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1.
PLoS One ; 15(8): e0234492, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790760

RESUMO

Endothelial injury is a common manifestation in IgA nephropathy (IgAN). After the previous identification of the upregulated soluble fms-like tyrosine kinase-1 (sFlt-1) correlated with endothelial injury in IgAN, in the present study, we further explored the role of sFlt-1 in endothelial injury in IgAN. We enrolled 72 patients with IgAN and detected the sFlt-1 levels. The polymeric IgA1 (pIgA1) complexes were isolated from the pooled plasma samples of another 10 patients with IgAN. Apoptosis proteins were detected in cultured human umbilical vein endothelial cells (HUVECs) with the stimulation of recombinant sFlt-1 or the caspase-9 inhibitor Z-LEHD-FMK. We identified there were positive correlations between sFlt-1 and IgA-IgG complex as well as vWF levels in patients with IgAN. The sFlt-1 levels in HUVECs were significantly upregulated by pIgA1 complex derived from IgAN patients in a concentration-dependent manner. The proliferation ability of HUVECs was damaged when stimulated with sFlt-1 protein in a time- and dose- dependent manner. And the apoptosis rate was up-regulated significantly as the stimulation concentrations of sFlt-1 increased. We found sFlt-1 challenge could significantly increase the expression of vWF. In addition, sFlt-1 increased the levels of caspase-9, caspase-3, Bax and mitochondrial membrane potential; facilitated the release of cytochrome C from mitochondria to cytoplasma. In contrast, Z-LEHD-FMK attenuated high sFlt-1-induced HUVECs apoptosis. In conclusion, our study demonstrated that sFlt-1 expression was up-regulated by the challenge of pIgA1 complex derived from patients with IgAN. Furthermore, increased sFlt-1 facilitated human umbilical vein endothelial cells apoptosis via the mitochondrial-dependent pathway.


Assuntos
Endotélio Vascular/fisiopatologia , Glomerulonefrite por IGA/fisiopatologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Adulto , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Caspase 9/efeitos dos fármacos , Inibidores de Caspase/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Feminino , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Oligopeptídeos/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto Jovem
3.
Life Sci ; 259: 118187, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32781061

RESUMO

AIMS: Voluntary exercise training has cardioprotective effects in humans, but the underlying mechanism is unknown. This research was done to estimate the effect of voluntary exercise training to attenuate middle-aged maturity-induced cardiac apoptosis. MATERIALS AND METHODS: The study was designed to divide 64 male mice randomly into four groups, consisting of a 9-month sedentary pre-middle-aged group (9M), 15-month sedentary middle-aged group (15M), and two exercise groups using a voluntary wheel running respectively (9M+EX, 15M+EX). After 3 months, the condition of cardiac apoptosis in different groups was measured by HE dying, TUNEL and DAPI staining, and Western Blot analysis. KEY FINDINGS: TUNEL-positive cells were increased in 15M group compared with 9M group, while decreased in 9M+EX and 15M+EX groups compared with their control groups respectively. Protein levels of AIF, Endo G, TNF-α, TNFR1, TRAF2, TRADD, Fas, FasL, FADD, activated caspase 8, 3, 9, Bax/Bcl2, Bak/BclxL, and tBid were decreased in 9M+EX and 15M+EX groups compared with their control groups respectively. The protein levels of pBad/Bad, 14-3-3, IGF1, IGFR1, pPI3K/PI3K, and pAKT/AKT were more activated in the 9M+EX and 15M+EX groups than those in their control groups respectively. Significant differences were found between 9M group and 15M group for the protein levels of TRAF2, FADD, Bax/Bcl2, tBid and pAKT/AKT. SIGNIFICANCE: Voluntary exercise training as an important lifestyle modification may prevent cardiac widely dispersed apoptosis and enhance cardiac survival at middle-aged maturity.


Assuntos
Envelhecimento/fisiologia , Apoptose/fisiologia , Coração/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/fisiologia , Músculo Esquelético/citologia , Músculo Esquelético/fisiologia , Corrida/fisiologia , Comportamento Sedentário
4.
J Environ Pathol Toxicol Oncol ; 39(2): 113-123, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749121

RESUMO

Liver cancer or hepatocellular carcinoma is considered to be the third leading cause of death among all other cancers. The rate of liver cancer occurrence is high, and the rate of recovery is low. In this study, we investigated the therapeutic efficacy of vicenin-2 against the diethylnitrosamine-induced liver carcinoma in experimental rats. Diethylnitrosamine was widely employed as a carcinogenic agent to stimulate the cancer in animal models. Our results indicated that vicenin-2 administration effectively attenuates the diethylnitrosamine-induced physiological and pharmacological alterations in the experimental rats. Vicenin-2 treatment significantly enhanced the pathological lesions and decreased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and α-fetoprotein (AFP) in serum. We also observed that vicenin-2 reduced the production of reactive oxygen species, decreased the liver weight, upregulated expression of apoptotic proteins, and decreased the histological changes in the liver, which are induced by the diethylnitrosamine in rats. Moreover, vicenin-2 downregulates antiapoptotic Bcl-2 and Bcl-xL, and upregulates the proapoptotic Bax and caspase. Hence, our results suggested that vicenin-2 had a highly therapeutic effect in reversing diethylnitrosamine-induced liver carcinoma in rats, which might be related to the apoptosis induced by vicenin-2. Therefore vicenin-2 could be a good candidate for future therapeutic use to inhibit chemically induced liver cancer.


Assuntos
Apigenina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Glucosídeos/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Biomarcadores Tumorais/sangue , Proteínas Sanguíneas/análise , Peso Corporal/efeitos dos fármacos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Dietilnitrosamina/toxicidade , Enzimas/sangue , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Soroglobulinas/análise
5.
J Environ Pathol Toxicol Oncol ; 39(2): 191-199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749127

RESUMO

We have proven that naringin, a phytonutrient, diminishes oxidative damage and inflammatory responses by modulating PPAR-γ expressions in ultraviolet-B radiation (UVB)-induced NIH-3T3 cells. However, the role of naringin against DNA damage, photoaging, and apoptosis in NIH-3T3 cells has yet to be studied, necessitating investigation. We show that Naringin pretreatment significantly reduces UVB-induced alkaline DNA damage and potentially modulates NER gene (XPC, TFIIH, XPE, ERCC1, and GAPDH) expression, thereby augmenting DNA repair. We determined experimentally that naringin pretreatment prevents UVB-induced nuclear fragmentation in NIH-3T3 cells, as well as altering UVB-induced apoptotic marker (Bax, BCl-2, Caspase-9, and Caspase-3) expression in them. In addition, naringin pretreatment inhibits UVB-stimulated matrix metalloproteinase (MMP-2, MMP-9 and MMP-13) expression in these 3T3 cells. Therefore, we report that naringin can effectively avert UVB-mediated DNA damage, photoaging, and apoptosis in NIH-3T3 cells.


Assuntos
Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Flavanonas/farmacologia , Raios Ultravioleta/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Apoptose/efeitos da radiação , Reparo do DNA/efeitos da radiação , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Camundongos , Células NIH 3T3 , Protetores contra Radiação/farmacologia , Envelhecimento da Pele/efeitos dos fármacos
6.
Nat Commun ; 11(1): 4071, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792491

RESUMO

Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in multiple sclerosis (MS) is associated with neurodegeneration and clinical worsening. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that Gsta4 loss impairs differentiation into myelinating OLs in vitro. In addition, we identify Gsta4 as a target of both dimethyl fumarate, an existing MS therapy, and clemastine fumarate, a candidate remyelinating agent in MS. Overexpression of Gsta4 reduces expression of Fas and activity of the mitochondria-associated Casp8-Bid-axis in adult oligodendrocyte precursor cells, leading to improved OL survival during differentiation. The Gsta4 effect on apoptosis during adult OL differentiation was corroborated in vivo in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis models, where Casp8 activity was reduced in Gsta4-overexpressing OLs. Our results identify Gsta4 as an intrinsic regulator of OL differentiation, survival and remyelination, as well as a potential target for future reparative MS therapies.


Assuntos
Glutationa Transferase/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Caspase 8/genética , Caspase 8/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glutationa Transferase/genética , Homeostase/genética , Homeostase/fisiologia , Imuno-Histoquímica , Masculino , Microglia/citologia , Microglia/metabolismo , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Fagocitose/genética , Fagocitose/fisiologia , Processamento de Proteína Pós-Traducional , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Remielinização/genética , Remielinização/fisiologia
7.
Free Radic Res ; 54(7): 477-496, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32842814

RESUMO

Smokeless tobacco (SLT) or chewing tobacco has been a highly addictive practice in India across ages, posing major threat to the systemic health and possibly neurodegeneration. Earlier studies showed components of SLT could be harmful to neuronal health. However, mechanism of SLT in neurodegeneration remained unexplored. This study investigated the detrimental role of SLT on differentiated neuronal cell lines, PC12 and SH-SY5Y by using graded doses of water soluble lyophilised SLT. Reduced cell viability, compromised mitochondrial structure and functions were observed when neuronal cell lines were treated with SLT (6 mg/mL) for 24 h. There was reduction of oxidative phosphorylation and aerobic glycolysis as determined by diminution of ATP production (2.5X) and basal respiration (1.9X). Mitochondrial membrane potential was dropped by 3.5 times. Bid, a pro-apoptotic Bcl-2 family protein, has imperative role in regulating mitochondrial outer membrane permeabilization and subsequent cytochrome c release leading to apoptosis. This article for the first time indicated the involvement of Bid in SLT mediated neurotoxicity and possibly neurodegeneration. SLT treatment enhanced expression of cleaved-Bid in time dependent manner. The involvement of Bid was further confirmed by using Bid specific shRNA which reversed the effects of SLT and conferred significant protection from apoptosis up to 72 h. Thus, our results clearly indicated that SLT induced neuronal cell death occurred via production of ROS, alteration of mitochondrial morphology, membrane potential and oxidative phosphorylation, inactivation of survival pathway and activation of apoptotic markers mediated by Bid. Therefore, Bid could be a potential future therapeutic target for SLT induced neurodegeneration.


Assuntos
Neurônios/patologia , Tabaco sem Fumaça/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Citocromos c/metabolismo , Dano ao DNA , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação Oxidativa , Células PC12 , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Proteína Supressora de Tumor p53/metabolismo
8.
Life Sci ; 258: 118225, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32771557

RESUMO

AIM: The aim of this study was considering the effects of taurine supplementation with combined aerobic and resistance training (CARE) on myocardial apoptosis and Protein Kinase B (akt) level changes in diabetic rat. MAIN METHODS: Forty male Wistar rats were randomly divided in to 5 groups of 8 animals in each: 1) control, 2) Diabetes Mellitus (DM), 3) DM with taurine supplementation (DM/T), 4) DM with CARE (DM/CARE), and 5) DM with combination of taurine and CARE (DM/T/CARE). DM was induced by injection of streptozotocin (STZ) and nicotine amid (NA) for 2, 3, 4 and 5 groups. Supplement groups received taurine in gavage, 100 mg/kg of body weight, 6 day per weeks, 8 weeks. CARE was performed at maximal speed and 1RM (40-60% of maximum for both). KEY FINDINGS: The results of this study showed that DM significantly increased blood glucose and caspase 3, caspase 9 expressions and apoptosis cells in heart tissue and reduced Akt expression (p < 0.001). However, taurine and CARE interventions significantly decreased apoptosis markers (caspase 3 and caspase 9) and significantly increased Akt in heart of diabetic rats compare to DM groups (p < 0.05). The highest improvement observed in DM/T/CARE group (p < 0.05). SIGNIFICANCE: Based on these results, it seems that the use of taurine with combined aerobic and exercise training minimize the cardiac damage caused by diabetes (especially apoptosis) trough increasing protein kinase Akt expression. This could improve cardiac remodeling after diabetes. However, more research is needed, especially on the human samples.


Assuntos
Apoptose/fisiologia , Diabetes Mellitus Experimental/metabolismo , Miocárdio/metabolismo , Condicionamento Físico Animal/fisiologia , Proteínas Proto-Oncogênicas c-akt/biossíntese , Taurina/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Terapia Combinada/métodos , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/terapia , Masculino , Miocárdio/patologia , Condicionamento Físico Animal/tendências , Distribuição Aleatória , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
9.
Gene ; 760: 144998, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32717304

RESUMO

The life cycle of holometabolous insects involves different stages and cathepsin plays an important role in insect metamorphosis. In the present study, we investigated the function of Bombyx mori cathepsin-L (Bm-CatL) during metamorphosis and analyzed their role in programmed cell death (PCD) of the fat body. The results showed that knockdown of Bm-CatL by RNA interference led to abnormal pupation and a delay in fat body degradation during metamorphosis. Furthermore, PCD inhibition was observed in the fat body after downregulation of Bm-CatL. To confirm this finding, PCD was induced in Bombyx mori embryonic (BmE) cells by ultraviolet ray irradiation. We found that the PCD of BmE cells was weakened after knocking down Bm-CatL. Moreover, overexpression of Bm-CatL in cells promoted PCD. Overall, our results showed that Bm-CatL is involved in the degradation of internal tissues and promotes the PCD of cells involved in the pupation of silkworms. Thus, this study provides us with a better understanding for function of cathepsin-L during metamorphosis.


Assuntos
Bombyx/fisiologia , Catepsina L/metabolismo , Tecido Adiposo/metabolismo , Animais , Apoptose/fisiologia , Bombyx/genética , Bombyx/metabolismo , Corpo Adiposo/metabolismo , Proteínas de Insetos/metabolismo , Metamorfose Biológica , Interferência de RNA
10.
Gene ; 760: 144991, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32717309

RESUMO

Breast cancer is the most frequently diagnosed cancer in women worldwide. Identifying reliable biomarkers and druggable molecular targets pose to be a significant quest in breast cancer research. p21-activated kinase 1 (PAK1) is a serine/threonine kinase that direct cell motility, cytoskeletal remodelling, and has been shown to function as a downstream regulator for various cancer signalling cascades that promote cell proliferation, apoptosis deregulation and hasten mitotic abnormalities, resulting in tumor formation and progression. The heterogeneity and acquired drug resistance are important factors that challenge the treatment of breast cancer. p21-activated kinase 1 signalling is crucial for activation of the Ras/RAF/MEK/ERK, PI3K/Akt/mTOR and Wnt signalling cascades which regulate cell survival, cell cycle progression, differentiation, and proliferation. A study involving proteogenomics analysis on breast cancer tissues showed the PAK1 as outlier kinase. In addition to this, few outlier molecules were identified specific to subtypes of breast cancer. A few substrates of PAK1 in breast cancer are already known. In this paper, we have discussed a similar approach called Kinase Interacting Substrate Screening (KISS) for the identification of novel oncogenic substrates of p21-activated kinase specific to subtypes of breast cancer. Such high throughput approaches are expected to accelerate the process of identifying novel drug targets and biomarkers.


Assuntos
Neoplasias da Mama/metabolismo , Quinases Ativadas por p21/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Feminino , Humanos , Transdução de Sinais , Quinases Ativadas por p21/genética
11.
Int Heart J ; 61(4): 806-814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32728001

RESUMO

This study aimed to explore the function of miR-24 in hypoxia/reoxygenation (H/R) -induced cardiomyocyte injury.We constructed a cardiomyocyte model of H/R using the primary cardiomyocytes isolated from Sprague-Dawley rats. To explore the role of miR-24, cells were transfected with a miR-24 mimic or miR-24 inhibitor. The RNA expression levels of miR-24 and Mapk14 were determined using qRT-PCR. The proliferation and apoptosis of cells were determined using a CCK8 assay and a flow cytometer. The TargetScan website was used to predict the targets of miR-24. A dual-luciferase reporter gene assay was conducted to verify whether Mapk14 is indeed a target of miR-24. A Western blot was applied for protein detection.H/R exposure decreased the expression of miR-24 in rat cardiomyocytes. Transfection of the miR-24 mimic into cardiomyocytes reduced H/R-induced injury as evidenced by an increase in proliferation and a decrease in the apoptotic rate. By contrast, transfection of the miR-24 inhibitor aggravated H/R-induced injury. The expression of Bcl-2 was increased while the levels of Bax and Active-caspase 3 were reduced in the H/R+miR-24 mimic group compared to those in the H/R group. H/R+miR-24 inhibitor group showed the opposite results. Mapk14 was identified as a target of miR-24. The mRNA level of Mapk14 and its protein (p38 MAPK) level were negatively affected by miR-24. Furthermore, we discovered that depletion of Mapk14 reduced the promoting effect of the miR-24 inhibitor on cell apoptosis.Overall, our results illustrated that miR-24 could attenuate H/R-induced injury partly by regulating Mapk14.


Assuntos
Hipóxia/metabolismo , MicroRNAs/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Apoptose/fisiologia , Caspase 3/metabolismo , Genes Reporter/genética , Genes bcl-2/genética , Humanos , Ratos , Ratos Sprague-Dawley , Transfecção/métodos , Proteína X Associada a bcl-2/metabolismo
12.
Braz J Med Biol Res ; 53(9): e9693, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32696821

RESUMO

Ischemic heart disease (IHD) is one of the leading causes of death worldwide. C-type lectin domain family 3 member B (CLEC3B) is a C-type lectin superfamily member and is reported to promote tissue remodeling. The serum levels of CLEC3B are downregulated in patients with cardiovascular disease. However, the molecular mechanisms of CLEC3B in IHD is not well-characterized. Therefore, we overexpressed CLEC3B and silenced CLEC3B in H9c2 rat cardiomyocytes for the first time. We then constructed a model of IHD in vitro through culturing H9c2 cardiomyocytes in serum-free medium under oxygen-deficit conditions. Then, Cell Counting Kit-8 (CCK-8), flow cytometry, qRT-PCR, and western blot assays were performed to investigate cell viability, apoptosis, and expression levels of CLEC3B, phosphatidylinositol 3-kinase (PI3K), phosphorylated PI3K (p-PI3K), protein kinase B (Akt), phosphorylated Akt (p-Akt), and cleaved-caspase 3. We observed that the mRNA expression of CLEC3B was decreased in hypoxic H9c2 cardiomyocytes (P<0.05). Overexpression of CLEC3B increased cell viability (P<0.01), inhibited cell apoptosis (P<0.05), upregulated the levels of p-PI3K/PI3K and p-Akt/Akt (P<0.01 or P<0.05), and downregulated expression of cleaved-caspase 3 (P<0.001) in hypoxic H9c2 cardiomyocytes while silencing of CLEC3B caused the opposite results. Inhibition of the PI3K/Akt pathway reversed the protective effect of CLEC3B on hypoxic H9c2 cardiomyocytes. Our study demonstrated that CLEC3B alleviated the injury of hypoxic H9c2 cardiomyocytes via the PI3K/Akt pathway.


Assuntos
Apoptose/fisiologia , Lectinas Tipo C/metabolismo , Animais , Humanos , Hipóxia , Miócitos Cardíacos/fisiologia , Fosfatidilinositol 3-Quinase , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais
13.
J Cancer Res Clin Oncol ; 146(10): 2439-2446, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32725355

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Alpha-fetoprotein (AFP) is considered as a diagnostic and prognostic tumorous marker for HCC, and up to 70% of HCC patients showed elevated serum levels of AFP. In the past two decades, evidences have shown that AFP not only is a tumorous biomarker for diagnosing HCC, but also plays a very complicated role in regulating proliferation, apoptosis, and autophagy and inhibiting the immune response of cells. Because AFP is significantly elevated during hepatocarcinogenesis, the role of AFP in the development of HCC is a scientific problem worthy of further exploration. In this review, we reviewed the effects of AFP on hepatocyte malignant transformation and the underlying mechanisms involved in the progression of HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , alfa-Fetoproteínas/metabolismo , Apoptose/fisiologia , Carcinoma Hepatocelular/genética , Transformação Celular Neoplásica , Progressão da Doença , Humanos , Neoplasias Hepáticas/genética , alfa-Fetoproteínas/biossíntese , alfa-Fetoproteínas/genética
14.
Life Sci ; 257: 118078, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663577

RESUMO

This study aimed to evaluate the modulatory role of sex-related hormone estradiol on cancer stem cells with the origin of colorectal adenocarcinoma in vitro. Cancer stem cells were incubated with 100 nM estradiol for 48 h. The cell survival rate was analyzed using the MTT assay. Immunocytochemistry staining of Ki-67 and Inhibin and Apoptosis PCR array were done to measure proliferation/apoptosis. Cell migration was monitored via the Transwell Migration assay. The expression of exosome biogenesis genes was measured using a real-time PCR assay. The fatty acid profile was monitored using gas chromatography. The level of FAK, SQSTM1, ER, and SIRT1 was examined using Western blotting. Cancer stem-endothelial cell interaction was investigated using Surface Plasmon Resonance assay. Data showed no significant differences in cancer stem cell viability and proliferation between control and estradiol-treated groups (p>0.05). PCR array highlighted the up-regulation of both pro- and anti-apoptosis effectors in the treatment group compared to the control cells (p<0.05). Cell migration capacity was increased after treatment with estradiol (p<0.001). Both exocytosis and exosome biogenesis were decreased in cancer stem cells exposed to estradiol (p<0.05). Data showed the reduction of palmitic acid, and increase of Palmitoleic and Linolenic acids in estradiol-treated cells. Estrogen induced estrogen receptor, SQSTM1 proteins and decreased SIRT1 factor after 48 h. Surface Plasmon Resonance revealed the suppression of cancer stem-endothelial cell interaction and affinity. Estradiol could change the migration, juxtacrine and paracrine activities of cancer stem cells, showing the importance of sex-related hormones in the dynamic of cancer development.


Assuntos
Neoplasias Colorretais/metabolismo , Células Endoteliais/metabolismo , Estradiol/metabolismo , Células-Tronco Neoplásicas/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Estradiol/farmacologia , Células HT29 , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Receptores Estrogênicos/metabolismo
15.
Nat Commun ; 11(1): 3520, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665551

RESUMO

PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains the activity of the PI3K/AKT/mTOR pathway and glycolysis in B-cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B-cell lymphomas and validate it as an attractive and previously unrecognized target in oncology.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Imunoprecipitação da Cromatina , Biologia Computacional , Proteínas de Ligação a DNA/genética , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Linfoma/genética , Linfoma/metabolismo , Camundongos , Camundongos SCID , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Distribuição Aleatória , Fatores de Transcrição/genética , Transcriptoma/genética
16.
Gene ; 761: 144971, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32707301

RESUMO

Diabetic nephropathy (DN) is a serious microvascular complication of diabetes across the world. Recently, many circular RNAs (circRNAs) can exert a crucial role in DN progression. Our investigation was designed to study whether circ_0123996 was associated with DN and aimed to find out the underlying mechanisms. We observed that circ_0123996 expression was significantly increased in Type 2 diabetes (T2D) with DN in comparison to those patients without DN. Consistently, circ_0123996 was also obviously elevated in DN mice models and high glucose (HG)-incubated MMCs. Then, it was proved transfection of circ_0123996 siRNA in mice mesangial cells (MMCs) restrained MMCs proliferation greatly. In addition, it was demonstrated that decrease of circ_0123996 alleviated fibrosis-related protein expression including FN and Col-4 in MMCs. Next, it was confirmed by our study that circ_0123996 can serve as a sponge for miR-149-5p. miR-149-5p has been identified in several diseases including diabetes. At present, we observed that miR-149-5p was decreased in DN. Overexpression of miR-149-5p greatly repressed the effect of circ_0123996 on MMCs. BTB and CNC homology 1 (Bach1) is reported in various disease including some vascular diseases.Here, Bach1 was confirmed as a target of miR-149-5p. Circ_0123996 upregulated Bach1 expression and restrained MMCs proliferation and fibrosis through sponging miR-149-5p. Thus, it was revealed that circ_0123996 was involved in DN via sponging miR-149-5p and modulating Bach1 expression.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/biossíntese , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Nefropatias Diabéticas/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , Adulto , Animais , Apoptose/fisiologia , Fatores de Transcrição de Zíper de Leucina Básica/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose/genética , Fibrose/metabolismo , Humanos , Masculino , Células Mesangiais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Circular/genética
17.
Life Sci ; 257: 118021, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621919

RESUMO

AIMS: Tribbles homolog 3 (TRIB3) is emerging as a multifunctional oncoprotein associated with various cellular events in different tumors. However, the regulatory mechanism of TRIB3 in acute myeloid leukemia (AML) remains unknown. This study aims to investigate the molecular mechanisms and uncover the functions of TRIB3 in AML. METHODS: Western blotting and quantitative real-time PCR were used to analyze the expression levels of TRIB3, peroxisome proliferator-activated receptor α (PPARα), apoptosis markers and autophagy markers in AML cells. Flow cytometry was used to assess cell apoptosis. The interaction of TRIB3 and PPARα was evaluated by immunofluorescence, coimmunoprecipitation, and in vivo ubiquitination assays. KEY FINDINGS: We demonstrated that downregulating TRIB3 in leukemic cells effectively induced apoptosis and autophagy by regulating the degradation of PPARα. Mechanistically, TRIB3 interacted with PPARα and contributed to its destabilization by promoting its ubiquitination. When PPARα was activated by its specific agonist clofibrate, the apoptosis and autophagy of AML cells were significantly enhanced. These results were confirmed by rescue experiments. Blocking PPARα expression using the PPARα inhibitor GW6471 reversed the functional influence of TRIB3 on AML cells. SIGNIFICANCE: The aim of this study is to provide evidence of the degradation of PPARα by TRIB3 via ubiquitin-dependent proteasomal degradation. This process meditates the progression of AML and prolongs the survival of leukemic cells. As a result, these data indicate that TRIB3 is a novel and promising therapeutic target for AML treatment.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Leucemia Mieloide Aguda/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Apoptose/fisiologia , Autofagia/fisiologia , Bases de Dados Genéticas , Humanos , Leucemia Mieloide Aguda/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteostase/fisiologia , Transdução de Sinais/fisiologia , Ubiquitina/metabolismo , Ubiquitinação
18.
Am J Physiol Cell Physiol ; 319(3): C579-C588, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32608990

RESUMO

Identification of specific biomarkers for ischemic stroke is necessary due to their abilities to improve treatment outcomes. Many studies have demonstrated the involvement of microRNAs (miRNAs) in the pathogenesis and complications of ischemic stroke and patient outcomes. We found that the expression of miR-874-3p was downregulated in clinical samples of ischemic stroke. Thus the present study explored the potential role of miR-874-3p in ischemic stroke and related mechanisms. A mouse model of ischemic stroke was constructed by middle cerebral artery occlusion. The relationship among miR-874-3p, C-X-C motif chemokine ligand 12 (CXCL12), and the Wnt/ß-catenin pathway was explored by dual luciferase reporter assay and Western blot analysis. Angiogenesis and brain tissue apoptosis were evaluated by immunofluorescence staining and TUNEL staining, respectively. ELISA was introduced to measure levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, IL-8, and IL-10 in brain tissues. Primary hippocampal neuronal cells were isolated from the mouse model of ischemic stroke and incubated with human umbilical vein endothelial cells (HUVECs) for HUVEC tube formation. High expression of CXCL12 and low expression of miR-874-3p were confirmed in ischemic stroke. In addition, miR-874-3p was found to target and downregulate CXCL12, thus reducing TNF-α, IL-1, IL-6, and IL-8 levels, but enhancing IL-10 level. Collectively, upregulating miR-874-3p inhibits CXCL12 expression to promote angiogenesis and inhibit inflammation in ischemic stroke mice by activating the Wnt/ß-catenin pathway, which may provide a new direction of ischemic stroke treatment.


Assuntos
Quimiocina CXCL12/metabolismo , Inflamação/metabolismo , MicroRNAs/genética , Acidente Vascular Cerebral/metabolismo , Animais , Apoptose/fisiologia , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Camundongos , Neurônios/metabolismo , Acidente Vascular Cerebral/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
19.
Am J Physiol Cell Physiol ; 319(3): C510-C532, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32667864

RESUMO

Neutrophils are polymorphonuclear leukocytes that play a central role in host defense against infection and tissue injury. They are rapidly recruited to the inflamed site and execute a variety of functions to clear invading pathogens and damaged cells. However, many of their defense mechanisms are capable of inflicting collateral tissue damage. Neutrophil-driven inflammation is a unifying mechanism underlying many common diseases. Efficient removal of neutrophils from inflammatory loci is critical for timely resolution of inflammation and return to homeostasis. Accumulating evidence challenges the classical view that neutrophils represent a homogeneous population and that halting neutrophil influx is sufficient to explain their rapid decline within inflamed loci during the resolution of protective inflammation. Hence, understanding the mechanisms that govern neutrophil functions and their removal from the inflammatory locus is critical for minimizing damage to the surrounding tissue and for return to homeostasis. In this review, we briefly address recent advances in characterizing neutrophil phenotypic and functional heterogeneity and the molecular mechanisms that determine the fate of neutrophils within inflammatory loci and the outcome of the inflammatory response. We also discuss how these mechanisms may be harnessed as potential therapeutic targets to facilitate resolution of inflammation.


Assuntos
Apoptose/fisiologia , Homeostase/fisiologia , Inflamação/metabolismo , Neutrófilos/citologia , Animais , Fatores Celulares Derivados do Hospedeiro/metabolismo , Humanos , Fenótipo
20.
Proc Natl Acad Sci U S A ; 117(31): 18771-18779, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32690704

RESUMO

Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of intrinsic, innate, and adaptive viral immune evasion. Here, we employed multiplexed tandem mass tag-based proteomics to characterize host proteins targeted for degradation late during HCMV infection. This approach revealed that mixed lineage kinase domain-like protein (MLKL), a key terminal mediator of cellular necroptosis, was rapidly and persistently degraded by the minimally passaged HCMV strain Merlin but not the extensively passaged strain AD169. The strain Merlin viral inhibitor of apoptosis pUL36 was necessary and sufficient both to degrade MLKL and to inhibit necroptosis. Furthermore, mutation of pUL36 Cys131 abrogated MLKL degradation and restored necroptosis. As the same residue is also required for pUL36-mediated inhibition of apoptosis by preventing proteolytic activation of procaspase-8, we define pUL36 as a multifunctional inhibitor of both apoptotic and necroptotic cell death.


Assuntos
Apoptose/fisiologia , Citomegalovirus , Necroptose/fisiologia , Proteínas Virais/metabolismo , Células Cultivadas , Citomegalovirus/química , Citomegalovirus/metabolismo , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/virologia , Humanos , Ligação Proteica , Proteólise
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