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1.
Biomed Pharmacother ; 139: 111603, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243596

RESUMO

The HtrA protein family is composed by evolutionally-conserved serine proteases, which are homologous to the HtrA protein of the model bacterium Escherichia coli. They are widely distributed in organisms including humans, prokaryotes and eukaryotes. Moreover, HtrA family proteins are important regulators of a variety of human physiological processes, which contains the maintenance of mitochondrial homeostasis, cellular signal transduction and apoptosis regulation. The HtrA family has been found to be associated with cancer and could be used as a target for future cancer treatments. The purpose of this article is to review the relationship between these HtrA and cancer and to summarize the latest researches on HtrA and cancer.


Assuntos
Neoplasias/metabolismo , Serina Proteases/metabolismo , Animais , Apoptose/fisiologia , Homeostase/fisiologia , Humanos , Mitocôndrias/metabolismo , Transdução de Sinais/fisiologia
2.
FASEB J ; 35(8): e21757, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34233045

RESUMO

Pyroptosis and intrinsic apoptosis are two forms of regulated cell death driven by active caspases where plasma membrane permeabilization is induced by gasdermin pores. Caspase-1 induces gasdermin D pore formation during pyroptosis, whereas caspase-3 promotes gasdermin E pore formation during apoptosis. These two types of cell death are accompanied by mitochondrial outer membrane permeabilization due to BAK/BAX pore formation in the external membrane of mitochondria, and to some extent, this complex also affects the inner mitochondrial membrane facilitating mitochondrial DNA relocalization from the matrix to the cytosol. However, the detailed mechanism responsible for this process has not been investigated. Herein, we reported that gasdermin processing is required to induce mitochondrial DNA release from cells during pyroptosis and apoptosis. Gasdermin targeted at the plasma membrane promotes a fast mitochondrial collapse along with the initial accumulation of mitochondrial DNA in the cytosol and then facilitates the DNA's release from the cell when the plasma membrane ruptures. These findings demonstrate that gasdermin action has a critical effect on the plasma membrane and facilitates the release of mitochondrial DNA as a damage-associated molecular pattern.


Assuntos
Apoptose/fisiologia , DNA Mitocondrial/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas de Ligação a Fosfato/fisiologia , Piroptose/fisiologia , Animais , Caspases/metabolismo , Membrana Celular/metabolismo , Células HEK293 , Humanos , Técnicas In Vitro , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Ligação a Fosfato/deficiência , Proteínas de Ligação a Fosfato/genética , Pirina/metabolismo , Receptores de Estrogênio/fisiologia
3.
Cells ; 10(7)2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201847

RESUMO

Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these processes can be present and can participate in the pathogenetic mechanisms of the disease. In this review, we describe some features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some immunopathogenic mechanisms characterizing the present coronavirus disease (COVID-19). Lymphopenia and monocytopenia are important contributors to COVID-19 immunopathogenesis. The fine mechanisms underlying these phenomena are still unknown, and several hypotheses have been raised, some of which assign a role to cell death as far as the reduction of specific types of immune cells is concerned. Thus, we discuss three major pathways such as apoptosis, necroptosis, and pyroptosis, and suggest that all of them likely occur simultaneously in COVID-19 patients. We describe that SARS-CoV-2 can have both a direct and an indirect role in inducing cell death. Indeed, on the one hand, cell death can be caused by the virus entry into cells, on the other, the excessive concentration of cytokines and chemokines, a process that is known as a COVID-19-related cytokine storm, exerts deleterious effects on circulating immune cells. However, the overall knowledge of these mechanisms is still scarce and further studies are needed to delineate new therapeutic strategies.


Assuntos
COVID-19/patologia , Morte Celular/fisiologia , SARS-CoV-2/patogenicidade , Apoptose/fisiologia , COVID-19/imunologia , COVID-19/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Citocinas/metabolismo , Humanos , Necroptose/fisiologia , Internalização do Vírus
4.
Gene ; 799: 145847, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34274473

RESUMO

BACKGROUND: Uncontrolled type 1 diabetes mellitus (T1D) impairs reproductive potential of males. Insulin treatment restores metabolic parameters but it is unclear how it protects male reproductive health. Herein, we hypothesized that insulin treatment to T1D rats protects testicular physiology by mediating mechanisms associated with apoptosis and cell cycle. METHODS: Mature male Wistar rats (n = 24) were divided into 3 groups: control, T1D-induced (received 40 mg kg-1 streptozotocin) and insulin-treated T1D (Ins T1D; received 40 mg kg-1 streptozotocin and then treated 0.9 IU/100 gr of insulin for 56 days) (N = 8/group). Expression levels of intrinsic apoptosis pathways regulators (Bcl-2, Bax, Caspase-3 and p53) and core regulators of cell cycle machinery (Cyclin D1, Cdk-4 and p21) were determined in testicular tissue by immunohistochemistry (IHC) and RT-PCR techniques. The percentage of testicular apoptotic cells was evaluated by TUNEL staining. RESULTS: Our data shows that insulin treatment to T1D rats restored (P < 0.05) T1D-induced increased of caspase-3 and p53 expression in testis. Moreover, the testis of T1D rats treated with insulin exhibited increased expression of Cyclin D1 and cdk-4, and a reduced expression of p21 when compared with the expression in testis of T1D rats. Finally, insulin treatment could fairly control T1D-induced apoptosis. Accordingly, treatment of T1D rats with insulin led to a remarkable reduction (p < 0.05) in the percentage of apoptotic cells in the testis. CONCLUSIONS: Insulin treatment is able to restore the network expression of apoptosis and proliferation-related genes caused by T1D in the testis and via this mechanism, preserve the fertility of males.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Insulina/fisiologia , Testículo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Fertilidade , Expressão Gênica/efeitos dos fármacos , Masculino , Substâncias Protetoras/farmacologia , Ratos Wistar , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Testículo/patologia , Testosterona/sangue
5.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067817

RESUMO

BACKGROUND: Exposure to intermittent hypoxia has been demonstrated to be an efficient tool for hypoxic preconditioning, preventing damage to cells and demonstrating therapeutic benefits. We aimed to evaluate the effects of respiratory intermittent hypobaric hypoxia (IHH) to avoid brain injury caused by exposure to acute severe hypoxia (ASH). METHODS: biomarkers of oxidative damage, mitochondrial apoptosis, and transcriptional factors in response to hypoxia were assessed by Western blot and immunohistochemistry in brain tissue. Four groups of rats were used: (1) normoxic (NOR), (2) exposed to ASH (FiO2 7% for 6 h), (3) exposed to IHH for 3 h per day over 8 days at 460 mmHg, and (4) ASH preconditioned after IHH. RESULTS: ASH animals underwent increased oxidative-stress-related parameters, an upregulation in apoptotic proteins and had astrocytes with phenotype forms compatible with severe diffuse reactive astrogliosis. These effects were attenuated and even prevented when the animals were preconditioned with IHH. These changes paralleled the inhibition of NF-κB expression and the increase of erythropoietin (EPO) levels in the brain. CONCLUSIONS: IHH exerted neuroprotection against ASH-induced oxidative injury by preventing oxidative stress and inhibiting the apoptotic cascade, which was associated with NF-κB downregulation and EPO upregulation.


Assuntos
Hipóxia/metabolismo , Hipóxia/prevenção & controle , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/farmacologia , Apoptose/fisiologia , Astrócitos/metabolismo , Encéfalo/metabolismo , Eritropoetina/farmacologia , Gliose/metabolismo , Masculino , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Neurônios/metabolismo , Neuroproteção/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
6.
Phytomedicine ; 88: 153604, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34130054

RESUMO

BACKGROUND: Blue light can directly penetrate the lens and reach the retina to induce retinal damage, causing dry age-related macular degeneration (dAMD). Cynaroside (Cyn), a flavonoid glycoside, was proved to alleviate the oxidative damage of retinal cells in vitro. However, whether or not Cyn also exerts protective effect on blue light-induced retinal degeneration and its mechanisms of action are unclear. PURPOSE: This study aims to evaluate the protective effects of Cyn against blue-light induced retinal degeneration and its underlying mechanisms in vitro and in vivo. STUDY DESIGN/METHODS: Blue light-induced N-retinylidene-N-retinylethanolamine (A2E)-laden adult retinal pigment epithelial-19 (ARPE-19) cell damage and retinal damage in SD rats were respectively used to evaluate the protective effects of Cyn on retinal degeneration in vitro and in vivo. MTT assay and AnnexinV-PI double staining assay were used to evaluate the in vitro efficacy. Histological analysis, TUNEL assay, and fundus imaging were conducted to evaluate the in vivo efficacy. ELISA assay, western blot, and immunostaining were performed to investigate the mechanisms of action of Cyn. RESULTS: Cyn decreased the blue light-induced A2E-laden ARPE-19 cell damage and oxidative stress. Intravitreal injection of Cyn (2, 4 µg/eye) reversed the retinal degeneration induced by blue light in SD rats. Furthermore, Cyn inhibited the nuclear translocation of NF-κB and induced autophagy, which led to the clearance of overactivated pyrin domain containing 3 (NLRP3) inflammasome in vitro and in vivo. CONCLUSION: Cyn protects against blue light-induced retinal degeneration by modulating autophagy and decreasing the NLRP3 inflammasome.


Assuntos
Apoptose/efeitos dos fármacos , Glucosídeos/farmacologia , Luteolina/farmacologia , Substâncias Protetoras/farmacologia , Degeneração Retiniana/tratamento farmacológico , Animais , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Linhagem Celular , Glucosídeos/administração & dosagem , Humanos , Inflamassomos/metabolismo , Injeções Intravítreas , Luz/efeitos adversos , Luteolina/administração & dosagem , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Ratos Sprague-Dawley , Degeneração Retiniana/etiologia , Degeneração Retiniana/patologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/patologia
7.
Nat Commun ; 12(1): 4026, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34188052

RESUMO

Iron is essential for a healthy pregnancy, and iron supplementation is nearly universally recommended, regardless of maternal iron status. A signal of potential harm is the U-shaped association between maternal ferritin, a marker of iron stores, and risk of adverse pregnancy outcomes. However, ferritin is also induced by inflammation and may overestimate iron stores during inflammation or infection. In this study, we use mouse models to determine whether maternal iron loading, inflammation, or their interaction cause poor pregnancy outcomes. Only maternal exposure to both iron excess and inflammation, but not either condition alone, causes embryo malformations and demise. Maternal iron excess potentiates embryo injury during both LPS-induced acute inflammation and obesity-induced chronic mild inflammation. The adverse interaction depends on TNFα signaling, causes apoptosis of placental and embryo endothelium, and is prevented by anti-TNFα or antioxidant treatment. Our findings raise important questions about the safety of indiscriminate iron supplementation during pregnancy.


Assuntos
Apoptose/fisiologia , Ferritinas/análise , Ferro/metabolismo , Obesidade/patologia , Placenta/patologia , Animais , Células Cultivadas , Embrião de Mamíferos/patologia , Feminino , Hepcidinas/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Ferro/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez , Complicações na Gravidez , Fator de Necrose Tumoral alfa/metabolismo
8.
AAPS PharmSciTech ; 22(5): 177, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34128106

RESUMO

Fluvastatin (FLV) is known to inhibit the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), which is over-expressed in various cancers. FLV has been reported to decrease cancer development and metastasis. However, because of low bioavailability, extensive first-pass metabolism and short half-life of FLV (1.2 h), it is not appropriate for clinical application. Therefore, FLV-loaded emulsomes were formulated and optimized using Box-Behnken experimental design to achieve higher efficiency of formulation. Antitumor activity of optimized FLV-loaded emulsomes was evaluated in prostate cancer cells using cell cytotoxicity, apoptotic activity, cell cycle analysis, and enzyme-linked immunosorbent assay. The FLV-loaded emulsomes exhibited a monodispersed size distribution with a mean particle size less than 100 nm as measured by zetasizer. The entrapment efficiency was found to be 93.74% with controlled drug release profile. FLV-EMLs showed a significant inhibitory effect on the viability of PC3 cells when compared to the free FLV (P < 0.0025). Furthermore, FLV-EMLs showed significant arrest in G2/M and increase in percentage of apoptotic cells as compared to free FLV. FLV-EMLs were more effective than free FLV in reducing mitochondrial membrane potential and increase in caspase-3 activity. These results suggesting that FLV-EMLs caused cell cycle arrest which clarifies its significant antiproliferative effect compared to the free drug. Therefore, optimized FLV-EMLs may be an effective carrier for FLV in prostate cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Citotoxinas/farmacologia , Portadores de Fármacos/farmacologia , Fluvastatina/farmacologia , Neoplasias da Próstata , Antineoplásicos/síntese química , Apoptose/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Citotoxinas/síntese química , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/síntese química , Fluvastatina/síntese química , Humanos , Masculino , Células PC-3 , Tamanho da Partícula
9.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069914

RESUMO

Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a decreased beta-cell mass was also reported to contribute to the pathophysiology of this metabolic disease. The decreased beta-cell mass in T2D is, at least in part, attributed to beta-cell apoptosis that is triggered by diabetogenic situations such as amyloid deposits, lipotoxicity and glucotoxicity. In this review, we discussed the molecular mechanisms involved in pancreatic beta-cell apoptosis under such diabetes-prone situations. Finally, we considered the molecular signaling pathways recruited by glucagon-like peptide-1-based therapies to potentially protect beta-cells from death under diabetogenic situations.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células Secretoras de Insulina/fisiologia , Animais , Apoptose/fisiologia , Células Cultivadas , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Transdução de Sinais
10.
Mutat Res ; 787: 108366, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083056

RESUMO

Breast cancer (BC) is a heterogeneous cancer with multiple subtypes affecting women worldwide. Triple-negative breast cancer (TNBC) is a prominent subtype of BC with poor prognosis and an aggressive phenotype. Recent understanding of metabolic reprogramming supports its role in the growth of cancer cells and their adaptation to their microenvironment. The Warburg effect is characterized by the shift from oxidative to reductive metabolism and external secretion of lactate. The Warburg effect prevents the use of the required pyruvate in the tricarboxylic acid (TCA) cycle progressing through pyruvate dehydrogenase inactivation. Therefore, it is a major regulatory mechanism to promote glycolysis and disrupt the TCA cycle. Glutamine (Gln) can supply the complementary energy for cancer cells. Additionally, it is the main substrate to support bioenergetics and biosynthetic activities in cancer cells and plays a vital role in a wide array of other processes such as ferroptosis. Thus, the switching of glucose to Gln in the TCA cycle toward reductive Gln metabolism is carried out by hypoxia-inducible factors (HIFs) conducted through the Warburg effect. The literature suggests that the addiction of TNBC to Gln could facilitate the proliferation and invasiveness of these cancers. Thus, Gln metabolism inhibitors, such as CB-839, could be applied to manage the carcinogenic properties of TNBC. Such inhibitors, along with conventional chemotherapy agents, can potentially improve the efficiency and efficacy of TNBC treatment. In this review, we discuss the associations between glucose and Gln metabolism and control of cancer cell growth from the perspective that Gln metabolism inhibitors could improve the current chemotherapy drug effects.


Assuntos
Glutamina/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Apoptose/fisiologia , Ferroptose/fisiologia , Humanos , Efeito Warburg em Oncologia
11.
Food Chem ; 362: 130189, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34087710

RESUMO

Structural changes of cytochrome c and its relationship with apoptosis and protein degradation of bovine muscle during postmortem aging were investigated. Results from amide I and amide II ~ VI showed that the π* orbital d electron decreased, the π electron density increased, and the frequency of the C-N stretching vibration increased. The distance between heme Fe and N atoms of the porphyrin decreased, the bond length decreased, and the heme core size decreased. Besides, Fe ligand vibration related Raman bands of cytochrome c had red (right) shift gradually with the extension of aging. The apoptotic rate and the degradation products of desmin and troponin-T were increased (P < 0.05). Correlation analysis results suggested that Fe ligand vibration, not amide I ~ VI related Raman bands were correlated with cytochrome c mediated apoptosis and degradation of myofibrillar protein of bovine muscle during aging.


Assuntos
Citocromos c/química , Músculo Esquelético/metabolismo , Amidas/química , Animais , Apoptose/fisiologia , Bovinos , Desmina/química , Desmina/metabolismo , Heme/química , Masculino , Proteínas Musculares/química , Proteínas Musculares/metabolismo , Músculo Esquelético/patologia , Porfirinas/química , Proteólise , Análise Espectral Raman/métodos , Fatores de Tempo , Troponina T/química , Troponina T/metabolismo
12.
Sci Adv ; 7(25)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34134991

RESUMO

Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R-like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2- and SARS-CoV-induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2-inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.


Assuntos
Antivirais/farmacologia , Apoptose/efeitos dos fármacos , COVID-19/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , eIF-2 Quinase/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Enzima de Conversão de Angiotensina 2/genética , Animais , Apoptose/fisiologia , COVID-19/etiologia , COVID-19/patologia , Linhagem Celular , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/patologia , Dipeptidil Peptidase 4/genética , Células Epiteliais/virologia , Feminino , Humanos , Indóis/farmacologia , Pulmão/virologia , Masculino , Camundongos Transgênicos , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética
13.
FASEB J ; 35(7): e21748, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34152016

RESUMO

Although adipose-derived human mesenchymal stem cell (hADSC) transplantation has recently emerged as a promising therapeutic modality for Parkinson's disease (PD), its underlying mechanism of action has not been fully elucidated. This study evaluated the therapeutic effects of stereotaxic injection of hADSCs in the striatum of the 6-OHDA-induced mouse model. Furthermore, an in vitro PD model was constructed using tissue-organized brain slices. The therapeutic effect was also evaluated using a co-culture of the hADSCs and 6-OHDA-treated brain slice. The analysis of hADSC exocrine proteins using RNA-sequencing, human protein cytokine arrays, and label-free quantitative proteomics identified key extracellular factors in the hADSC secretion environment. The degeneration and apoptosis of the dopaminergic neurons were measured in the PD samples in vivo and in vitro, and the beneficial effects were evaluated using quantitative reverse transcription-polymerase chain reaction, western blotting, Fluoro-Jade C, TUNEL assay, and immunofluorescence analysis. This study found that hADSCs protected the dopaminergic neurons in the in vivo and vitro models. We identified Pentraxin 3 (PTX3) as a key extracellular factor in the hADSC secretion environment. Moreover, we found that human recombinant PTX3 (rhPTX3) treatment could rescue the pathophysiological behavior of the PD mice in vivo, prevent dopaminergic neuronal death, and increase neuronal terminals in the ventral tegmental area + substantia nigra pars compacta and striatum in the PD brain slices in vitro. Furthermore, testing of the pro-apoptotic markers in the PD mouse brain following rhPTX3 treatment revealed that rhPTX3 can prevent apoptosis and degeneration of the dopaminergic neurons. This study discovered that PTX3, a hADSC-secreted protein, potentially protected the dopaminergic neurons against apoptosis and degeneration during PD progression and improved motor performance in PD mice, indicating the possible mechanism of action of hADSC replacement therapy for PD. Thus, our study discovered potential translational implications for the development of PTX3-based therapeutics for PD.


Assuntos
Tecido Adiposo/metabolismo , Apoptose/fisiologia , Proteína C-Reativa/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Doença de Parkinson/metabolismo , Componente Amiloide P Sérico/metabolismo , Animais , Morte Celular/fisiologia , Células Cultivadas , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
FASEB J ; 35(7): e21706, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34160104

RESUMO

Acute kidney injury (AKI) is a devastating condition with high morbidity and mortality rates. The pathological features of AKI are tubular injury, infiltration of inflammatory cells, and impaired vascular integrity. Pyruvate kinase is the final rate-limiting enzyme in the glycolysis pathway. We previously showed that pyruvate kinase M2 (PKM2) plays an important role in regulating the glycolytic reprogramming of fibroblasts in renal interstitial fibrosis. The present study aimed to determine the role of PKM2 in fibroblast activation during the pathogenesis of AKI. We found increased numbers of S100A4 positive cells expressing PKM2 in renal tissues from mice with AKI induced via folic acid or ischemia/reperfusion (I/R). The loss of PKM2 in fibroblasts impaired fibroblast proliferation and promoted tubular epithelial cell death including apoptosis, necroptosis, and ferroptosis. Mechanistically, fibroblasts produced less hepatocyte growth factor (HGF) in response to a loss of PKM2. Moreover, in two AKI mouse models, fibroblast-specific deletion of PKM2 blocked HGF signal activation and aggravated AKI after it was induced in mice via ischemia or folic acid. Fibroblast proliferation mediated by PKM2 elicits pro-survival signals that repress tubular cell death and may help to prevent AKI progression. Fibroblast activation mediated by PKM2 in AKI suggests that targeting PKM2 expression could be a novel strategy for treating AKI.


Assuntos
Injúria Renal Aguda/metabolismo , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Células Epiteliais/metabolismo , Fibroblastos/metabolismo , Piruvato Quinase/metabolismo , Animais , Apoptose/fisiologia , Morte Celular/fisiologia , Linhagem Celular , Modelos Animais de Doenças , Fibrose/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necroptose/fisiologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/fisiologia
15.
Int J Nanomedicine ; 16: 3661-3678, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093011

RESUMO

Introduction: Brain ischemia is a common neurological disorder worldwide that activates a cascade of pathophysiological events involving decreases in oxygen and glucose levels. Despite substantial efforts to explore its pathogenesis, the management of ischemic neuronal injury remains an enormous challenge. Accumulating evidence suggests that VEGF modified nanofiber (NF) materials and the fatty-acid amide hydrolase (FAAH) inhibitor URB597 exert an influence on alleviating ischemic brain damage. We aimed to further investigate their effects on primary hippocampal neurons, as well as the underlying mechanisms following oxygen-glucose deprivation (OGD). Methods: Different layers of VEGF-A loaded polycaprolactone (PCL) nanofibrous membranes were first synthesized by using layer-by-layer (LBL) self-assembly of electrospinning methods. The physicochemical and biological properties of VEGF-A NF membranes, and their morphology, hydrophilicity, and controlled-release of VEGF-A were then estimated. Furthermore, the effects of VEGF-A NF and URB597 on OGD-induced mitochondrial oxidative stress, inflammatory responses, neuronal apoptosis, and endocannabinoid signaling components were assessed. Results: The VEGF-A NF membrane and URB597 can not only promote hippocampal neuron adhesion and viability following OGD but also exhibited antioxidant/anti-inflammatory and mitochondrial membrane potential protection. The VEGF-A NF membrane and URB597 also inhibited OGD-induced cellular apoptosis through activating CB1R signaling. These results indicate that VEGF-A could be controlled-released by LBL self-assembled NF membranes. Discussion: The VEGF-A NF membrane and URB597 displayed positive synergistic neuroprotective effects through the inhibition of mitochondrial oxidative stress and activation of CB1R/PI3K/AKT/BDNF signaling, suggesting that a VEGF-A loaded NF membrane and the FAAH inhibitor URB597 could be of therapeutic value in ischemic cerebrovascular diseases.


Assuntos
Benzamidas/farmacologia , Carbamatos/farmacologia , Nanofibras/química , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Células Cultivadas , Endocanabinoides/metabolismo , Glucose/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Membranas Artificiais , Neurônios/metabolismo , Neurônios/patologia , Oxigênio/metabolismo , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/química
16.
J Dermatol Sci ; 102(2): 101-108, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33933312

RESUMO

BACKGROUND: REGγ acts as a proteasome activating factor mediating proteasome degradation of substrate proteins in an ATP and ubiquitination independent manner and also as an important regulator of cell cycle, proliferation and apoptosis. Hair cycle involves dynamic, continuous morphological changes of three stages (anagen, catagen and telogen). OBJECTIVE: The function of REGγ in hair cycling is still unclear. METHODS: Here, we used REGγ knockout 293 T cells, inducible 293WT and 293N151Y cell, REGγ knockout mice to identify the novel molecular mechanism of REGγ in regulating hair follicle stem cells. RESULTS: In the present study, we found that REGγ deletion markedly delayed the transition of hair follicles from telogen to anagen and hair regeneration in mice. We also observed significant decrease of hair follicle stem cell number, stem-like property and proliferation ability. Interestingly, the results from real-time PCR, FACS, Western Blot and immunofluorescent analysis showed that REGγ deletion could greatly downregulate Lgr5 expression in the hair follicles. Meanwhile, REGγ was demonstrated to directly interact with LHX2 and promotes its degradation. Importantly, REGγ specific deletion in Lgr5+ stem cells induced the marked delay of hair regeneration after depilation. CONCLUSION: These data together indicate that REGγ was a new mediator of Lgr5 expression in hair follicle at least partly by promoting the degradation of its suppressive transcription factor LHX2. It seemed that REGγ regulated hair anagen entry and hair regrowth by activating Lgr5 positive hair follicle stem cells.


Assuntos
Autoantígenos/metabolismo , Folículo Piloso/crescimento & desenvolvimento , Proteínas com Homeodomínio LIM/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Células-Tronco/fisiologia , Fatores de Transcrição/metabolismo , Animais , Apoptose/fisiologia , Autoantígenos/genética , Proliferação de Células/fisiologia , Técnicas de Silenciamento de Genes , Células HEK293 , Folículo Piloso/metabolismo , Humanos , Queratinócitos , Masculino , Camundongos , Camundongos Knockout , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/genética , Proteólise , Receptores Acoplados a Proteínas G/metabolismo , Regeneração/fisiologia , Regulação para Cima/fisiologia
17.
Aging (Albany NY) ; 13(9): 12378-12394, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33982668

RESUMO

Aging is a universal biological process characterized by a progressive deterioration in functional capacity and an increased risk of morbidity and mortality over time. In the lungs, there are considerable changes in lung structure and function with advancing age; however, research on the transcriptomic profile implicated in this process is scanty. In this study, we addressed the lung transcriptome changes during aging, through a global gene expression analysis of normal lungs of mice aged 4- and 18-months old. Functional pathway enrichment analysis by Ingenuity Pathway Analysis (IPA) revealed that the most enriched signaling pathways in aged mice lungs are involved in the regulation of cell apoptosis, senescence, development, oxidative stress, and inflammation. We also found 25 miRNAs significantly different in the lungs of old mice compared with their younger littermates, eight of them upregulated and 17 downregulated. Using the miRNet database we identified TNFα, mTOR, TGFß, WNT, FoxO, Apoptosis, Cell cycle, and p53 signaling pathways as the potential targets of several of the dysregulated miRNAs supporting that old lungs have increased susceptibility for apoptosis, inflammation, and fibrosis. These findings reveal differential expression profiles of genes and miRNAs affecting cell survival and the inflammatory response during lung aging.


Assuntos
Envelhecimento/metabolismo , Apoptose/fisiologia , Inflamação/metabolismo , Pulmão/metabolismo , Transcriptoma/fisiologia , Animais , Fibrose/metabolismo , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia
18.
Int J Biol Macromol ; 182: 1229-1237, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33991557

RESUMO

ß-Glucans are polysaccharides generally obtained from the cell wall of bacteria, fungi, yeasts, and aleurone layer of cereals. ß-Glucans are polymers, with ß-1,3 glucose as core linear structure, but they differ in their main branch length, linkages and branching patterns, giving rise to high and low-molecular-weight ß-glucans. They are well-known cell response modifiers with immune-modulating, nutraceutical and health beneficial effects, including anticancer and pro-apoptotic properties. ß-Glucan extracts have shown positive responses in controlling tumor cell proliferation and activation of the immune system. The immunomodulatory action of ß-glucans enhances the host's antitumor defense against cancer. In consonance with the above, many studies have shown that ß-glucan treatment leads to the induction of apoptotic death of cancer cells. The ability of ß-glucans to stimulate apoptotic pathways or the proteins involved in apoptosis prompting a new domain in cancer therapy. ß-glucan can be a potential therapeutic agent for the treatment of cancer. However, there is a need to legitimize the ß-glucan type, as most of the studies include ß-glucan from different sources having different physicochemical properties. The body of literature presented here focuses on the effects of ß-glucan on immunomodulation, proliferation, cell death and the possible mechanisms and pathways involved in these processes.


Assuntos
beta-Glucanas/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Humanos , Fatores Imunológicos/metabolismo , beta-Glucanas/química
19.
Toxicology ; 457: 152807, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33961949

RESUMO

Polybrominated diphenyl ethers (PBDEs) are world-wide used flame retardants before they were listed as Persistent Organic Pollutants (POPs) by the Stockholm Convention. Previously, our studies indicated that a quinone type of PBDE metabolite (PBDEQ) exposure was linked with neurotoxicity via excess free radical formation and oxidative stress. However, it is current unknown the effect of PBDEQ on genetic biomacromolecules DNA and corresponding biological consequences in neurological cells. Here, by employing phosphorylated histone H2AX in Serine 139 (γ-H2AX) and comet assay in microglia BV2 cells, our data suggested PBDEQ could triggered DNA damage. Furthermore, PBDEQ exposure led to the caspase 3-dependent cell apoptosis. Moreover, PBDEQ induced G2/M-phase cell arrest in a p53-dependent manner. Notably, p53 activation coordinated cell cycle progression, alleviated DNA damage and ultimately mitigated apoptosis in BV2 cells. Finally, antioxidant N-acetyl-l-cysteine (NAC) inhibited p53 activation upon PBDEQ exposure, and then ameliorated PBDEQ-induced DNA damage, cell cycle arrest and apoptosis, which illustrated that PBDEQ-induced DNA damage and p53 activation were mediated by reactive oxygen species (ROS). Together, the current findings unveil the fundamental toxicological mechanisms of PBDEQ, which propose a potential therapeutic strategy against the adverse effect caused by PBDE exposure.


Assuntos
Benzoquinonas/toxicidade , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Microglia/efeitos dos fármacos , Proteína Supressora de Tumor p53 , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Dano ao DNA/fisiologia , Relação Dose-Resposta a Droga , Camundongos , Microglia/metabolismo , Proteína Supressora de Tumor p53/metabolismo
20.
Methods Mol Biol ; 2256: 217-236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34014525

RESUMO

Viruses have evolved to interact with their hosts. Some viruses such as human papilloma virus, dengue virus, SARS-CoV, or influenza virus encode proteins including a PBM that interact with cellular proteins containing PDZ domains. There are more than 400 cellular protein isoforms with these domains in the human genome, indicating that viral PBMs have a high potential to influence the behavior of the cell. In this review we analyze the most relevant cellular processes known to be affected by viral PBM-cellular PDZ interactions including the establishment of cell-cell interactions and cell polarity, the regulation of cell survival and apoptosis and the activation of the immune system. Special attention has been provided to coronavirus PBM conservation throughout evolution and to the role of the PBMs of human coronaviruses SARS-CoV and MERS-CoV in pathogenesis.


Assuntos
Moléculas de Adesão Celular/metabolismo , Interações Hospedeiro-Patógeno , Proteínas Virais/metabolismo , Viroses/metabolismo , Vírus/metabolismo , Apoptose/fisiologia , Proliferação de Células/fisiologia , Humanos , Domínios PDZ , Ligação Proteica , Estrutura Secundária de Proteína , Viroses/virologia , Vírus/isolamento & purificação
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