RESUMO
Glomerulonephritis (GN) is the most common cause of end-stage renal failure worldwide; in most cases, it cannot be cured and can only delay the progression of the disease. At present, the main treatment methods include symptomatic therapy, immunosuppressive therapy, and renal replacement therapy. However, effective treatment of GN is hindered by issues such as steroid resistance, serious side effects, low bioavailability, and lack of precise targeting. With the widespread application of nanoparticles in medical treatment, novel methods have emerged for the treatment of kidney diseases. Targeted transportation of drugs, nucleic acids, and other substances to kidney tissues and even kidney cells through nanodrug delivery systems can reduce the systemic effects and adverse reactions of drugs and improve treatment effectiveness. The high specificity of nanoparticles enables them to bind to ion channels and block or enhance channel gating, thus improving inflammation. This review briefly introduces the characteristics of GN, describes the treatment status of GN, systematically summarizes the research achievements of nanoparticles in the treatment of primary GN, diabetic nephropathy and lupus nephritis, analyzes recent therapeutic developments, and outlines promising research directions, such as gas signaling molecule nanodrug delivery systems and ultrasmall nanoparticles. The current application of nanoparticles in GN is summarized to provide a reference for better treatment of GN in the future.
Assuntos
Nefropatias Diabéticas , Glomerulonefrite , Nefrite Lúpica , Humanos , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/metabolismo , Rim/metabolismo , NanotecnologiaRESUMO
Previous studies have shown that puerarin plays a key role in protecting humans and animals from cardiovascular diseases. The exact mechanism of the therapeutic effect of puerarin on various cardiovascular diseases (protective effect on cardiomyocytes) is still unclear. In the present study, we identify the role of puerarin in an animal model of experimental heart failure (HF) and explore its underlying mechanisms. The HF rat model is induced by intraperitoneal injection of adriamycin (ADR), and puerarin is administered intragastrically at low, medium, and high concentrations. We demonstrate that puerarin significantly improves myocardial fibrosis and inflammatory infiltration and, as a result, improves cardiac function in ADR-induced HF rats. Mechanistically, we find for the first time that puerarin inhibits overactivated Na +/H + exchange isoform 1 (NHE1) in HF, which may improve HF by decreasing Na + and Ca 2+ ion concentrations and attenuating mitochondrial damage caused by calcium overload; on the other hand, puerarin inhibits the activation of the p38 pathway in HF, reduces the expressions of TGF-ß and proinflammatory cytokines, and suppresses myocardial fibrosis. In conclusion, our results suggest that Puerarin is an effective drug against HF and may play a protective role in the myocardium by inhibiting the activation of p38 and its downstream NHE1.
Assuntos
Cardiomiopatias , Doenças Cardiovasculares , Insuficiência Cardíaca , Isoflavonas , Animais , Ratos , Cálcio/metabolismo , Cardiomiopatias/metabolismo , Doenças Cardiovasculares/metabolismo , Fibrose , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismoRESUMO
The role of m6A in ankylosing spondylitis (AS) remains largely obscure. In this study, we found that m6A modification was decreased in T cells of AS, and the abnormal m6A modification was attributed to the downregulation of methyltransferase-like 14 (METTL14). METTL14 exerted a critical role in regulating autophagy activity and inflammation via targeting Forkhead box O3a (FOXO3a). Mechanistically, the loss of METTL14 decreased the expression of FOXO3a, leading to the damage of autophagic flux and the aggravation of inflammation. Inversely, the forced expression of METTL14 upregulated the expression of FOXO3a, thereby activating autophagy and alleviating inflammation. Furthermore, our results revealed that METTL14 targeted FOXO3a mRNA and regulated its expression and stability in a m6A-dependent manner. These findings uncovered the functional importance of m6A methylation mechanisms in the regulation of autophagy and inflammation, which expanded our understanding of this interaction and was critical for the development of therapeutic strategies for AS.
Assuntos
Adenina , Autofagia , Proteína Forkhead Box O3 , Inflamação , Metiltransferases , Espondilite Anquilosante , Humanos , Adenina/metabolismo , Autofagia/genética , Inflamação/genética , Metiltransferases/genética , Espondilite Anquilosante/genética , Espondilite Anquilosante/patologia , Proteína Forkhead Box O3/metabolismoRESUMO
The proton-coupled folate transporter (PCFT, SLC46A1) is required for folate intestinal absorption and transport across the choroid plexus. Recent work has identified a F392V mutation causing hereditary folate malabsorption. However, the residue properties responsible for this loss of function remains unknown. Using site-directed mutagenesis, we observed complete loss of function with charged (Lys, Asp, and Glu) and polar (Thr, Ser, and Gln) Phe-392 substitutions and minimal function with some neutral substitutions; however, F392M retained full function. Using the substituted-cysteine accessibility method (with N-biotinyl aminoethyl methanethiosulfonate labeling), Phe-392 mutations causing loss of function, although preserving membrane expression and trafficking, also resulted in loss of accessibility of the substituted cysteine in P314C-PCFT located within the aqueous translocation pathway. F392V function and accessibility of the P314C cysteine were restored by insertion of a G305L (suppressor) mutation. A S196L mutation localized in proximity to Gly-305 by homology modeling was inactive. However, when inserted into the inactive F392V scaffold, function was restored (mutually compensatory mutations), as was accessibility of the P314C cysteine residue. Reduced function, documented with F392H PCFT, was due to a 15-fold decrease in methotrexate influx Vmax, accompanied by a decreased influx Kt (4.5-fold) and Ki (3-fold). The data indicate that Phe-392 is required for rapid oscillation of the carrier among its conformational states and suggest that this is achieved by dampening affinity of the protein for its folate substrates. F392V and other inactivating Phe-392 PCFT mutations lock the protein in its inward-open conformation. Reach (length) and hydrophobicity of Phe-392 appear to be features required for full activity.
Assuntos
Transportador de Folato Acoplado a Próton/metabolismo , Sequência de Aminoácidos , Animais , Transporte Biológico , Cisteína/química , Cisteína/metabolismo , Deficiência de Ácido Fólico/patologia , Células HeLa , Humanos , Cinética , Síndromes de Malabsorção/patologia , Metotrexato/metabolismo , Mutagênese Sítio-Dirigida , Estrutura Terciária de Proteína , Transportador de Folato Acoplado a Próton/química , Transportador de Folato Acoplado a Próton/genéticaRESUMO
Depression is the most significant risk factor for suicide, yet the causes are complex and disease mechanism remains unclear. The incidence and disability rate of depression are very high and the efficacy of some traditional antidepressants is not completely satisfactory. Recently, some studies have found that benzofurans have anti-oxidation and anti-monoamine oxidase properties, which are related to depression. Euparin is a monomer compound of benzofuran, previous work by our team found that it improves the behavior of depressed mice. However, additional antidepressant effects and mechanisms of Euparin have not been reported. In this study, the Chronic Unpredictable Mild Stress (CUMS) model of mice was used to further investigate the effect and mechanism of Euparin on depression. Results showed that Euparin (8, 16 and 32 mg/kg) reduced depression-like behavior in mice compared with the model group. Meanwhile, all doses of Euparin were found to increase the contents of monoamine neurotransmitter and decrease monoamine oxidase and reactive oxygen species (ROS) levels in brain of depression mice. Additionally, Euparin restored CUMS-induced decrease of Spermidine/Spermine N1-Acetyltransferase 1 (SAT1), N-methyl-D-aspartate receptor subtype 2B (NMDAR2B) and brain derived neurotrophic factor (BDNF) expression. These findings demonstrate that Euparin has antidepressant properties, and its mechanism involves the SAT1/NMDAR2B/BDNF signaling pathway.
Assuntos
Benzofuranos/farmacologia , Depressão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/complicações , Acetiltransferases/metabolismo , Animais , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Benzofuranos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/diagnóstico , Depressão/patologia , Depressão/psicologia , Modelos Animais de Doenças , Dopamina , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Serotonina/metabolismo , Organismos Livres de Patógenos Específicos , Estresse Psicológico/psicologiaRESUMO
PURPOSE: The aim of this study was to analyze the radiological features of peripheral primitive neuroectodermal tumor (pPNET). MATERIALS AND METHODS: The radiological and clinical findings for 16 patients with pPNETs were retrospectively reviewed. The 16 tumors were classified into 4 groups (meninges group, n = 4; spine group, n = 3; bone group, n = 5; soft-tissue group, n = 4), and clinical data, size, and common and unique CT/MRI characteristics were assessed. RESULTS: Peripheral primitive neuroectodermal tumors presented as large solid masses with aggressive extension into the neighboring tissue. Most tumors (11/16) presented with necrosis, and 5 of the 16 cases showed signs of hemorrhage. The "dural tail sign" was observed in the meninges and spine groups. The pPNETs of bone demonstrated bony destruction with spiculated periosteal reaction, and small nourishing vessels were found in tumors in the soft-tissue group. CONCLUSIONS: Peripheral primitive neuroectodermal tumor should be suggested as an important differential diagnosis when the tumor presents as a large, ill-defined solid mass with aggressive extension and significant enhancement.
Assuntos
Imageamento por Ressonância Magnética/métodos , Tumores Neuroectodérmicos Primitivos Periféricos/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and high mortality rate. Panax Notoginseng Saponins (PNS), extracted from Panax Notoginseng as a traditional Asian medicine, displayed a significant anti-fibrosis effect in liver and lung. However, whether Ginsenoside Rg1 (Rg1), an important and active ingredient of PNS, exerts anti-fibrotic activity on IPF still remain unclear. In this study, we investigated the effect of Rg1 on bleomycin-induced pulmonary fibrosis in rats. Bleomycin (5 mg/kg body weight) was intratracheally administrated to male rats. Rg1 (18, 36 and 72 mg/kg) was orally administered on the next day after bleomycin. Lungs were harvested at day 7 and 28 for the further experiments. Histological analysis revealed that bleomycin successfully induced pulmonary fibrosis, and that Rg1 restored the histological alteration of bleomycin-induced pulmonary fibrosis (PF), significantly decreased lung coefficient, scores of alveolitis, scores of PF as well as contents of alpha smooth muscle actin (α-SMA) and hydroxyproline (Hyp) in a dose-dependent manner in PF rats. Moreover, Rg1 increased the expression levels of Caveolin-1 (Cav-1) mRNA and protein, lowered the expression of transforming growth factor-ß1 (TGF-ß1) mRNA and protein in the lung tissues of PF rats. These data suggest that Rg1 exhibits protective effect against bleomycin-induced PF in rats, which is potentially associated with the down-regulation of TGF-ß1 and up-regulation of Cav-1.
Assuntos
Caveolina 1/metabolismo , Ginsenosídeos , Substâncias Protetoras , Fibrose Pulmonar/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo , Actinas/metabolismo , Animais , Bleomicina , Caveolina 1/genética , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Hidroxiprolina/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genéticaRESUMO
Papillary renal cell carcinoma (PRCC) is a highly heterogeneous cancer, and PRCC patients with advanced/metastatic subgroup showed obviously shorter survival compared to other kinds of renal cell carcinomas. However, the molecular mechanism and prognostic predictors of PRCC remain unclear and are worth deep studying. The aim of this study is to identify novel molecular classification and construct a reliable prognostic model for PRCC. The expression data were retrieved from TCGA, GEO, GTEx and TARGET databases. CRISPR data was obtained from Depmap database. The key genes were selected by the intersection of CRISPR-Cas9 screening genes, differentially expressed genes, and genes with prognostic capacity in PRCC. The molecular classification was identified based on the key genes. Drug sensitivity, tumor microenvironment, somatic mutation, and survival were compared among the novel classification. A prognostic model utilizing multiple machine learning algorithms based on the key genes was developed and tested by independent external validation set. Our study identified three clusters (C1, C2 and C3) in PRCC based on 41 key genes. C2 had obviously higher expression of the key genes and lower survival than C1 and C3. Significant differences in drug sensitivity, tumor microenvironment, and mutation landscape have been observed among the three clusters. By utilizing 21 combinations of 9 machine learning algorithms, 9 out of 41 genes were chosen to construct a robust prognostic signature, which exhibited good prognostic ability. SERPINH1 was identified as a critical gene for its strong prognostic ability in PRCC by univariate and multiple Cox regression analyses. Quantitative real-time PCR and Western blot demonstrated that SERPINH1 mRNA and protein were highly expressed in PRCC cells compared with normal human renal cells. This study exhibited a new molecular classification and prognostic signature for PRCC, which may provide a potential biomarker and therapy target for PRCC patients.
RESUMO
Liver disease is a severe public health concern worldwide. There is a close relationship between the liver and cytokines, and liver inflammation from a variety of causes leads to the release and activation of cytokines. The functions of cytokines are complex and variable, and are closely related to their cellular origin, target molecules and mode of action. Interleukin (IL)-20 has been studied as a pro-inflammatory cytokine that is expressed and regulated in some diseases. Furthermore, accumulating evidences has shown that IL-20 is highly expressed in clinical samples from patients with liver disease, promoting the production of pro-inflammatory molecules involved in liver disease progression, and antagonists of IL-20 can effectively inhibit liver injury and produce protective effects. This review highlights the potential of targeting IL-20 in liver diseases, elucidates the potential mechanisms of IL-20 inducing liver injury, and suggests multiple viable strategies to mitigate the pro-inflammatory response to IL-20. Genomic CRISPR/Cas9-based screens may be a feasible way to further explore the signaling pathways and regulation of IL-20 in liver diseases. Nanovector systems targeting IL-20 offer new possibilities for the treatment and prevention of liver diseases.
RESUMO
Human decidual natural killer (dNK) cells are a unique type of tissue-resident NK cells at the maternal-fetal interface. dNK cells are likely to have pivotal roles during pregnancy, including in maternal-fetal immune tolerance, trophoblast invasion, and fetal development. However, detailed insights into these cells are still lacking. In this study, we performed metabolomic and proteomic analyses on human NK cells derived from decidua and peripheral blood. We found that 77 metabolites were significantly changed in dNK cells. Notably, compared to peripheral blood NK (pNK) cells, 29 metabolites involved in glycerophospholipid and glutathione metabolism were significantly decreased in dNK cells. Moreover, we found that 394 proteins were differentially expressed in dNK cells. Pathway analyses and network enrichment analyses identified 110 differentially expressed proteins involved in focal adhesion, cytoskeleton remodeling, oxidoreductase activity, and fatty acid metabolism in dNK cells. The integrated proteomic and metabolomic analyses revealed significant downregulation in glutathione metabolism in dNK cells compared to pNK cells. Our data indicate that human dNK cells have unique metabolism and protein-expression features, likely regulating their function in pregnancy and immunity.
Assuntos
Células Matadoras Naturais , Proteômica , Gravidez , Feminino , Humanos , Regulação para Baixo , Glutationa/metabolismoRESUMO
The long non-coding RNA, maternally expressed gene 3 (MEG3), are involved in myocardial fibrosis and compensatory hypertrophy, but its role on cardiomyocyte apoptosis and autophagy in heart failure (HF) remains unclear. The aim of this study was to investigate the effect of MEG3 on cardiomyocyte apoptosis and autophagy and the underlying mechanism. A mouse model of HF was established by subcutaneous injection of isoproterenol (ISO) for 14 days, and an in vitro oxidative stress injury model was replicated with H2O2 for 6â h. SiRNA-MEG3 was administered in mice and in vitro cardiomyocytes to knock down MEG3 expression. Our results showed that cardiac silencing of MEG3 can significantly ameliorate ISO-induced cardiac dysfunction, hypertrophy, oxidative stress, apoptosis, excessive autophagy and fibrosis induced by ISO. In addition, inhibition of MEG3 attenuated H2O2-induced cardiomyocyte oxidative stress, apoptosis and autophagy in vitro. Downregulation of MEG3 significantly inhibited excessive cardiomyocyte apoptosis and autophagy induced by ISO and H2O2 through miRNA-129-5p/ATG14/Akt signaling pathways, and reduced H2O2-induced cardiomyocyte apoptosis by inhibiting autophagy. In conclusion, inhibition of MEG3 ameliorates the maladaptive cardiac remodeling induced by ISO, probably by targeting the miRNA-129-5p/ATG14/Akt signaling pathway and may provide a tool for pharmaceutical intervention.
Assuntos
Insuficiência Cardíaca , MicroRNAs , RNA Longo não Codificante , Animais , Camundongos , Apoptose/genética , Autofagia/genética , Insuficiência Cardíaca/genética , Peróxido de Hidrogênio/farmacologia , Hipertrofia/metabolismo , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genéticaRESUMO
The problem-based learning (PBL) is increasingly used in undergraduate education. However, the application of integrated PBL to medical undergraduate education has not been well assessed. An observational study was designed to compare integrated PBL combined with lecture-based classroom (LBC) with traditional LBC teaching in 2 semesters of a Medical School in China. This study was conducted from March 2021 to July 2022. A total of 118 undergraduates majoring in clinical medicine were randomly allocated in 2 groups, 1 group receiving the integrated PBL + LBC teaching (experimental group, n = 60) and another group receiving LBC teaching (control group, n = 58). The experimental group attended the integrated PBL courses for the basic and clinical medicine conducted in the 6th and 8th semesters, respectively, as well as taking the LBC courses. The experimental group was required to preview the course materials before class, make presentations in class and take online feedback questionnaires after class, while the control group was required to preview the textbooks and listen to the traditional LBC courses. The students' scores of these 2 groups were compared, and feedback questionnaires were performed to evaluate the effectiveness of the experimental group over the control group. Results showed that the experimental group scored significantly higher than the control group in Clinical Skills (95% confidence interval [CI] 4.19-5.89), Internal Medicine I (95% CI: 1.85-9.93), Internal Medicine II (95% CI: 8.07-15.90), Introduction to Surgery (95% CI: 5.08-10.25), Surgery (General Surgery) (95% CI: 7.82-12.72), Surgery (Specialty) (95% CI: 6.47-9.97), and Clinical Medical Level Test (95% CI: 1.60-5.15) (all P < .01). In the feedback questionnaires of integrated PBL, up to 80% and 90% of students were satisfied with the teaching methods and lecturers, respectively. More than 80% of students agreed that the integrated PBL improved their abilities to learn independently, understand knowledge, and to raise, analyze and solve problems. In terms of stress in and out of class, a small number of students, <36.7%, felt stressed. The integrated PBL combined with LBC is an effective teaching approach, which may provide new ideas for teaching research and reform on undergraduate medical education in clinical medicine specialty and other medical majors.
Assuntos
Educação de Graduação em Medicina , Aprendizagem Baseada em Problemas , Humanos , Faculdades de Medicina , China , Medicina InternaRESUMO
Vascular dementia (VD) is one of the most common causes of dementia, taking account for about 20% of all cases. Although studies have found that selenium supplementation can improve the cognitive ability of Alzheimer's patients, there is currently no research on the cognitive impairment caused by VD. This study aimed to investigate the role and mechanism of Amorphous selenium nanodots (A SeNDs) in the prevention of VD. The bilateral common carotid artery occlusion (BCCAO) method was used to establish a VD model. The neuroprotective effect of A SeNDs was evaluated by Morris water maze, Transcranial Doppler TCD, hematoxylin-eosin (HE) staining, Neuron-specific nuclear protein (Neu N) staining and Golgi staining. Detect the expression levels of oxidative stress and Calcium-calmodulin dependent protein kinase II (CaMK II), N-methyl-D-aspartate receptor subunit NR2A, and postsynaptic dense protein 95 (PSD95). Finally, measure the concentration of calcium ions in neuronal cells. The results showed that A SeNDs could significantly improve the learning and memory ability of VD rats, restore the posterior arterial blood flow of the brain, improve the neuronal morphology and dendritic remodeling of pyramidal cells in hippocampal CA1 area, reduce the level of oxidative stress in VD rats, increase the expression of NR2A, PSD95, CaMK II proteins and reduce intracellular calcium ion concentration, but the addition of selective NR2A antagonist NVP-AAMO77 eliminated these benefits. It suggests that A SeNDs may improve cognitive dysfunction in vascular dementia rats by regulating the NMDAR pathway.
Assuntos
Demência Vascular , Selênio , Ratos , Animais , Demência Vascular/tratamento farmacológico , Demência Vascular/metabolismo , Selênio/farmacologia , Selênio/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Cálcio/metabolismo , Estresse Oxidativo , Hipocampo , Neurônios/metabolismo , Aprendizagem em LabirintoRESUMO
Diabetic cardiomyopathy (DCM) is a kind of idiopathic heart disease, which is one of the main complications of diabetes and seriously threatens the life of diabetic patients. Rubiadin, an anthraquinone compound extracted from the stems and roots of rubiaceae, has been widely discussed for its anti-diabetes, anti-oxidation and other pharmacological effects. However, Rubiadin can cause drug-induced liver injury. Therefore, A-cycloglycosylated derivative of Rubiadin (ACDR) was obtained by modifying its structure. The purpose of this study was to investigate the effect of ACDR on DCM cardiac injury and its mechanism. The DCM animal model was established by streptozotocin, and the success of DCM was verified by blood glucose level, echocardiographic evidence of impaired myocardial functions along with enhanced myocardial fibrosis. We performed liver function tests, morphological staining of the heart and tests for oxidative stress to evaluate cardiac functional and structural changes. Finally, the expression of Na+/H+ exchanger (NHE1) protein was analyzed by immunohistochemistry and western bolt, and the expression of hairy/enhancer-of-split related with YRPW motif 1 (Hey1) and P-p38 protein was detected by immunofluorescence chemistry and western blotting. The results showed that ACDR can improve cardiac dysfunction, reduce myocardial injury, reduce oxidative stress, and protect the liver in DCM rats. Interestingly, all variations were countered by LiCl. Our study suggests that, along with controlling hyperglycemia, ACDR may improve DCM by reducing NHE1 expression, further inhibiting P-p38 activity and increasing Hey1 expression to reduce oxidative stress.
Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Ratos , Animais , Cardiomiopatias Diabéticas/etiologia , Diabetes Mellitus Experimental/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Antraquinonas/farmacologiaRESUMO
Sorafenib (Sor), a novel multi-target anticancer drug also induces severe toxicity in heart, while the mechanism of its cardiotoxicity remains to be fully elucidated. Dysregulation of autophagy and mitochondrial dynamics imbalance have been implicated in cardiomyocyte death. The aim of this study is to test the hypothesis that Sor disrupts autophagy and mitochondrial dynamics, thereby aggravating Sor-induced oxidative stress damage to cardiomyocytes. Our results revealed that Sor (≥ 5 µM) concentration- and time-dependently reduced cell viability and induced apoptosis in H9c2 myoblasts. Sor treatment promoted intracellular reactive oxygen species (ROS) generation, and subsequent Ca2+ overload as well as apoptosis, which were abolished by the ROS scavenger MPG. Sor inhibited the basal autophagy activity of cells, as supported by the fact that ERK1/2 inhibition-dependent decreases of autophagosomes and autolysosomes, and p62 accumulation in a concentration- and time-dependent manner. Improving autophagy with rapamycin abrogated Sor-induced ROS and Ca2+ overloads, and cell apoptosis. Furthermore, Sor compromised mitochondrial morphology and caused excessive mitochondrial fragmentation in cells. The imbalance of mitochondrial dynamics was attributed to ROS-mediated CaMKII overactivity, and increased phosphorylation of dynamin-related protein 1 (phosph-Drp1). Suppression of CaMKII with KN-93 or mitochondrial fission with mitochondrial division inhibitor-1 (Mdivi-1) attenuated Sor-induced ROS and Ca2+ overloads as well as apoptosis. In conclusion, these results provide the first evidence that impairments in autophagy and mitochondrial dynamics are involved in Sor-induced cardiomyocyte apoptosis. The present study may provide a potential strategy for preventing or reducing cardiotoxicity of Sor.
Assuntos
Dinâmica Mitocondrial , Miócitos Cardíacos , Humanos , Sorafenibe/toxicidade , Sorafenibe/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Miócitos Cardíacos/metabolismo , Cardiotoxicidade/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dinaminas/metabolismo , Apoptose , AutofagiaRESUMO
Doxorubicin (DOX), a broad-spectrum anti-tumor drug, has severe cardiotoxic side effects that limit its clinical application. Perillaldehyde (PAE) is the main component of volatile oil extracted from the stems and leaves of Herbaceous plant-perilla, which demonstrates antioxidant, anti-inflammatory, hypolipidemic, and other health functions. The present study aimed to explore the protective effect of perillaldehyde on DOX-induced cardiotoxicity in rats and to confirm its possible mechanism. The results showed that PAE could significantly improve cardiac function, alleviate myocardial fibrosis, and attenuate oxidative stress and inflammatory responses in DOX-induced cardiotoxicity in rats. Mechanistically, PAE could DOX-induced cardiotoxicity, which is related to its regulation of the PI3K/Akt signaling pathway and inhibition of NHE1 phosphorylation. Therefore, the finding demonstrates that perillaldehyde may be a promising cardioprotective agent for the prevention and treatment of cardiotoxicity caused by DOX.
Assuntos
Cardiotoxicidade , Proteínas Proto-Oncogênicas c-akt , Ratos , Animais , Cardiotoxicidade/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Doxorrubicina/efeitos adversos , Estresse Oxidativo , Apoptose , Miócitos Cardíacos/metabolismoRESUMO
In type 2 diabetes mellitus (T2DM), oxidative stress induces endothelial dysfunction (ED), which is closely related to the formation of atherosclerosis. However, there are few effective drugs to prevent and cure it. Citronellal (CT) is an aromatic active substance extracted from citronella plants. Recently, CT has been shown to prevent ED, but the underlying mechanism remains unclear. The purpose of this study was to investigate whether CT ameliorated T2DM-induced ED by inhibiting the TRPM2/NHE1 signal pathway. Transient receptor potential channel M2 (TRPM2) is a Ca2+-permeable cation channel activated by oxidative stress, which damages endothelial cell barrier function and further leads to ED or atherosclerosis in T2DM. The Na+/H+ exchanger 1 (NHE1), a transmembrane protein, also plays an important role in ED. Whether TRPM2 and NHE1 are involved in the mechanism of CT improving ED in T2DM still needs further study. Through the evaluations of ophthalmoscope, HE and Oil red staining, vascular function, oxidative stress level, and mitochondrial membrane potential evaluation, we observed that CT not only reduced the formation of lipid deposition but also inhibited ED and suppressed oxidative stress-induced mitochondrial damage in vasculature of T2DM rats. The expressions of NHE1 and TRPM2 was up-regulated in the carotid vessels of T2DM rats; NHE1 expression was also upregulated in endothelial cells with overexpression of TRPM2, but CT reversed the up-regulation of NHE1 in vivo and in vitro. In contrast, CT had no inhibitory effect on the expression of NHE1 in TRPM2 knockout mice. Our study show that CT suppressed the expression of NHE1 and TPRM2, alleviated oxidative stress-induced mitochondrial damage, and imposed a protective effect on ED in T2DM rats.
RESUMO
This study is to investigate the effect of the major chemical composition in rhizome of Pterocypsela elata, lactuside B, on expression of bcl-2, bax mRNA and their protein in rats' cerebral cortex after cerebral ischemia-reperfusion injury. First, middle cerebral artery ischemia-reperfusion injury model was established, and each group was treated with the corresponding medicines. Animals were separately sacrificed at 24 h and 72 h. The brain infarct volumes were detected by TTC dye, bcl-2 and bax mRNA expression was checked by RT-PCR, and the proteins of bcl-2 and bax were explored by two-step immunohistochemistry in cerebral cortex of rats. Lactuside B can reduce brain infarct volume of cerebral cortex of rats, increase the expression of bcl-2 mRNA and decrease that of bax mRNA. Moreover, the ratio of bcl-2 to bax mRNA is higher in 12.5 and 25 mg kg(-1) dose group, respectively, which is significantly different from that of model group (P < 0.05 or P < 0.01). Generally, either 12.5 or 25 mg kg(-1) dose group is better than positive control medicine nimodipine (P < 0.05 or P < 0.01). In addition, the expression of bcl-2 and bax protein is consistent with their gene expression. Infarct volume and the ratio of bcl-2 to bax mRNA expression are significantly different (P < 0.05 or P < 0.01) between 72 h and 24 h group. The results demonstrated that lactuside B could play a good role in resisting cerebral ischemia by upregulating the expression of bcl-2 mRNA and protein and downregulating that of bax mRNA and protein.
Assuntos
Isquemia Encefálica/metabolismo , Glucosídeos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Traumatismo por Reperfusão/metabolismo , Proteína X Associada a bcl-2/metabolismo , Animais , Apoptose/efeitos dos fármacos , Asteraceae/química , Isquemia Encefálica/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Relação Dose-Resposta a Droga , Glucosídeos/administração & dosagem , Glucosídeos/isolamento & purificação , Masculino , Neurônios/efeitos dos fármacos , Neurônios/patologia , Plantas Medicinais/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Rizoma/química , Vasodilatadores/administração & dosagem , Vasodilatadores/isolamento & purificação , Vasodilatadores/farmacologia , Proteína X Associada a bcl-2/genéticaRESUMO
OBJECTIVE: To observe the clinicopathologic and genetic features of follicular variant of peripheral T-cell lymphoma (FV-PTCL), with particular attention to the relationship of this type of lymphoma with angioimmunoblastic T-cell lymphoma (AITL). METHODS: The clinical data, hematoxylin and eosin-stained sections of lymph node biopsies from 2 FV-PTCL cases were reviewed. Immunohistochemical phenotyping and detection of EBV-encoded RNAs (EBER) through in situ hybridization (ISH) were performed. The EnVision two-step method was used for all antibodies except CXCL13 (by using three-step streptavidin immunoperoxidase method). Analysis of clonality and ITK/SYK gene rearrangement was conducted using PCR and RT-PCR assays, respectively. RESULTS: Clinically, the two patients presented with superficial lymphadenopathy similarly. Histologically, case 1 showed a follicular/nodular lymphoid proliferation without marked germinal centers. The neoplastic cells comprised mainly medium sized cells with abundant, sometimes clear cytoplasms. Similar histologic findings were seen in case 2 in addition to a concurrent component mimicking typical AITL noticed. Of both cases, the neoplastic cells showed positive reactivity to CD3, CD4, CD10, PD1, and CXCL13. Positive hybridization signals for EBER were only seen in case 2, and double stains demonstrated that those EBV-positive cells were mostly the reactive transformed B-cells. Monoclonal T-cell proliferation was proved by the rearranged TCR gene detection in both cases. Neither of the current cases expressed ITK/SYK fusion transcripts. CONCLUSION: FV-PTCL shows the similar or overlapped morphological and immunophenotypic features to those of AITL, possibly suggesting the presence of a potential relationship between these two types of lymphomas.
Assuntos
Rearranjo Gênico do Linfócito T , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Idoso , Antígenos CD/metabolismo , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Reguladoras de Apoptose/metabolismo , Quimiocina CXCL13/metabolismo , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Endostatinas/uso terapêutico , Feminino , Humanos , Linfadenopatia Imunoblástica/genética , Linfadenopatia Imunoblástica/metabolismo , Linfadenopatia Imunoblástica/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Queratinas/metabolismo , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/metabolismo , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Prednisona/uso terapêutico , Receptor de Morte Celular Programada 1 , Proteínas Tirosina Quinases/genética , Proteínas Recombinantes , Indução de Remissão , Quinase Syk , Vincristina/uso terapêuticoRESUMO
t(6;11) translocation renal cell carcinoma (RCC) is classified as a subset of the MiT family translocation RCCs and characterized by harboring the Alpha-TFEB fusion gene. However, the development mechanism of this tumor and its effective treatment have not been fully identified yet. The purpose of this study was to explore the relationship between TFEB and BCL-2 in Alpha-TFEB stably transfected cell lines and in t(6;11) RCC tumor tissue. An Alpha-TFEB eukaryotic expression vector was constructed and stably transfected into CaKi-2 and HK-2 cells. RT-PCR and real-time RT-PCR were used to measure the mRNA expressions of TFEB and BCL-2, and immunohistochemistry, Western blot and dual immunofluorescence assays were used to evaluate the TFEB and BCL-2 protein expressions. MTT proliferation assays and flow cytometry were also performed. Furthermore, luciferase reporter assays were used to evaluate the BCL-2 promoter activity. An Alpha-TFEB eukaryotic expression vector was successfully constructed and stably transfected into CaKi-2 and HK-2 cells (named CaKi-2-TFEB and HK-2-TFEB cells). Compared with the CaKi-2 and HK-2 groups, the TFEB and BCL-2 mRNA expression levels were significantly upregulated in the CaKi-2-TFEB and HK-2-TFEB groups respectively. The TFEB and BCL-2 protein expressions showed a similar result. The overexpression of TFEB and BCL-2 promoted cell proliferation and inhibited cell apoptosis. Moreover, the overexpression of TFEB upregulated the promoter activity of BCL-2. Our data suggest that the overexpression of TFEB promotes BCL-2 expression by upregulating its promoter activity and ultimately results in the development of t(6;11) translocation RCC. BCL-2 inhibitors may serve as potential therapeutic targets for t(6;11) translocation RCC.