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1.
Front Aging Neurosci ; 16: 1390324, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38586827

RESUMO

Phosphatase and tensin homologue deleted on chromosome ten (PTEN) was initially recognized as a significant regulator of cancer suppression and could impede cancer cell survival, proliferation, and energy metabolism. PTEN is highly expressed in neurons and performs crucial functions in neurogenesis, synaptogenesis, and neuronal survival. Disruption of PTEN activity may also result in abnormal neuronal function and is associated with various neurological disorders, including stroke, seizures, and autism. Although several studies have shown that PTEN is involved in the development and degenerative processes of the nervous system, there is still a lack of in-depth studies that summarize and analyse patterns of cooperation between authors, institutions, countries, and journals, as well as research hotspots and trends in this important field. To identify and further visualize the cooperation and comprehend the development and trends of PTEN in the nervous system, especially in neural development and neurological diseases, we used a bibliometric analysis to identify relevant publications on this topic. We first found that the number of publications displayed a growing trend with time, but this was not stable. Universities, institutions, and authors from the United States are leading in this area of research. In addition, many cutting-edge research results have been discovered, such as key regulatory molecules and cellular mechanisms of PTEN in the nervous system, which may provide novel intervention targets and precise therapeutic strategies for related pathological injuries and diseases. Finally, the literature published within the last 5 years is discussed to identify future research trends regarding PTEN in the nervous system. Taken together, our findings, analysed using bibliometrics, may reflect research hotspots and trends, providing a reference for studying PTEN in the nervous system, especially in neural development and neurological diseases. These findings can assist new researchers in developing their research interests and gaining basic information. Moreover, our findings also may provide precise clinical guidelines and strategies for treating nervous system injuries and diseases caused by PTEN dysfunction.

2.
Front Surg ; 10: 1180624, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37151861

RESUMO

Background: Skin regeneration is a challenging issue worldwide. Increasing research has highlighted the role of immune cells in healing and the underlying regulatory mechanism. The purpose of this study was to identify the hotspots and trends in skin regeneration and inflammation research through bibliometrics and to provide insights into the future development of fundamental research and disease treatment. Methods: Publications were collected from the Web of Science Core Collection on March 1, 2022. Articles and reviews published in English from January 1, 1999, to December 31, 2022, were selected, and statistical analyses of countries, institutions, authors, references, and keywords were performed using VOSviewer 1.6.18 and CiteSpace 5.8. Results: A total of 3,894 articles and reviews were selected. The number of publications on skin inflammation and regeneration showed an increasing trend over time. Additionally, authors and institutions in the United States, United Kingdom, Canada, and China appeared to be at the forefront of research in the field of skin inflammation and regeneration. Werner Sabine published some of the most cited papers. Wound Repair and Regeneration was the most productive journal, while Journal of Investigative Dermatology was the most cited journal. Angiogenesis, diamonds, collagen, cytokine, and keratinocytes were the five most commonly used keywords. Conclusion: The number of publications on skin inflammation and regeneration show an increasing trend. Moreover, a series of advanced technologies and treatments for skin regeneration, such as exosomes, hydrogels, and wound dressings, are emerging, which will provide precise information for the treatment of skin wounds. This study can enhance our understanding of current hotspots and future trends in skin inflammation and regeneration research, as well as provide guidelines for fundamental research and clinical treatment.

3.
Front Neurosci ; 17: 1105158, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36814788

RESUMO

Background: Glaucoma is the first irreversible and second blindness disease, which is characterized by the death of retinal ganglion cells (RGCs) and degeneration of the optic nerve. Previous works have indicated that apoptosis is the main reason for RGC death in glaucoma. Although many studies have investigated the mechanism of apoptosis and different strategies targeting apoptosis to protect the RGCs and finally recover the impaired vision in the glaucoma. However, the global trend and hotspots of apoptosis in glaucoma have not been well illustrated and discussed. Methods: Documents were extracted from the Web of Science Core Collection on November 2, 2022. We selected articles and reviews published in English from January 1, 1999 to November 1, 2022 to perform visual analysis and statistical analysis of countries, institutions, authors, references and keywords by VOSviewer 1.6.18 and CiteSpace 5.8. Results: The publications about apoptosis in glaucoma show an increasing trend over time. Besides, the authors, institutions in the US and China published the most numbers of articles with the highest citation, which may be leading the research in the field of apoptosis in glaucoma. Last, series of advanced research results, technology and treatment for glaucoma, such as the discovery of key regulatory mechanisms on RGC apoptosis are emerging and will provide precise strategies for the treatment of glaucoma. Conclusion: This research will broaden our comprehension about the role of apoptosis in the process of glaucoma, and provide guidelines for us in basic research and disease treatment in the further.

4.
Curr Med Sci ; 43(1): 166-172, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36255664

RESUMO

OBJECTIVE: Numerous studies have indicated that excitatory amino acid toxicity, such as glutamate toxicity, is involved in glaucoma. In addition, excessive glutamate can lead to an intracellular calcium overload, resulting in regulated necrosis. Our previous studies have found that the calpastatin (CAST)-calpain pathway plays an important role in retinal neuron-regulated necrosis after glutamate injury. Although inhibition of the calpain pathway can decrease regulated necrosis, necrotic cells remain. It has been suggested that there are other molecules that participate in retinal neuron-regulated necrosis. CAST is an important regulator of dynamin-related protein 1 (Drp1)-mediated mitochondrial defects. Thus, the aim of this study was to determine whether the CAST-Drp1 pathway may be an underlying signaling axis in neuron-regulated necrosis. METHODS: Using cultured retinal neurons and in an in-vivo glaucoma model induced by glutamate overload, members of the CAST-Drp1 pathway were assessed by immunofluorescence, Western blotting, Phos-tagTM SDS-PAGE, and co-immunoprecipitation assays. Moreover, the black and white box test was performed on the rats. RESULTS: We found that more retinal neuron-regulated necrosis and Drp1 activation as well as lower CAST levels were present in the glutamate-induced glaucoma model. Rats with glutamate-induced glaucoma exhibited impaired visual function. We also observed retinal neuron-regulated necrosis and Drp1 activity decreased, and impaired vision recovered after CAST active peptide application, indicating that the CAST-Drp1 pathway plays a critical role in retinal neuron-regulated necrosis and visual function. CONCLUSION: The results of this study indicate that the CAST-Drp1 pathway protects against retinal neuron-regulated necrosis, which may expand the therapeutic targets for the treatment of neurodegenerative disorders involving dysfunction of glutamate metabolism, such as glaucoma.


Assuntos
Glaucoma , Neurônios Retinianos , Animais , Ratos , Calpaína/metabolismo , Dinaminas/metabolismo , Glaucoma/metabolismo , Ácido Glutâmico/farmacologia , Necrose , Neurônios Retinianos/metabolismo
5.
Neural Regen Res ; 18(1): 74-80, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35799512

RESUMO

Regulated cell death predominantly involves apoptosis, autophagy, and regulated necrosis. It is vital that we understand how key regulatory signals can control the process of cell death. Pin1 is a cis-trans isomerase that catalyzes the isomerization of phosphorylated serine or threonine-proline motifs of a protein, thereby acting as a crucial molecular switch and regulating the protein functionality and the signaling pathways involved. However, we know very little about how Pin1-associated pathways might play a role in regulated cell death. In this paper, we review the role of Pin1 in regulated cell death and related research progress and summarize Pin1-related pathways in regulated cell death. Aside from the involvement of Pin1 in the apoptosis that accompanies neurodegenerative diseases, accumulating evidence suggests that Pin1 also plays a role in regulated necrosis and autophagy, thereby exhibiting distinct effects, including both neurotoxic and neuroprotective effects. Gaining an enhanced understanding of Pin1 in neuronal death may provide us with new options for the development of therapeutic target for neurodegenerative disorders.

6.
Front Cell Dev Biol ; 10: 1043725, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36393861

RESUMO

Background: Regulation of cell death plays a key role in numerous diseases. As a proline isomerase, prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is important for the regulation of signaling pathways. An in-depth understanding of how Pin1 participates in the process of cell death, which affects the occurrence and development of diseases, will aid in the discovery of new disease mechanisms and therapeutic methods. Thus, the purpose of our study was to discover the research trends and hotspots of Pin1 and cell death through bibliometric analyses and to provide insights for understanding the future development of basic research and treatment of diseases. Methods: Documents were extracted from the Web of Science Core Collection on 7 May 2022. We selected articles and reviews published in English from 2000 to 2021, and visual and statistical analyses of countries, institutions, authors, references and keywords were performed using VOSviewer 1.6.18 and CiteSpace 5.8. Results: A total of 395 articles and reviews were selected. Since 2001, the number of articles on Pin1 and cell death has increased annually. Publications come from 43 countries, with the US having the most publications and citations. We identified 510 authors, with Giannino Del Sal having the most articles and Paola Zacchi having the most co-citations. The Journal of Biological Chemistry is the most researched journal, and Nature and its subjournals are the most cited journals. Apoptosis, phosphorylation, and breast cancer were the three most common keywords. Conclusion: The number of documents showed an increasing trend from 2001 to 2014. Stagnant growth after 2014 may be related to the absence of new research hotspots. Cooperative links between core institutions need to be strengthened, and the institution with the highest citation count in recent years is Fujian Medical University in China. The role of Pin1 in cell death requires further research to discover new research hotspots. Before breakthroughs in molecular mechanism or signaling pathway research, future research will focus more on the treatment of diseases represented by Pin1 inhibitors.

7.
Eur Radiol ; 32(4): 2672-2682, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34677668

RESUMO

OBJECTIVES: Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide. The optimal management of computed tomography (CT)-indeterminate pulmonary nodules is important. To optimize individualized follow-up strategies, we developed a radiomics nomogram for predicting 2-year growth in case of indeterminate small pulmonary nodules. METHODS: A total of 215 histopathology-confirmed small pulmonary nodules (21 benign and 194 malignant) in 205 patients with ultra-high-resolution CT (U-HRCT) were divided into growth and nongrowth nodules and were randomly allocated to the primary (n = 151) or validation (n = 64) group. The least absolute shrinkage and selection operator (LASSO) method was used for radiomics feature selection and radiomics signature determination. Multivariable logistic regression analysis was used to develop a radiomics nomogram that integrated the radiomics signature with significant clinical parameters (sex and nodule type). The area under the curve (AUC) was applied to assess the predictive performance of the radiomics nomogram. The net benefit of the radiomics nomogram was assessed using a clinical decision curve. RESULTS: The radiomics signature and nomogram yielded AUCs of 0.892 (95% confidence interval [CI]: 0.843-0.940) and 0.911 (95% CI: 0.867-0.955), respectively, in the primary group and 0.826 (95% CI: 0.727-0.926) and 0.843 (95% CI: 0.749-0.937), respectively, in the validation group. The clinical usefulness of the nomogram was demonstrated by decision curve analysis. CONCLUSIONS: A radiomics nomogram was developed by integrating the radiomics signature with clinical parameters and was easily used for the individualized prediction of two-year growth in case of CT-indeterminate small pulmonary nodules. KEY POINTS: • A radiomics nomogram was developed for predicting the two-year growth of CT-indeterminate small pulmonary nodules. • The nomogram integrated a CT-based radiomics signature with clinical parameters and was valuable in developing an individualized follow-up strategy for patients with indeterminate small pulmonary nodules.


Assuntos
Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/patologia , Nomogramas , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
8.
Biochem Biophys Res Commun ; 586: 129-136, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34839191

RESUMO

Taxol is commonly used chemotherapy regimen for esophageal squamous cell carcinoma (ESCC). Study of the underlying mechanisms of Taxol chemoresistance provides better understanding of esophageal cancer treatment and may provide a rational molecular target for diagnosis and intervention. Here we showed FBXO31, which was reported to be highly expressed in ESCC and significantly associated with poor prognosis, could regulate ESCC chemosensitivity to Taxol. Silencing of FBXO31 in ESCC cells sensitized cells to Taxol treatment, evidenced by FACS analysis and TUNEL assay, showing as an increased apoptotic population in FBXO31-knockdown cells compared to the control cells. The mass spectrometry data and coimmunoprecipitation results showed FBXO31 could bind with cofilin-1. Cofilin-1 knockdown in FBXO31-overexpression cells reversed FBXO31-induced suppression of cell apoptosis, suggesting FBXO31-mediated Taxol chemoresistance is associated with cofilin-1. Furthermore, in vivo experiments confirmed that knockdown of FBXO31 sensitized ESCC to Taxol treatment. This finding substantiated a pivotal role of FBOX31 in ESCC chemoresistance, indicating that FBXO31 may be a potential indicator or target for drug resistance in ESCC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cofilina 1/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Proteínas F-Box/genética , Paclitaxel/farmacologia , Proteínas Supressoras de Tumor/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cofilina 1/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Proteínas F-Box/antagonistas & inibidores , Proteínas F-Box/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Nus , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Front Pharmacol ; 12: 716394, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349659

RESUMO

Methamphetamine (METH) is one of the most widely abused synthetic drugs in the world. The users generally present hyperthermia (HT) and psychiatric symptoms. However, the mechanisms involved in METH/HT-induced neurotoxicity remain elusive. Here, we investigated the role of heat shock protein 90 alpha (HSP90α) in METH/HT (39.5°C)-induced necroptosis in rat striatal neurons and an in vivo rat model. METH treatment increased core body temperature and up-regulated LDH activity and the molecular expression of canonical necroptotic factors in the striatum of rats. METH and HT can induce necroptosis in primary cultures of striatal neurons. The expression of HSP90α increased following METH/HT injuries. The specific inhibitor of HSP90α, geldanamycin (GA), and HSP90α shRNA attenuated the METH/HT-induced upregulation of receptor-interacting protein 3 (RIP3), phosphorylated RIP3, mixed lineage kinase domain-like protein (MLKL), and phosphorylated MLKL. The inhibition of HSP90α protected the primary cultures of striatal neurons from METH/HT-induced necroptosis. In conclusion, HSP90α plays an important role in METH/HT-induced neuronal necroptosis and the HSP90α-RIP3 pathway is a promising therapeutic target for METH/HT-induced neurotoxicity in the striatum.

10.
J Thorac Dis ; 13(5): 2803-2811, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34164172

RESUMO

BACKGROUND: Due to submucosal infiltration's biological nature along the airway, adenoid cystic carcinoma (ACC) frequently leaves positive surgical margins. This study evaluated the clinicopathologic, and computed tomography (CT) features for predicting surgical margin status in central airway ACC. METHODS: We retrospectively analyzed the files of 71 patients with ACC of the central airway proven by histopathology and surgery who had presented between January 2010 and December 2018. All patients were classified into positive and negative surgical margin groups according to margin status. Univariate analysis and multivariable logistic regression models were then performed to compare demography, histopathology, and CT characteristics between ACC patients with positive and negative margins. RESULTS: After surgical resection, 59 (83.1%) patients had positive margins, and 12 (16.9%) had negative margins. The contrast-enhanced CT (CECT) longitudinal tail sign (LTS) was identified in 55 of 59 (93.2%) patients with positive margins and was the only feature that had a significant association with positive margins (odds ratio 41.250, 95% CI: 7.886-215.767; P<0.001). Moreover, positive margins in upper or/and lower directions were associated with the LTS in corresponding directions (P<0.001). CONCLUSIONS: Most central airway ACC patients exhibited positive margins following surgery. The appearance of the LTS on CECT was significantly associated with positive margins and could help preoperatively predict the submucosal invasion of ACC.

11.
Eur J Radiol ; 140: 109746, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33992979

RESUMO

PURPOSE: To evaluate computed tomography (CT) features and establish a predictive model for the clinical diagnosis and prognosis of tracheal adenoid cystic carcinoma (ACC). METHOD: From January 2010 to December 2018, 82 patients with tracheal tumors, including 46 patients with ACC confirmed by surgery and histopathology, were enrolled in this study. These patients' clinicopathologic information, CT features and survival outcomes were recorded and analyzed. Independent predictors of diagnosis and prognosis of tracheal ACC were determined by both univariate and multivariate analyses. RESULTS: Compared with tracheal non-ACC patients, univariate analysis showed that ACC patients were more likely to have extensive longitudinal length (p < 0.001) and to appear as annular wall thickening (p = 0.001), transmural growth (p = 0.036), poorly defined border (p = 0.003) and mild enhancement (p = 0.001). Multivariate logistic analysis showed that longitudinal length and enhancement degree were independent predictors of tracheal ACC. The 3-year and 5-year disease-free survival (DFS) were 75.7 % and 64.5 %, respectively. Longitudinal length (≥ 34 mm), transverse length (≥ 20 mm) and transmural growth were associated with poor DFS in univariate analysis. After multivariate adjustment, only transverse length (≥ 20 mm) was an adverse prognostic factor for DFS (hazard ratio = 4.594, 95 % confidence interval = 1.240-17.017; p = 0.022). CONCLUSIONS: CT longitudinal length and enhancement degree of tumors showed satisfactory discrimination for tracheal ACC. Excessive CT transverse length might be an unfavorable indicator for ACC recurrence and could be helpful for predicting the survival outcomes of ACC at the initial diagnosis.


Assuntos
Carcinoma Adenoide Cístico , Neoplasias da Traqueia , Carcinoma Adenoide Cístico/diagnóstico por imagem , Humanos , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Neoplasias da Traqueia/diagnóstico por imagem
12.
N Engl J Med ; 380(22): 2116-2125, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31141633

RESUMO

BACKGROUND: In 2017, surveillance for tickborne diseases in China led to the identification of a patient who presented to a hospital in Inner Mongolia with a febrile illness that had an unknown cause. The clinical manifestation of the illness was similar to that of tickborne encephalitis virus (TBEV) infection, but neither TBEV RNA nor antibodies against the virus were detected. METHODS: We obtained a blood specimen from the index patient and attempted to isolate and identify a causative pathogen, using genome sequence analysis and electron microscopy. We also initiated a heightened surveillance program in the same hospital to screen for other patients who presented with fever, headache, and a history of tick bites. We used reverse-transcriptase-polymerase-chain-reaction (RT-PCR) and cell-culture assays to detect the pathogen and immunofluorescence and neutralization assays to determine the levels of virus-specific antibodies in serum specimens from the patients. RESULTS: We found that the index patient was infected with a previously unknown segmented RNA virus, which we designated Alongshan virus (ALSV) and which belongs to the jingmenvirus group of the family Flaviviridae. ALSV infection was confirmed by RT-PCR assay in 86 patients from Inner Mongolia and Heilongjiang who presented with fever, headache, and a history of tick bites. Serologic assays showed that seroconversion had occurred in all 19 patients for whom specimens were available from the acute phase and the convalescent phase of the illness. CONCLUSIONS: A newly discovered segmented virus was found to be associated with a febrile illness in northeastern China. (Funded by the National Key Research and Development Program of China and the National Natural Science Foundation of China.).


Assuntos
Doenças Transmissíveis Emergentes/virologia , Flaviviridae/isolamento & purificação , Doenças Transmitidas por Carrapatos/virologia , Adulto , Idoso , Animais , China/epidemiologia , Doenças Transmissíveis Emergentes/epidemiologia , Fadiga/etiologia , Feminino , Febre/etiologia , Flaviviridae/classificação , Flaviviridae/genética , Flaviviridae/ultraestrutura , Cefaleia/etiologia , Humanos , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Filogenia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Avaliação de Sintomas , Doenças Transmitidas por Carrapatos/complicações , Doenças Transmitidas por Carrapatos/epidemiologia , Carrapatos/virologia
13.
Pathol Res Pract ; 214(11): 1749-1757, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30244947

RESUMO

This review briefly introduces the mechanism and detection methods of necroptosis in recent years. The most significant points of this review focus on the involvement of necroptotic proteins in disease progression. The following aspects are summarized: 1) RIPs, MLKL, and the upstream and downstream molecules that mediate necroptosis; 2) The development of detection methods for necroptosis; 3) The involvement of related necroptotic proteins in diverse diseases etiology; and 4) The application of necroptotic proteins in disease diagnosis.


Assuntos
Morte Celular/fisiologia , Animais , Humanos
14.
Neural Regen Res ; 13(3): 556-562, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29623944

RESUMO

Calpains are a group of calcium-dependent proteases that are over activated by increased intracellular calcium levels under pathological conditions. A wide range of substrates that regulate necrotic, apoptotic and autophagic pathways are affected by calpain. Calpain plays a very important role in neuronal death and various neurological disorders. This review introduces recent research progress related to the regulatory mechanisms of calpain in neuronal death. Various neuronal programmed death pathways including apoptosis, autophagy and regulated necrosis can be divided into receptor interacting protein-dependent necroptosis, mitochondrial permeability transition-dependent necrosis, pyroptosis and poly (ADP-ribose) polymerase 1-mediated parthanatos. Calpains cleave series of key substrates that may lead to cell death or participate in cell death. Regarding the investigation of calpain-mediated programed cell death, it is necessary to identify specific inhibitors that inhibit calpain mediated neuronal death and nervous system diseases.

15.
Histol Histopathol ; 33(8): 773-789, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29393502

RESUMO

Necroptosis is programmed necrosis, a process which has been studied for over a decade. The most common accepted mechanism is through the RIP1-RIP3-MLKL axis to regulate necroptotic cell death. As a result of previous studies on necroptosis, positive regulation for promoting necroptosis such as HSP90 stabilization and hyperactivation of TAK1 on RIP1 is clear. Similarly, the negative regulation of necroptosis, such as through caspase 8, c-FLIP, CHIP, MK2, PELI1, ABIN-1, is also clear. Therefore, the promise of corresponding applications in treating diseases becomes hopeful. Studies have shown that necroptosis is involved in the development of many diseases, such as ischemic injury diseases in various organs, neurodegenerative diseases, infectious diseases, and cancer. Given these results, drugs that inhibit or trigger necroptosis can be discovered to treat diseases. In this review, we briefly introduce up to date concepts concerning the mechanism of necroptosis, the diseases that involve necroptosis, and the drugs that can be applied to treat such diseases.


Assuntos
Apoptose/efeitos dos fármacos , Desenho de Fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Terapia de Alvo Molecular/métodos , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Estrutura Molecular , Necrose , Relação Estrutura-Atividade
16.
J Cell Physiol ; 233(6): 4864-4884, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29334122

RESUMO

Heat shock protein 90α (HSP90α) maintains cell stabilization and regulates cell death, respectively. Recent studies have shown that HSP90α is involved in receptor interacting protein 3 (RIP3)-mediated necroptosis in HT29 cells. It is known that oxygen and glucose deprivation (OGD) can induce necroptosis, which is regulated by RIP3 in neurons. However, it is still unclear whether HSP90α participates in the process of OGD-induced necroptosis in cultured neurons via the regulation of RIP3. Our study found that necroptosis occurs in primary cultured cortical neurons and PC-12 cells following exposure to OGD insult. Additionally, the expression of RIP3/p-RIP3, MLKL/p-MLKL, and the RIP1/RIP3 complex (necrosome) significantly increased following OGD, as measured through immunofluorescence (IF) staining, Western blotting (WB), and immunoprecipitation (IP) assay. Additionally, data from computer simulations and IP assays showed that HSP90α interacts with RIP3. In addition, HSP90α was overexpressed following OGD in cultured neurons, as measured through WB and IF staining. Inhibition of HSP90α in cultured neurons, using the specific inhibitor, geldanamycin (GA), and siRNA/shRNA of HSP90α, protected cultured neurons from necrosis. Our study showed that the inhibitor of HSP90α, GA, rescued cultured neurons not only by decreasing the expression of total RIP3/MLKL, but also by decreasing the expression of p-RIP3/p-MLKL and the RIP1/RIP3 necrosome. In this study, we reveal that inhibition of HSP90α protects primary cultured cortical neurons and PC-12 cells from OGD-induced necroptosis through the modulation of RIP3 expression.


Assuntos
Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Córtex Cerebral/efeitos dos fármacos , Glucose/deficiência , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Hipóxia Celular , Córtex Cerebral/embriologia , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Regulação para Baixo , Feminino , Idade Gestacional , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Necrose , Neurônios/enzimologia , Neurônios/patologia , Células PC12 , Gravidez , Cultura Primária de Células , Ligação Proteica , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
17.
Lancet HIV ; 4(4): e177-e188, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28159548

RESUMO

BACKGROUND: Worldwide, 30% of the world's population have antibodies to the intracellular protozoan parasite Toxoplasma gondii and about 36·7 million people are infected with HIV, but little is known about the prevalence of co-infection with T gondii and HIV. We aimed to characterise the epidemiology and burden of T gondii co-infection in people with HIV infection. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, Google Scholar, ScienceDirect, Chinese Web of Knowledge, Wanfang, and Chongqing VIP databases for studies reporting T gondii infection in HIV-infected people from inception to Feb 29, 2016. Studies were included if they investigated people with HIV infection and presented data that allowed us to establish the prevalence of T gondii infection. We excluded reviews, repeated studies, or animal studies, as well as studies that provided the final results without raw data, had a sample size less than 30 people, had unclear diagnostic methods of T gondii infection, or that included populations with increased risk of T gondii infection. We extracted the numbers of patients with HIV infection and T gondii co-infection from the identified studies. We estimated pooled prevalence of T gondii infection in HIV-infected people by a random-effects model, and evaluated its overall infection burden worldwide. FINDINGS: Our search identified 7843 records and after removal of duplicates and initial screening, we reviewed 312 studies in full. Of these articles, 238 were excluded, leaving 74 studies that included 25 989 HIV-infected people from 34 countries. Of these people, 7326 had T gondii co-infection and we estimated the pooled worldwide prevalence of T gondii infection to be 35·8% (95% CI 30·8-40·7). 2353 of 8837 of people in Asia and the Pacific had co-infection with T gondii and HIV (prevalence 25·1%, 95% CI 19·0-31·2), and prevalence was low in this region compared with that in sub-Saharan Africa (44·9%, 32·3-57·5, 2129/5686; odds ratio [OR] 0·61), Latin America and the Caribbean (49·1%, 27·9-70·4, 510/980; OR 0·33), and North Africa and the Middle East (60·7%, 24·1-97·3, 245/439; OR 0·29). 1561 of 3780 people in low-income countries had co-infection (54·7%, 95% CI 35·8-73·5), which was higher than in middle-income countries (34·2%, 27·4-40·9, 3632/11 540; OR 1·53) and high-income countries (26·3%, 20·4-32·2, 2133/10 669; OR 2·82). Worldwide, we calculated that there were roughly 13 138 600 (95% CI 11 303 600-14 936 900) cases of T gondii co-infection in HIV-infected people, with 87·1% in sub-Saharan Africa (11 449 500 cases, 95% CI 8 236 500-14 662 500). INTERPRETATION: Our findings suggest that people with HIV infection have a very high burden of T gondii infection, especially in sub-Saharan Africa, and emphasise the importance of routine surveillance for T gondii infection in all HIV-infected people. FUNDING: National Natural Science Foundation and the Special Fund for Agro-scientific Research in the Public Interest in China.


Assuntos
Coinfecção/epidemiologia , Efeitos Psicossociais da Doença , Infecções por HIV/complicações , Toxoplasmose/complicações , Toxoplasmose/epidemiologia , Adolescente , África Subsaariana/epidemiologia , Região do Caribe/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , América Latina/epidemiologia , Prevalência , Toxoplasma/isolamento & purificação , Toxoplasmose/parasitologia
18.
Arch Virol ; 162(1): 247-257, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27722994

RESUMO

Rabies is a lethal neurological disease caused by the neurotropic rabies virus (RABV). To investigate the innate immune response in the brain during rabies infection, key gene transcripts indicative of innate immunity in a mouse model system were measured using real-time RT-PCR. Mice were infected via the intracerebral or intramuscular route with either attenuated rabies virus (SRV9) or pathogenic rabies virus (BD06). Infection with SRV9 resulted in the early detection of viral replication and the rapid induction of innate immune response gene expression in the brain. BD06 infection elicited innate immune response gene expression during only the late stage of infection. We measured Na-fluorescein uptake to assess blood-brain barrier (BBB) permeability, which was enhanced during the early stage of SRV9 infection and significantly enhanced during the late stage of BD06 infection. Furthermore, early SRV9 replication increased the maturation and differentiation of dendritic cells (DCs) and B cells in the inguinal lymph nodes and initiated the generation of virus-neutralizing antibodies (VNAs), which cooperate with the innate immune response to eliminate virus from the CNS. However, BD06 infection did not stimulate VNA production; thus, the virus was able to evade the host immune response and cause encephalitis. The rabies virus phosphoprotein has been reported to counteract IFN activation. In an in vitro study of the relationship between IFN antagonism and RABV pathogenicity, we demonstrated that SRV9 more strongly antagonized IFN activity than did BD06. Therefore, there is no positive relationship between the IFN antagonist activity of the virus and its pathogenicity.


Assuntos
Encéfalo/patologia , Imunidade Inata , Vacina Antirrábica/administração & dosagem , Vacina Antirrábica/imunologia , Vírus da Raiva/imunologia , Raiva/patologia , Animais , Barreira Hematoencefálica , Diferenciação Celular , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Evasão da Resposta Imune , Injeções Intramusculares , Interferons/antagonistas & inibidores , Linfonodos/imunologia , Camundongos Endogâmicos BALB C , Permeabilidade , Reação em Cadeia da Polimerase em Tempo Real
19.
Neurotox Res ; 30(3): 392-406, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27194525

RESUMO

N-acetyl-leucyl-leucyl-norleucinal (ALLN), an inhibitor of proteasomes and calpain, is widely used to reduce proteasomes or calpain-mediated cell death in rodents. However, ALLN is toxic to retinal neurons to some extent. At the concentration of 10 µM, ALLN is non-toxic to cortical neurons, but induces cell death of retinal neurons in vitro. The tolerance concentration of ALLN for retinal neurons is unclear, and the precise mechanism of cell death induced by ALLN remains elusive. In this study, we investigated the toxic effect of ALLN on primary retinal neurons. The 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed no significant changes of cell viability at 1 µM but decreased cell viability after treatment of ALLN at 2.5, 5, and 7.5 µM. Lactate dehydrogenase (LDH) release was highly elevated and propidium iodide (PI)-positive cells were significantly increased at 2.5, 5, and 7.5 µM after all treatment times. Moreover, the protein levels of caspase-3 were up-regulated at 5 and 7.5 µM after 12 and 24 h of ALLN treatment. The ratio of Bax/Bcl-2 was raised and Annexin V-positive cells were increased at 5 and 7.5 µM after 12 and 24 h of ALLN treatment. However, there were no significant changes in either the ratio of microtubule-associated protein 1 light chain 3 (LC3) II/LC3 I or monodansylcadaverine (MDC) staining. Our data clearly show that at the concentrations equal to and higher than 2.5 µM, ALLN may induce cell death of primary retinal neurons by necrosis and apoptosis, but not autophagy. These suggest that primary retinal neurons are more susceptible to ALLN treatment and provide a possible mechanism for the cell death of ALLN-sensitive cells in ALLN injury.


Assuntos
Leupeptinas/toxicidade , Neurônios Retinianos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Western Blotting , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Imunofluorescência , L-Lactato Desidrogenase/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Necrose/induzido quimicamente , Necrose/metabolismo , Necrose/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Neurônios Retinianos/metabolismo , Neurônios Retinianos/patologia , Fatores de Tempo , Proteína X Associada a bcl-2/metabolismo
20.
Foodborne Pathog Dis ; 13(2): 88-92, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26682614

RESUMO

Toxoplasma gondii is prevalent in humans and animals worldwide. The present study aimed to determine the genetic diversity of T. gondii isolates from pigs in Jilin province, northeastern China. A total of 100 DNA samples were extracted from the hilar lymph nodes of slaughtered pigs, and 9 (9.0%, 95% confidence interval: 3.4-14.6%) were detected positive for T. gondii B1 gene by a nested polymerase chain reaction (PCR). The positive DNA samples were typed at 11 genetic markers, including 10 nuclear loci (SAG1, 5'-SAG2, and 3'-SAG2, alternative SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, and PK1) and an apicoplast locus (Apico) using the multilocus PCR-restriction fragment length polymorphism technology. Only three isolates were completely typed at all loci, showing that they all belonged to the clonal type I. One isolate was typed at five loci, including 5' +3'-SAG2, SAG2, SAG3, GRA6, and L358, revealing the possible clonal type I. This is the first report of the genetic characterization of T. gondii isolates in pigs in Jilin province, northeastern China, which has implications for better understanding the population structure of T. gondii infection in China.


Assuntos
DNA de Protozoário/análise , Variação Genética , Suínos/microbiologia , Toxoplasma/genética , Matadouros , Animais , China/epidemiologia , Marcadores Genéticos , Linfonodos/parasitologia , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Prevalência , Doenças dos Suínos/epidemiologia , Doenças dos Suínos/parasitologia , Toxoplasma/isolamento & purificação , Toxoplasmose Animal/epidemiologia , Toxoplasmose Animal/parasitologia
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