) and mitochondrial fission (FIS1, DRP1). This occurs along with over-expression of VPS34, an early gene placed upstream in the autophagy pathway. The topographic stoichiometry of proteins coded by these genes within mitochondria indicates that, a remarkable polarization of proteins involved in fission and mitophagy within mitochondria including LC3 takes place. Co-localization of these proteins within mitochondria, persists for weeks following rapamycin, which produces long-lasting mitochondrial plasticity. Thus, rapamycin restores mitochondrial status in GBM cells. These findings add novel evidence about mitochondria and GBM, while fostering a novel therapeutic approach to restore healthy mitochondria through mTOR inhibition.


Assuntos
Glioblastoma/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Sirolimo/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Humanos , Mitocôndrias/metabolismo , Serina-Treonina Quinases TOR/metabolismo
7.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070303

RESUMO

Colorectal cancer (CRC) is the third leading malignant tumor in the world, which has high morbidity and mortality. In this study we found that trichodermic acid (TDA), a secondary metabolite isolated from the plant endophytic fungus Penicillium ochrochloronthe with a variety of biological and pharmacological activities, exhibited the antitumor effects on colorectal cancer cells in vitro and in vivo. Our results showed that TDA inhibited the proliferation of colon cancer cells in a dose-dependent manner. TDA induces sustained endoplasmic reticulum stress, which triggers apoptosis through IRE1α/XBP1 and PERK/ATF4/CHOP pathways. In addition, we found that TDA mediated endoplasmic reticulum stress also induces autophagy as a protective mechanism. Moreover, combined treatment of TDA with autophagy inhibitors significantly enhanced its anticancer effect. In conclusion, our results indicated that TDA can induce ER stress and autophagy mediated apoptosis, suggesting that targeting ER stress and autophagy may be an effective strategy for the treatment of CRC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias do Colo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Animais , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070401

RESUMO

Transition metal coordination compounds play an important role in the treatment of neoplastic diseases. However, due to their low selectivity and bioavailability, as well as the frequently occurring phenomenon of drug resistance, new chemical compounds that could overcome these phenomena are still being sought. The solution seems to be the synthesis of new metal complexes conjugated with drug carriers, e.g., dendrimers. Numerous literature data have shown that dendrimers improve the bioavailability of the obtained metal complexes, solving the problem of their poor solubility and stability in an aqueous environment and also breaking down inborn and acquired drug resistance. Therefore, the aim of this study was to synthesize a novel imidazole platinum(II) complex conjugated with and without the second-generation PAMAM dendrimer (PtMet2-PAMAM and PtMet2, respectively) and to evaluate its antitumor activity. Cell viability studies indicated that PtMet2-PAMAM exhibited higher cytotoxic activity than PtMet2 in MCF-7 and MDA-MB-231 breast cancer cells at relatively low concentrations. Moreover, our results indicated that PtMet2-PAMAM exerted antiproliferative effects in a zebrafish embryo model. Treatment with PtMet2-PAMAM substantially increased apoptosis in a dose-dependent manner via caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) activation along with pro-apoptotic protein expression modulation. Additionally, we showed that apoptosis can be induced by activating POX, which induces ROS production. Furthermore, our results also clearly showed that the tested compounds trigger autophagy through p38 pathway activation and increase Beclin-1, LC3, AMPK, and mTOR inhibition. The high pro-apoptotic activity and the ability to activate autophagy by the imidazole platinum(II) complex conjugated with a dendrimer may be due to its demonstrated ability to reverse multidrug resistance (MDR) and thereby increase cellular accumulation in breast cancer cells.


Assuntos
Antineoplásicos , Neoplasias da Mama , Complexos de Coordenação , Dendrímeros , Imidazóis , Platina , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/farmacologia , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/farmacologia , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Platina/química , Platina/farmacocinética , Platina/farmacologia
9.
Cells ; 10(5)2021 05 06.
Artigo em Inglês | MEDLINE | ID: covidwho-1223960

RESUMO

Viral pathogens often exploit host cell regulatory and signaling pathways to ensure an optimal environment for growth and survival. Several studies have suggested that 5'-adenosine monophosphate-activated protein kinase (AMPK), an intracellular serine/threonine kinase, plays a significant role in the modulation of infection. Traditionally, AMPK is a key energy regulator of cell growth and proliferation, host autophagy, stress responses, metabolic reprogramming, mitochondrial homeostasis, fatty acid ß-oxidation and host immune function. In this review, we highlight the modulation of host AMPK by various viruses under physiological conditions. These intracellular pathogens trigger metabolic changes altering AMPK signaling activity that then facilitates or inhibits viral replication. Considering the COVID-19 pandemic, understanding the regulation of AMPK signaling following infection can shed light on the development of more effective therapeutic strategies against viral infectious diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antivirais/farmacologia , Transdução de Sinais/imunologia , Viroses/imunologia , Antivirais/uso terapêutico , Autofagia/efeitos dos fármacos , Autofagia/imunologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , COVID-19/imunologia , Proliferação de Células/efeitos dos fármacos , Desenvolvimento de Medicamentos , Humanos , Pandemias/prevenção & controle , SARS-CoV-2/imunologia , Transdução de Sinais/efeitos dos fármacos , Viroses/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
10.
Life Sci ; 280: 119743, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166711

RESUMO

AIMS: Saxagliptin, a selective/potent dipeptidyl peptidase-4 inhibitor, has revealed remarkable anti-inflammatory features in murine models of nephrotoxicity, hepatic injury, and neuroinflammation. However, its potential effect on ethanol-induced gastric mucosal injury has not been examined. Hence, the present work investigated the prospect of saxagliptin to attenuate ethanol-evoked gastric injury, with emphasis on the AMPK/mTOR-driven autophagy and NLRP3/ASC/caspase-1 pathway. MATERIALS AND METHODS: In ethanol-induced gastropathy, the gastric tissues were examined by immunohistochemistry, immunoblotting, histopathology, and ELISA. KEY FINDINGS: The results demonstrated that saxagliptin (10 mg/kg; by gavage) suppressed the gastric pathological signs (area of gastric ulcer and ulcer index scores), histopathologic aberrations/damage scores, without provoking hypoglycemia in rats. These protective features were attributed to the enhancement of gastric mucosal autophagy flux, as proven with increased expression of LC3-II and Beclin 1, decreased accumulation of p62 SQSTM1, and activation of the autophagy-linked AMPK/mTOR pathway by increasing the expression of p-AMPK/AMPK and decreasing the expression of the autophagy suppressor p-mTOR/mTOR signal. In tandem, saxagliptin counteracted the ethanol-induced pro-apoptotic events by downregulating Bax, upregulating Bcl2 protein, and lowering the Bax/Bcl2 ratio. Equally important, saxagliptin suppressed the NLRP3 inflammasome in the gastric tissue by lowering the expression of NLRP3, ASC, and nuclear NF-κBp65, decreasing the activity of caspase-1, and diminishing the IL-1ß levels. In the same regard, saxagliptin suppressed the mucosal oxidative stress by lowering lipid peroxide levels, increasing GSH and GPx antioxidants, and activating Nrf2/HO-1 pathway. SIGNIFICANCE: Saxagliptin may be a promising intervention against ethanol-evoked gastropathy by activating AMPK/mTOR-driven autophagy and inhibiting NLRP3 inflammasome.


Assuntos
Adamantano/análogos & derivados , Autofagia/efeitos dos fármacos , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Etanol/efeitos adversos , Gastropatias/induzido quimicamente , Gastropatias/tratamento farmacológico , Adamantano/uso terapêutico , Animais , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Quinases/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Gastropatias/patologia , Serina-Treonina Quinases TOR/metabolismo
11.
Aging (Albany NY) ; 13(12): 16178-16197, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34182538

RESUMO

Tamoxifen (TAM) resistance constitutes a challenge in managing estrogen receptor (ER)α+ breast cancer patients. G-protein-coupled estrogen receptor (GPR30/GPER), which reportedly initiates TAM resistance in ERα+/ GPR30+ breast cancers, is detected in the breast cancer microenvironment, especially cancer associated fibroblasts (CAFs). Herein, considering that GPR30 mediates transcriptional regulation in different cell backgrounds, a microarray strategy was applied in immortalized CAFs derived from primary breast cancer samples, resulting in the identification of 165 GPR30 target genes, among which HMGB1 was confirmed to be upregulated by 17-ß estradiol(E2)- and TAM-triggered GPR30 activation in CAFs. Activated GPR30 increased extracellular HMGB1 secretion by CAFs, which was reduced by blocking PI3K/AKT signaling using G15 or LY294002. GPR30-induced HMGB1 upregulation triggered MEK/ERK signaling, leading to increased autophagic behavior to protect cancer cells from TAM-induced apoptosis, mimicking the recombinant HMGB1-mediated increase in cancer cell resistance potential to TAM. MEK/ERK signaling blockage by U0126 decreased the autophagic behavior and resistance ability of cancer cells to TAM. CAF-expressed GPR30 induced TAM resistance via HMGB1 in vivo. Overall, TAM upregulated HMGB1 expression and secretion in CAFs via GPR30/PI3K/AKT signaling, and the secreted HMGB1 induced autophagy to enhance TAM resistance in MCF-7 cells in an ERK-dependent manner. Thus, targeting GPR30 and downstream cascades may be an effective strategy to attenuate the resistance of ERα-positive breast tumors to endocrine therapy.


Assuntos
Autofagia , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteína HMGB1/metabolismo , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Tamoxifeno/farmacologia , Regulação para Cima , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/genética , Fibroblastos Associados a Câncer/patologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína HMGB1/genética , Humanos , Células MCF-7 , Camundongos Nus , Modelos Biológicos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
Nat Commun ; 12(1): 3651, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131122

RESUMO

Extracellular cytokines are enriched in the tumor microenvironment and regulate various important properties of cancers, including autophagy. However, the precise molecular mechanisms underlying the link between autophagy and extracellular cytokines remain to be elucidated. In the present study, we demonstrate that IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway and promotes chemotherapy resistance in colorectal cancer (CRC). Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. Furthermore, we investigate BECN1 Y333 phosphorylation as a predictive marker for poor CRC prognosis and chemotherapy resistance. Combination treatment with autophagy inhibitors or pharmacological agents targeting the IL-6/JAK2/BECN1 signaling pathway may represent a potential strategy for CRC cancer therapy.


Assuntos
Autofagia/fisiologia , Proteína Beclina-1/metabolismo , Tratamento Farmacológico , Interleucina-6/metabolismo , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/metabolismo , Proteína Beclina-1/química , Proteína Beclina-1/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/farmacologia , Janus Quinase 2/química , Janus Quinase 2/metabolismo , Fosforilação , Domínios e Motivos de Interação entre Proteínas , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Ecotoxicol Environ Saf ; 221: 112442, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34166936

RESUMO

Arsenic (As) and antimony (Sb) are commonly accumulated environmental pollutants that often coexist in nature and cause serious widespread biological toxicity. To investigate the nephrotoxicity induced by As and Sb in detail, we explored the mechanism by which As and Sb cotreatment induced autophagy and pyroptosis in vivo and in vitro. In this study, mice were treated with 4 mg/kg arsenic trioxide (ATO) or/and 15 mg/kg antimony trichloride (SbCl3) by intragastric intubation for 60 days. TCMK-1 cells were treated with ATO (12.5 µM), SbCl3 (25 µM) or a combination of As and Sb for 24 h. The results of the in vivo experiment demonstrated that As or/and Sb exposure could induce histopathological changes in the kidneys, and increase the levels of biochemical indicators of nephrotoxicity. In addition, As and Sb can co-induce oxidative stress, which further activate autophagy and pyroptosis. In an in vitro experiment, As and/or Sb coexposure increased ROS generation and decreased MMP. Moreover, the results of related molecular experiments further confirmed that As and Sb coactivated autophagy and pyroptosis. In conclusion, our results indicated that As and Sb co-exposure could cause autophagy and pyroptosis via the ROS pathway, and these two metals might have a synergistic effect on nephrotoxicity.


Assuntos
Antimônio/toxicidade , Trióxido de Arsênio/toxicidade , Cloretos/toxicidade , Rim/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Poluentes Ambientais/toxicidade , Rim/fisiopatologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
14.
Ecotoxicol Environ Saf ; 221: 112438, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34175825

RESUMO

Microcystin-leucine arginine (MCLR), a widespread environmental contaminant produced by cyanobacteria, poses a severe threat to the male reproductive system. However, the mechanisms of MCLR-induced testis injury accompanied by autophagy are still obscure. This study aimed to investigate the effects of MCLR on autophagy and apoptosis on the male reproductive system and its mechanism both in vitro and in vivo. MCLR caused damage to the testis of zebrafish, resulting in decreased hatching and growth retardation in the offspring. It also remarkably enhanced autophagic flux by elevating the expression of LC3BII, ATG5, and ATG12 proteins. The autophagic flux was also confirmed through the formation of autophagosomes in the ultrastructure of the zebrafish testis and the accumulation of LC3-positive puncta in zebrafish testis and mouse TM4 cells. Further evaluations revealed that inhibition of autophagy by 3-methyladenine (3-MA) significantly attenuated MCLR-induced apoptosis. This finding indicated that autophagy plays an essential role in cell death in the male reproductive system. Besides, inhibiting endoplasmic reticulum (ER) stress using 4-phenylbutyrate (4-PBA) remarkably blocked autophagy and partially suppressed apoptosis in TM4 cells induced by MCLR. This phenomenon suggested that ER stress-related autophagy was involved in MCLR-induced apoptosis. This study reveals crosstalk between ER stress and autophagy via the PERK/eIF2α/ATF4 signaling pathway. It further suggests that ER stress-related autophagy contributes to MCLR-induced apoptosis and injury in the male reproductive system. These findings provide a novel insight into MCLR-induced impairments of the testis.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Microcistinas/toxicidade , Testículo/efeitos dos fármacos , Animais , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Linhagem Celular , Masculino , Camundongos , Fenilbutiratos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Testículo/ultraestrutura , Peixe-Zebra
15.
Ecotoxicol Environ Saf ; 221: 112450, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34186417

RESUMO

Bisphenol A (BPA) is a widely distributed environmental endocrine disruptor. The accumulation of BPA has been proved that produce various toxic effects both on human and animals. However, the strategies to reduce the damage of BPA on the body and related mechanisms remain to be studied. Coenzyme Q10 (CoQ10), as a powerful antioxidant, is ubiquitous in many eukaryotic cells, which can improve the integrity of lysosomal membrane, lysosomal degradation function and promote autophagy. Here, we examined the ability of CoQ10 to alleviate oxidative stress and apoptosis in BPA-induced damages in C2C12 cells, and how to alleviate it. Our results showed that BPA treatment significantly reduced cell viability, increased the number of cell apoptosis and ROS production, decreased mitochondrial membrane potential, and inhibited the gene expression of mitochondria biogenesis. Moreover, we demonstrated that exposure to BPA increased expression levels of autophagy protein (LC3-II, p62), inhibited autophagy flux, and disrupted the acidic pH environment of lysosomes. Importantly, CoQ10 supplementation effectively restored these abnormalities caused by BPA. CoQ10 significantly decreased the apoptotic incidence and ROS levels, improved mitochondrial membrane potential. Moreover, CoQ10 improved lysosome function and enhanced autophagy flux. Taken together, our results indicate that CoQ10 supplementation is a feasible and effective way to promote the level of autophagy by improving lysosomal function, thereby reducing the apoptosis caused by BPA accumulation. This study aims to provide evidence for the role of CoQ10 in repairing BPA-induced cell damage in clinical practice.


Assuntos
Antioxidantes/toxicidade , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Ubiquinona/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular , Lisossomos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Ubiquinona/farmacologia
16.
Nat Commun ; 12(1): 3898, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162854

RESUMO

One topical area of supramolecular chemistry is the binding of anionic species but despite the importance of anions in diverse cellular processes and for cancer development, anion receptors or 'binders' have received little attention as potential anti-cancer therapeutics. Here we report self-assembling trimetallic cryptands (e.g. [L2(Metal)3]6+ where Metal = Cu2+, Zn2+ or Mn2+) which can encapsulate a range of anions and which show metal-dependent differences in chemical and biological reactivities. In cell studies, both [L2Cu3]6+ and [L2Zn3]6+ complexes are highly toxic to a range of human cancer cell lines and they show significant metal-dependent selective activity towards cancer cells compared to healthy, non-cancerous cells (by up to 2000-fold). The addition of different anions to the complexes (e.g. PO43-, SO42- or PhOPO32-) further alters activity and selectivity allowing the activity to be modulated via a self-assembly process. The activity is attributed to the ability to either bind or hydrolyse phosphate esters and mechanistic studies show differential and selective inhibition of multiple kinases by both [L2Cu3]6+ and [L2Zn3]6+ complexes but via different mechanisms.


Assuntos
Ânions/química , Antineoplásicos/química , Complexos de Coordenação/química , Metais/química , Células A549 , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Células HCT116 , Células HT29 , Humanos , Concentração Inibidora 50 , Neoplasias/metabolismo , Neoplasias/patologia , Fosfotransferases/antagonistas & inibidores , Fosfotransferases/metabolismo
17.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067074

RESUMO

The recently discovered interleukin (IL)- 32 isoform IL-32θ exerts anti-metastatic effects in the breast tumor microenvironment. However, the involvement of IL-32θ in breast cancer cell proliferation is not yet fully understood; therefore, the current study aimed to determine how IL-32θ affects cancer cell growth and evaluated the responses of IL-32θ-expressing cells to other cancer therapy. We compared the functions of IL-32θ in triple-negative breast cancer MDA-MB-231 cells that stably express IL-32θ, with MDA-MB-231 cells transfected with a mock vector. Slower growth was observed in cells expressing IL-32θ than in control cells, and changes were noted in nuclear morphology, mitotic division, and nucleolar size between the two groups of cells. Interleukin-32θ significantly reduced the colony-forming ability of MDA-MB-231 cells and induced permanent cell cycle arrest at the G1 phase. Long-term IL-32θ accumulation triggered permanent senescence and chromosomal instability in MDA-MB-231 cells. Genotoxic drug doxorubicin (DR) reduced the viability of MDA-MB-231 cells not expressing IL-32θ more than in cells expressing IL-32θ. Overall, these findings suggest that IL-32θ exerts antiproliferative effects in breast cancer cells and initiates senescence, which may cause DR resistance. Therefore, targeting IL-32θ in combination with DR treatment may not be suitable for treating metastatic breast cancer.


Assuntos
Senescência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Interleucinas/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Forma do Núcleo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Instabilidade Genômica , Humanos , Fenótipo , Ploidias
18.
Cells ; 10(5)2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066434

RESUMO

Viral pathogens often exploit host cell regulatory and signaling pathways to ensure an optimal environment for growth and survival. Several studies have suggested that 5'-adenosine monophosphate-activated protein kinase (AMPK), an intracellular serine/threonine kinase, plays a significant role in the modulation of infection. Traditionally, AMPK is a key energy regulator of cell growth and proliferation, host autophagy, stress responses, metabolic reprogramming, mitochondrial homeostasis, fatty acid ß-oxidation and host immune function. In this review, we highlight the modulation of host AMPK by various viruses under physiological conditions. These intracellular pathogens trigger metabolic changes altering AMPK signaling activity that then facilitates or inhibits viral replication. Considering the COVID-19 pandemic, understanding the regulation of AMPK signaling following infection can shed light on the development of more effective therapeutic strategies against viral infectious diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antivirais/farmacologia , Transdução de Sinais/imunologia , Viroses/imunologia , Antivirais/uso terapêutico , Autofagia/efeitos dos fármacos , Autofagia/imunologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , COVID-19/imunologia , Proliferação de Células/efeitos dos fármacos , Desenvolvimento de Medicamentos , Humanos , Pandemias/prevenção & controle , SARS-CoV-2/imunologia , Transdução de Sinais/efeitos dos fármacos , Viroses/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
19.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071600

RESUMO

Autophagy is a process of self-degradation that plays an important role in removing damaged proteins, organelles or cellular fragments from the cell. Under stressful conditions such as hypoxia, nutrient deficiency or chemotherapy, this process can also become the strategy for cell survival. Autophagy can be nonselective or selective in removing specific organelles, ribosomes, and protein aggregates, although the complete mechanisms that regulate aspects of selective autophagy are not fully understood. This review summarizes the most recent research into understanding the different types and mechanisms of autophagy. The relationship between apoptosis and autophagy on the level of molecular regulation of the expression of selected proteins such as p53, Bcl-2/Beclin 1, p62, Atg proteins, and caspases was discussed. Intensive studies have revealed a whole range of novel compounds with an anticancer activity that inhibit or activate regulatory pathways involved in autophagy. We focused on the presentation of compounds strongly affecting the autophagy process, with particular emphasis on those that are undergoing clinical and preclinical cancer research. Moreover, the target points, adverse effects and therapeutic schemes of autophagy inhibitors and activators are presented.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo
20.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072647

RESUMO

Steroid-induced glaucoma is a severe pathological condition, sustained by a rapidly progressive increase in intraocular pressure (IOP), which is diagnosed in a subset of subjects who adhere to a glucocorticoid (GC)-based therapy. Molecular and clinical studies suggest that either natural or synthetic GCs induce a severe metabolic dysregulation of Trabecular Meshwork Cells (TMCs), an endothelial-derived histotype with phagocytic and secretive functions which lay at the iridocorneal angle in the anterior segment of the eye. Since TMCs physiologically regulate the composition and architecture of trabecular meshwork (TM), which is the main outflow pathway of aqueous humor, a fluid which shapes the eye globe and nourishes the lining cell types, GCs are supposed to trigger a pathological remodeling of the TM, inducing an IOP increase and retina mechanical compression. The metabolic dysregulation of TMCs induced by GCs exposure has never been characterized at the molecular detail. Herein, we report that, upon dexamethasone exposure, a TMCs strain develops a marked inhibition of the autophagosome biogenesis pathway through an enhanced turnover of two members of the Ulk-1 complex, the main platform for autophagy induction, through the Ubiquitin Proteasome System (UPS).


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia/efeitos dos fármacos , Dexametasona/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Complexos Multiproteicos/metabolismo , Malha Trabecular/efeitos dos fármacos , Malha Trabecular/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proliferação de Células/efeitos dos fármacos , Dexametasona/efeitos adversos , Suscetibilidade a Doenças , Glaucoma/etiologia , Glaucoma/metabolismo , Glaucoma/fisiopatologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Complexo de Endopeptidases do Proteassoma/metabolismo
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