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1.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443600

RESUMO

Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric acid, a well-known HDAC inhibitor with antitumor properties. The conjugated compounds were synthesized and characterised by FTIR spectroscopy, multi-nuclear (1H, 13C and 119Sn) NMR, and mass spectrometry (ESI-MS). In the triorganotin(IV) complexes, an anionic monodentate butyrate ligand was observed, which coordinated the tin atom on a tetra-coordinated, monomeric environment similar to ester. FTIR and NMR findings confirm this structure both in solid state and solution. The antitumor efficacy of the triorganotin(IV) butyrates was tested in colon cancer cells and, among them, tributyltin(IV) butyrate (BT2) was selected as the most efficacious. BT2 induced G2/M cell cycle arrest, ER stress, and apoptotic cell death. These effects were obtained using low concentrations of BT2 up to 1 µM, whereas butyric acid alone was completely inefficacious, and the parent compound TBT was poorly effective at the same treatment conditions. To assess whether butyrate in the coordinated form maintains its epigenetic effects, histone acetylation was evaluated and a dramatic decrease in acetyl-H3 and -H4 histones was found. In contrast, butyrate alone stimulated histone acetylation at a higher concentration (5 mM). BT2 was also capable of preventing histone acetylation induced by SAHA, another potent HDAC inhibitor, thus suggesting that it may activate HDACs. These results support a potential use of BT2, a novel epigenetic modulator, in colon cancer treatment.


Assuntos
Apoptose/genética , Ácido Butírico/química , Neoplasias do Colo/patologia , Estresse do Retículo Endoplasmático/genética , Epigênese Genética/efeitos dos fármacos , Compostos de Trialquitina/química , Compostos de Trialquitina/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
2.
Nutrients ; 13(7)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34371808

RESUMO

Endoplasmic reticulum stress (ERS) and autophagy pathways are implicated in disuse muscle atrophy. The effects of high eicosapentaenoic (EPA) or high docosahexaenoic (DHA) fish oils on soleus muscle ERS and autophagy markers were investigated in a rat hindlimb suspension (HS) atrophy model. Adult Wistar male rats received daily by gavage supplementation (0.3 mL per 100 g b.w.) of mineral oil or high EPA or high DHA fish oils (FOs) for two weeks. Afterward, the rats were subjected to HS and the respective treatments concomitantly for an additional two-week period. After four weeks, we evaluated ERS and autophagy markers in the soleus muscle. Results were analyzed using two-way analysis of variance (ANOVA) and Bonferroni post hoc test. Gastrocnemius muscle ω-6/ω-3 fatty acids (FAs) ratio was decreased by both FOs indicating the tissue incorporation of omega-3 fatty acids. HS altered (p < 0.05) the protein content (decreasing total p38 and BiP and increasing p-JNK2/total JNK2 ratio, and caspase 3) and gene expressions (decreasing BiP and increasing IRE1 and PERK) of ERS and autophagy (decreasing Beclin and increasing LC3 and ATG14) markers in soleus. Both FOs attenuated (p < 0.05) the increase in PERK and ATG14 expressions induced by HS. Thus, both FOs could potentially attenuate ERS and autophagy in skeletal muscles undergoing atrophy.


Assuntos
Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Óleos de Peixe/farmacologia , Músculo Esquelético/metabolismo , Atrofia Muscular/terapia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Elevação dos Membros Posteriores , Masculino , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Ratos , Ratos Wistar
3.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360909

RESUMO

Neurodegenerative diseases are an ever-increasing problem for the rapidly aging population. Despite this, our understanding of how these neurodegenerative diseases develop and progress, is in most cases, rudimentary. Protein kinase RNA (PKR)-like ER kinase (PERK) comprises one of three unfolded protein response pathways in which cells attempt to manage cellular stress. However, because of its role in the cellular stress response and the far-reaching implications of this pathway, error within the PERK pathway has been shown to lead to a variety of pathologies. Genetic and clinical studies show a correlation between failure of the PERK pathway in neural cells and the development of neurodegeneration, but the wide array of methodology of these studies is presenting conflicting narratives about the role of PERK in these affected systems. Because of the connection between PERK and pathology, PERK has become a high value target of study for understanding neurodegenerative diseases and potentially how to treat them. Here, we present a review of the literature indexed in PubMed of the PERK pathway and some of the complexities involved in investigating the protein's role in the development of neurodegenerative diseases as well as how it may act as a target for therapeutics.


Assuntos
Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Transdução de Sinais/genética , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo , Idoso , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular/métodos , Doenças Neurodegenerativas/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/efeitos dos fármacos , Resposta a Proteínas não Dobradas , eIF-2 Quinase/antagonistas & inibidores
4.
FASEB J ; 35(9): e21777, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403519

RESUMO

Mycobacterium bovis is the causative agent of bovine tuberculosis and also responsible for serious threat to public health. Koumiss is a fermented mare's milk product, used as traditional drink. Here, we explored the effect of koumiss on gut microbiota and the host immune response against M bovis infection. Therefore, mice were treated with koumiss and fresh mare milk for 14 days before M bovis infection and continue for 5 weeks after infection. The results showed a clear change in the intestinal flora of mice treated with koumiss, and the lungs of mice treated with koumiss showed severe edema, inflammatory infiltration, and pulmonary nodules in M bovis-infected mice. Notably, we found that the content of short-chain fatty acids was significantly lower in the koumiss-treated group compared with the control group. However, the expression of endoplasmic reticulum stress and apoptosis-related proteins in the lungs of koumiss-treated mice were significantly decreased. Collectively, these findings suggest that koumiss treatment disturb the intestinal flora of, which is associated with disease severity and the possible mechanism that induces lungs pathology. Our current findings can be exploited further to establish the "gut-lung" axis which might be a novel strategy for the control of tuberculosis.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Kumis/efeitos adversos , Mycobacterium bovis/efeitos dos fármacos , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Ácidos Graxos/análise , Fezes/química , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Cavalos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium bovis/imunologia , Tuberculose Pulmonar/dietoterapia , Tuberculose Pulmonar/metabolismo
5.
Ecotoxicol Environ Saf ; 221: 112463, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34198188

RESUMO

BACKGROUND: Cooking oil fumes (COF) is one of the primary sources of indoor air pollution in China, which is associated with respiratory diseases such as acute lung injury and lung cancer. However, evidence of COF toxic effect was few. OBJECTIVES: The research was aimed to investigate the toxic effect and the underlying mechanisms induced by COF. METHODS: The female Wistar rats were randomly divided into several groups, including control group, COF exposure group and VE protection group, and instilled intratracheally with different COF suspensions (0.2, 2, 20 mg/kg) or saline once every 3 days for 30 days. After 24 h of final exposure, all rat were anesthetic euthanasia to draw materials. The alveolar lavage fluid (BALF) was for inflammatory cell count. The lung homogenate was to determine the biochemical indexes such as oxidative stress, apoptosis factors, carcinogenic toxicity and endoplasmic reticulum (ER) stress. The left lung was made for immunohistochemical and histopathological analysis. RESULTS: The results showed that the levels of oxidative stress (ROS), apoptosis factors (NF-κB), carcinogenic toxicity (P53 and 8-OhdG), ER stress (IRE-1α and Caspase-12) in 2 mg/kg and 20 mg/kg COF exposure groups were significantly increased compared with the saline groups. The above pathological changes were improved after vitamin E (VE) supplementation. In addition, the immunohistochemical and histopathological analysis found the same trend. CONCLUSION: The COF had health risk of heredity and potential carcinogenicity. Besides, COFs can not only induce oxidative stress, but also induce ER stress in lung and airway epithelial cells of female rats through the unfolded protein reaction (UPR) pathway. It revealed that the oxidative stress and ER stress interacted in aggravating lung injury. VE could effectively alleviate the lung injury causing by COF exposure.


Assuntos
Poluentes Atmosféricos/toxicidade , Culinária , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Óleos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Feminino , Pulmão/efeitos dos fármacos , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Vitamina E/uso terapêutico
6.
Molecules ; 26(14)2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34299486

RESUMO

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.


Assuntos
Berberina/análogos & derivados , Diabetes Mellitus Experimental/complicações , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/etiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Berberina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças Vasculares/metabolismo
7.
Cell Death Dis ; 12(7): 696, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257270

RESUMO

Trastuzumab resistance negatively influences the clinical efficacy of the therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC), and the underlying mechanisms remain elusive. Exploring the mechanisms and finding effective approaches to address trastuzumab resistance are of great necessity. Here, we confirmed that endoplasmic reticulum (ER) stress-induced trastuzumab resistance by up-regulating miR-301a-3p in HER2-positive GC cells. Moreover, we elucidated that miR-301a-3p mediated trastuzumab resistance by down-regulating the expression of leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) and subsequently activating the expression of insulin-like growth factor 1 receptor (IGF-1R) and fibroblast growth factor receptor 1 (FGFR1) under ER stress. We also found that intercellular transfer of miR-301a-3p by exosomes disseminated trastuzumab resistance. The present study demonstrated that exosomal miR-301a-3p could serve as a non-invasive biomarker for trastuzumab resistance, which was maybe a novel potential therapeutic target to overcome trastuzumab resistance and improve the curative effect of trastuzumab in HER2-positive GC patients.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , MicroRNAs/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Receptor ErbB-2/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cell Death Dis ; 12(7): 659, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193827

RESUMO

Cellular stress can lead to several human disease pathologies due to aberrant cell death. The p53 family (tp53, tp63, and tp73) and downstream transcriptional apoptotic target genes (PUMA/BBC3 and NOXA/PMAIP1) have been implicated as mediators of stress signals. To evaluate the importance of key stress response components in vivo, we have generated zebrafish null alleles in puma, noxa, p53, p63, and p73. Utilizing these genetic mutants, we have deciphered that the apoptotic response to genotoxic stress requires p53 and puma, but not p63, p73, or noxa. We also identified a delayed secondary wave of genotoxic stress-induced apoptosis that is p53/puma independent. Contrary to genotoxic stress, ER stress-induced apoptosis requires p63 and puma, but not p53, p73, or noxa. Lastly, the oxidative stress-induced apoptotic response requires p63, and both noxa and puma. Our data also indicate that while the neural tube is poised for apoptosis due to genotoxic stress, the epidermis is poised for apoptosis due to ER and oxidative stress. These data indicate there are convergent as well as unique molecular pathways involved in the different stress responses. The commonality of puma in these stress pathways, and the lack of gross or tumorigenic phenotypes with puma loss suggest that a inhibitor of Puma may have therapeutic application. In addition, we have also generated a knockout of the negative regulator of p53, mdm2 to further evaluate the p53-induced apoptosis. Our data indicate that the p53 null allele completely rescues the mdm2 null lethality, while the puma null completely rescues the mdm2 null apoptosis but only partially rescues the phenotype. Indicating Puma is the key mediator of p53-dependent apoptosis. Interestingly the p53 homozygous null zebrafish develop tumors faster than the previously described p53 homozygous missense mutant zebrafish, suggesting the missense allele may be hypomorphic allele.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Dano ao DNA , Estresse do Retículo Endoplasmático , Estresse Oxidativo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proteínas Reguladoras de Apoptose/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica , Macrolídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosfoproteínas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais , Acetato de Tetradecanoilforbol/farmacologia , Tapsigargina/farmacologia , Fatores de Tempo , Transativadores/genética , Transcrição Genética , Proteína Supressora de Tumor p53/genética , Raios X , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
9.
Toxicol Lett ; 350: 98-110, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34214594

RESUMO

Methamphetamine (METH) is a highly addictive amphetamine-type drug that has caused persistent harm to society and human health in recent years. Most studies have shown that METH severely damages the central nervous system, and this drug has been found to be toxic to the cardiovascular system in recent years. Therefore, we hypothesized that METH may also damage vascular smooth muscle. We examined the expression of the apoptosis-related proteins Caspase 3 and PARP after METH treatment in vivo and in vitro and detected the expression of endoplasmic reticulum stress-related proteins. After treatment with the endoplasmic reticulum stress inhibitor 4-PBA, changes in the above indicators were examined. C/EBP homologous protein (Chop) expression was also detected, and the relationship between endoplasmic reticulum stress and apoptosis was further determined by siRNA silencing of Chop. The results indicated that METH can induce apoptosis of vascular smooth muscle cells (VSMCs) and upregulate the expression of Chop and endoplasmic reticulum stress-related proteins. Chop inhibits protein kinase B phosphorylation and further inhibits forkhead box class O3a (Foxo3a) dephosphorylation, resulting in increased p53 upregulated molecular of apoptosis (PUMA) transcription. Increased PUMA induces apoptosis through the mitochondrial pathway. These results indicate that Chop is involved in the METH-induced endoplasmic reticulum stress and apoptosis in VSMCs and may be a potential therapeutic target for METH-induced VSMC injury.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metanfetamina/toxicidade , Músculo Liso Vascular/efeitos dos fármacos , Animais , Humanos , Masculino , Modelos Animais , Ratos Sprague-Dawley , Fator de Transcrição CHOP/metabolismo
10.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298862

RESUMO

Copper is an essential trace element and possesses critical roles in various brain functions. A considerable amount of copper accumulates in the synapse and is secreted in neuronal firings in a manner similar to zinc. Synaptic copper and zinc modulate neuronal transmission and contribute to information processing. It has been established that excess zinc secreted during transient global ischemia plays central roles in ischemia-induced neuronal death and the pathogenesis of vascular dementia. We found that a low concentration of copper exacerbates zinc-induced neurotoxicity, and we have demonstrated the involvement of the endoplasmic reticulum (ER) stress pathway, the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) signaling pathway, and copper-induced reactive oxygen species (ROS) production. On the basis of our results and other studies, we discuss the collaborative roles of copper in zinc-induced neurotoxicity in the synapse and the contribution of copper to the pathogenesis of vascular dementia.


Assuntos
Cobre/efeitos adversos , Demência Vascular/etiologia , Demência Vascular/patologia , Síndromes Neurotóxicas/etnologia , Síndromes Neurotóxicas/patologia , Zinco/efeitos adversos , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Transdução de Sinais/efeitos dos fármacos
11.
Int Heart J ; 62(4): 900-909, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34234076

RESUMO

Virus myocarditis (VMC) is a common cardiovascular disease and a major cause of sudden death in young adults. However, there is still a lack of effective treatments. Our previous studies found that calpain activation was involved in VMC pathogenesis. This study aims to explore the underlying mechanisms further. Neonatal rat cardiomyocytes (NRCMs) and transgenic mice overexpressing calpastatin (Tg-CAST), the endogenous calpain inhibitor, were used to establish VMC model. Hematoxylin and eosin and Masson staining revealed inflammatory cell infiltration and fibrosis. An ELISA array detected myocardial injury. Cardiac function was measured using echocardiography. CVB3 replication was assessed by capsid protein VP1. Apoptosis was measured by TUNEL staining, flow cytometry, and western blot. The endoplasmic reticulum (ER) stress-related proteins were detected by western blot. Our data showed that CVB3 infection resulted in cardiac injury, as evidenced by increased inflammatory responses and fibrosis, which induced myocardial apoptosis. Inhibiting calpain, both by PD150606 and calpastatin overexpression, could attenuate these effects. Furthermore, ER stress was activated during CVB3 infection. However, calpain inhibition could downregulate some ER stress-associated protein levels such as GRP78, pancreatic ER kinase-like ER kinase (PERK), and inositol-requiring enzyme-1α (IRE-1α), and ER stress-related apoptotic factors, during CVB3 infection. In conclusion, calpain inhibition attenuated CVB3-induced myocarditis by suppressing ER stress, thereby inhibiting cardiomyocyte apoptosis.


Assuntos
Acrilatos/uso terapêutico , Calpaína/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Miocardite/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Acrilatos/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Calpaína/antagonistas & inibidores , Infecções por Coxsackievirus/tratamento farmacológico , Infecções por Coxsackievirus/metabolismo , Avaliação Pré-Clínica de Medicamentos , Enterovirus Humano B , Camundongos Transgênicos , Miocardite/tratamento farmacológico , Miocardite/virologia , Ratos Sprague-Dawley
12.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199510

RESUMO

During aggressive cancer progression, cancer cells adapt to unique microenvironments by withstanding various cellular stresses, including endoplasmic reticulum (ER) stress. However, the mechanism whereby cancer cells overcome the ER stress to survive remains to be elucidated. Herein, we demonstrated that microtubule acetylation in cancer cells grown on a stiff matrix promotes cancer progression by preventing excessive ER stress. Downregulation of microtubule acetylation using shRNA or CRSIPR/Cas9 techniques targeting ATAT1, which encodes α-tubulin N-acetyltransferase (αTAT1), resulted in the upregulation of ER stress markers, changes in ER morphology, and enhanced tunicamycin-induced UPR signaling in cancer cells. A set of genes involved in cancer progression, especially focal adhesion genes, were downregulated in both ATAT1-knockout and tunicamycin-treated cells, whereas ATAT1 overexpression restored the gene expression inhibited by tunicamycin. Finally, the expression of ATAT1 and ER stress marker genes were negatively correlated in various breast cancer types. Taken together, our results suggest that disruption of microtubule acetylation is a potent therapeutic tool for preventing breast cancer progression through the upregulation of ER stress. Moreover, ATAT1 and ER stress marker genes may be useful diagnostic markers in various breast cancer types.


Assuntos
Acetiltransferases/genética , Neoplasias da Mama/genética , Estresse do Retículo Endoplasmático/genética , Proteínas dos Microtúbulos/genética , Tunicamicina/farmacologia , Acetilação/efeitos dos fármacos , Acetiltransferases/antagonistas & inibidores , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas dos Microtúbulos/antagonistas & inibidores , Microtúbulos/efeitos dos fármacos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Microambiente Tumoral/efeitos dos fármacos
13.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204139

RESUMO

The prohibitin (PHB)-binding compound fluorizoline as well as PHB-downregulation activate the integrated stress response (ISR) in HEK293T and U2OS human cell lines. This activation is denoted by phosphorylation of eIF2α and increases in ATF4, ATF3, and CHOP protein levels. The blockage of the activation of the ISR by overexpression of GRP78, as well as an increase in IRE1 activity, indicate the presence of ER stress after fluorizoline treatment. The inhibition of the ER stress response in HEK293T and U2OS led to increased sensitivity to fluorizoline-induced apoptosis, indicating a pro-survival role of this pathway after fluorizoline treatment in these cell lines. Fluorizoline induced an increase in calcium concentration in the cytosol and the mitochondria. Finally, two different calcium chelators reduced fluorizoline-induced apoptosis in U2OS cells. Thus, we have found that fluorizoline causes increased ER stress and activation of the integrated stress response, which in HEK293T and U2OS cells are protective against fluorizoline-induced apoptosis.


Assuntos
Apoptose , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Tiazóis/farmacologia , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células HEK293 , Homeostase/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207084

RESUMO

Advanced glycation end products (AGEs) are formed via nonenzymatic reactions between reducing sugars and proteins. Recent studies have shown that methylglyoxal, a potent precursor for AGEs, causes a variety of biological dysfunctions, including diabetes, inflammation, renal failure, and cancer. However, little is known about the function of methylglyoxal-derived AGEs (AGE4) in kidney cells. Therefore, we verified the expression of endoplasmic reticulum (ER) stress-related genes and apoptosis markers to determine the effects of AGE4 on human proximal epithelial cells (HK-2). Moreover, our results showed that AGE4 induced the expression of apoptosis markers, such as Bax, p53, and kidney injury molecule-1, but downregulated Bcl-2 and cyclin D1 levels. AGE4 also promoted the expression of NF-κB, serving as a transcription factor, and the phosphorylation of c-Jun NH2-terminal kinase (JNK), which induced cell apoptosis and ER stress mediated by the JNK inhibitor. Furthermore, AGE4 induced mitochondrial dysfunction by inducing the permeabilization of the mitochondrial membrane and ATP synthesis. Through in vitro and in vivo experiments, this study provides a new perspective on renal dysfunction with regard to the AGE4-induced RAGE /JNK signaling pathway, which leads to renal cell apoptosis via the imbalance of mitochondrial function and ER stress in kidney damage.


Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Produtos Finais de Glicação Avançada/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mitocôndrias/metabolismo , Aldeído Pirúvico/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/metabolismo , Produtos Finais de Glicação Avançada/farmacologia , Humanos , Rim/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Modelos Biológicos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo
15.
Int J Mol Sci ; 22(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205571

RESUMO

Studies of recent decades have repeatedly demonstrated the cytotoxic effect of selenium-containing compounds on cancer cells of various origins. Particular attention in these studies is paid to methylseleninic acid, a widespread selenium-containing compound of organic nature, for several reasons: it has a selective cytotoxic effect on cancer cells, it is cytotoxic in small doses, it is able to generate methylselenol, excluding the action of the enzyme ß-lyase. All these qualities make methylseleninic acid an attractive substrate for the production of anticancer drugs on its basis with a well-pronounced selective effect. However, the studies available to date indicate that there is no strictly specific molecular mechanism of its cytotoxic effect in relation to different cancer cell lines and cancer models. This review contains generalized information on the dose- and time-dependent regulation of the toxic effect of methylseleninic acid on the proliferative properties of a number of cancer cell lines. In addition, special attention in this review is paid to the influence of this selenium-containing compound on the regulation of endoplasmic reticulum stress and on the expression of seven selenoproteins, which are localized in the endoplasmic reticulum.


Assuntos
Carcinogênese/efeitos dos fármacos , Citotoxinas/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Compostos Organosselênicos/toxicidade , Animais , Humanos , Compostos Organosselênicos/uso terapêutico , Selenoproteínas/metabolismo
16.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202188

RESUMO

Various natural compounds have been successfully tested for preventing or counteracting the toxic effects of exposure to heavy metals. In this study, we analyzed the effects of cadmium chloride (CdCl2) on immortalized, non-tumorigenic thyroid cells Nthy-ori-3-1. We investigated the molecular mechanism underlying its toxic action as well as the potential protective effect of quercetin against CdCl2-induced damage. CdCl2 suppressed cell growth in a dose- and time-dependent manner (IC50 value ~10 µM) associated with a decrease in levels of phospho-ERK. In addition, CdCl2 elicited an increase in reactive oxygen species (ROS) production and lipid peroxidation. A significant increase in GRP78, an endoplasmic reticulum (ER) stress-related protein, was also observed. Supplementation of quercetin counteracted the growth-inhibiting action of CdCl2 by recovering ERK protein phosphorylation levels, attenuating ROS overproduction, decreasing MDA content and reducing the expression of GRP78 in cells exposed to CdCl2. Thus, in addition to revealing the molecular effects involved in cadmium-induced toxicity, the present study demonstrated, for the first time, a protective effect of quercetin against cadmium-induced damages to normal thyroid cells.


Assuntos
Cádmio/toxicidade , Disruptores Endócrinos/toxicidade , Substâncias Protetoras/farmacologia , Quercetina/farmacologia , Glândula Tireoide/citologia , Glândula Tireoide/efeitos dos fármacos , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cloreto de Cádmio/toxicidade , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Glândula Tireoide/metabolismo
17.
Life Sci ; 279: 119673, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34081991

RESUMO

BACKGROUND: Chronic alcoholism induces kidney injury (KI), leading to increased mortality in alcoholic hepatitis patients. Endoplasmic reticulum stress (ER) represents the main initiator of kidney diseases and alcoholic nephropathy. AIMS: We used alcoholic nephropathy rat model followed by 10-dehydrogingerdione (10-DHGD) intake as potential modulator. This is to focus on ER/oxidative stress/inflammatory and apoptotic pathways involvement. MAIN METHOD: Alcoholic nephropathy was induced by alcohol administration (3.7 g/kg/body weight) orally and daily for 45 days. 10-DHGD (10 mg/kg/day) was administered either alone or along with alcohol. KEY FINDINGS: Our results demonstrated significant increase in kidney function parameters like f creatinine, urea, uric acid, and blood urea nitrogen (BUN) levels. Renal ER/oxidative stress markers such as cytochrome P450 family two subfamily E member 1 (CYP2E1), C/EBP homologous protein (CHOP), and endoplasmic glucose-regulated protein 78 (GRP-78) demonstrated also significant increase. Inflammatory mediators like nuclear factor-kappa B (NF-kB), tumor necrosis factor-α (TNF-α), and transforming growth factor-ß (TGF-ß along with apoptotic marker caspase-3 behaved similarly. Antioxidant molecules like reduced glutathione (GSH), superoxide dismutase (SOD), and catalase demonstrated marked decrease. SIGNIFICANCE: 10-DHGD administration resulted in significant modulation represented by an enhancement in the kidney functions and the histopathological patterns in a conclusion of its potential to ameliorate the pathological changes (kidney injury) induced by alcohol intake.


Assuntos
Alcoolismo/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Etanol/toxicidade , Guaiacol/análogos & derivados , Nefropatias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Alcoolismo/etiologia , Alcoolismo/patologia , Animais , Depressores do Sistema Nervoso Central/toxicidade , Guaiacol/farmacologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Masculino , Ratos
18.
Mol Cell Biochem ; 476(10): 3869-3877, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34129155

RESUMO

Brefeldin A (BFA) disrupts the structure of the Golgi apparatus to trigger ER stress signaling pathways. On the other hand, treatment with BFA induces the activation of CREB3, the protein structure of which is similar to that of ATF6. In this study, we established Neuro2a cells in which three different transcription factors, namely, ATF4, ATF3 and CREB3, were deficient using the CRISPR/Cas9 approach, and we investigated the BFA-induced ER and Golgi stress response in these cells. BFA treatment rapidly induced ATF4, ATF3, Herp and GADD153 protein expression in Neuro2a cells. ATF4-deficient Neuro2a cells exhibited significantly decreased mRNA and protein expression of ATF3 and Herp but not GADD153; however, cells deficient in ATF3 exhibited minimal effects on GADD34, GADD153 and Herp expression. The cleavage of CREB3 in Neuro2a cells was triggered by BFA; however, the expression of several ER and Golgi stress-related factors was hardly influenced by the CREB3 deficiency in these Neuro2a cells. This study shows that CREB3 minimally associates with typical ER stress-inducible responses in Neuro2a cells. Therefore, identification and characterization of the downstream transcriptional targets of CREB3 is required to clarify not only Golgi stress response but also its relationship with ER stress signaling pathways.


Assuntos
Brefeldina A/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Complexo de Golgi/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/genética , Complexo de Golgi/genética , Camundongos , Transdução de Sinais/genética
19.
Ecotoxicol Environ Saf ; 220: 112394, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34091186

RESUMO

Arsenic (As) and antimony (Sb) are known as an environmental contaminant with cardiotoxicity properties. The endoplasmic reticulum (ER) is the largest calcium reservoir in the cell, and its calcium homeostasis disorder plays a vital role in endoplasmic reticulum stress (ERS) and apoptosis. The objective of this study was to investigate whether As and Sb induced apoptosis via endoplasmic reticulum stress (ERS) linked to calcium homeostasis disturbance. In this study, thirty-two adult mice were gavage-fed daily with As2O3 (4 mg/kg), SbCl3 (15 mg/kg) and co-treat with SbCl3 (15 mg/kg) and As2O3 (4 mg/kg) daily for 60 days. It was observed that As or/and Sb caused histopathological lesions and ER expansion of the heart. Meanwhile, the gene expression of ER Ca2+ release channels (RyR2 and IP3R) and calmodulin-dependent protein kinase II (CaMKII) increased while the levels of mRNA and protein of ER Ca2+ uptake channel (SERCA2) downregulated significantly compared to the controls. Then, As or/and Sb induced ERS and triggered the ER apoptotic pathway by activating unfolded protein response (UPR)-associated genes ((PERK, ATF6, IRE1, XBP1, JNK, GRP78), and apoptosis-related genes (Caspase12, Caspase3, p53, CHOP). Above indicators in As + Sb group became more severe than that of As group and Sb group. Overall, our results proved that the cardiotoxicity caused by As or/and Sb might be concerning disturbing calcium homeostasis, which induced apoptosis through the ERS pathway.


Assuntos
Antimônio/toxicidade , Arsênio/toxicidade , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Coração/efeitos dos fármacos , Animais , Antimônio/metabolismo , Apoptose , Arsênio/metabolismo , Canais de Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiotoxicidade/metabolismo , Cardiotoxinas , Caspase 3/metabolismo , Morte Celular , Regulação para Baixo , Retículo Endoplasmático/metabolismo , Poluentes Ambientais/toxicidade , Homeostase/efeitos dos fármacos , Masculino , Metais Pesados/toxicidade , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Resposta a Proteínas não Dobradas
20.
Toxicol Appl Pharmacol ; 425: 115601, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34081941

RESUMO

Obesity is recognized as a risk for the development of chronic kidney disease. Excessive fat accumulation in obesity is associated with the overproduction of reactive oxygen species with the underproduction of antioxidant mechanisms generating oxidative stress together with chronic low-grade inflammation which subsequently leads to the development of several obesity-related complications. It has been suggested that the abnormal lipid accumulation can induce endoplasmic reticulum (ER) stress and cellular apoptosis in several tissue types. Agomelatine is a relatively new antidepressant which is a synthetic agonist of melatonin. Previous study reported the antioxidant and anti-inflammatory effects of agomelatine. In this study, we investigated the therapeutic effects of agomelatine in obesity-related renal injury. Male Wistar rats were fed with normal diet or high-fat diet (HF) for 16 weeks. After that, vehicle or agomelatine or vildagliptin was orally administered to HF rats for 4 weeks. Our results indicated that HF rats demonstrated insulin resistance which was accompanied by an impairment of renal function and renal organic anion transporter 3 (Oat3) function as well as renal oxidative stress, ER stress, and apoptosis. Interestingly, agomelatine treatment not only improved the metabolic parameters, renal function and renal Oat3 function but also attenuated renal oxidative stress, ER stress and subsequent apoptosis. Therefore, agomelatine exerted renoprotective effects in obese insulin-resistant condition. These results suggested that agomelatine could be used as a drug to improve metabolic disturbance and prevent kidney dysfunction in obese condition.


Assuntos
Acetamidas/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Nefropatias/etiologia , Obesidade/complicações , Animais , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Resistência à Insulina , Nefropatias/prevenção & controle , Masculino , Obesidade/induzido quimicamente , Distribuição Aleatória , Ratos , Ratos Wistar
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