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1.
Article in Chinese | WPRIM | ID: wpr-941006

ABSTRACT

OBJECTIVE@#To explore the mechanism by which inositol-requiring enzyme-1α (IRE1α) regulates autophagy function of chondrocytes through calcium homeostasis endoplasmic reticulum protein (CHERP).@*METHODS@#Cultured human chondrocytes (C28/I2 cells) were treated with tunicamycin, 4μ8c, rapamycin, or both 4μ8c and rapamycin, and the expressions of endoplasmic reticulum (ER) stress- and autophagy-related proteins were detected with Western blotting. Primary chondrocytes from ERN1 knockout (ERN1 CKO) mice and wild-type mice were examined for ATG5 and ATG7 mRNA expressions, IRE1α and p-IRE1α protein expressions, and intracellular calcium ion content using qPCR, Western blotting and flow cytometry. The effect of bafilomycin A1 treatment on LC3 Ⅱ/LC3 Ⅰ ratio in the isolated chondrocytes was assessed with Western blotting. Changes in autophagic flux of the chondrocytes in response to rapamycin treatment were detected using autophagy dual fluorescent virus. The changes in autophagy level in C28/I2 cells overexpressing CHERP and IRE1α were detected using immunofluorescence assay.@*RESULTS@#Tunicamycin treatment significantly up-regulated ER stress-related proteins and LC3 Ⅱ/LC3 Ⅰ ratio and down-regulated the expression of p62 in C28/I2 cells (P < 0.05). Rapamycin obviously up-regulated LC3 Ⅱ/LC3 Ⅰ ratio (P < 0.001) in C28/I2 cells, but this effect was significantly attenuated by co-treatment with 4μ8c (P < 0.05). Compared with the cells from the wild-type mice, the primary chondrocytes from ERN1 knockout mice showed significantly down-regulated mRNA levels of ERN1 (P < 0.01), ATG5 (P < 0.001) and ATG7 (P < 0.001), lowered or even lost expressions of IRE1α and p-IRE1α proteins (PP < 0.01), and increased expression of CHERP (P < 0.05) and intracellular calcium ion content (P < 0.001). Bafilomycin A1 treatment obviously increased LC3 Ⅱ/ LC3 Ⅰ ratio in the chondrocytes from both wild-type and ERN1 knockout mice (P < 0.01 or 0.05), but the increment was more obvious in the wild-type chondrocytes (P < 0.05). Treatment with autophagy dual-fluorescence virus resulted in a significantly greater fluorescence intensity of LC3-GFP in rapamycin-treated ERN1 CKO chondrocytes than in wild-type chondrocytes (P < 0.05). In C28/I2 cells, overexpression of CHERP obviously decreased the fluorescence intensity of LC3, and overexpression of IRE1α enhanced the fluorescence intensity and partially rescued the fluorescence reduction of LC3 caused by CHERP.@*CONCLUSION@#IRE1α deficiency impairs autophagy in chondrocytes by upregulating CHERP and increasing intracellular calcium ion content.


Subject(s)
Animals , Autophagy , Calcium/metabolism , Chondrocytes , Endoplasmic Reticulum/metabolism , Endoribonucleases/pharmacology , Homeostasis , Inositol , Mice , Mice, Knockout , Protein Serine-Threonine Kinases , RNA, Messenger/metabolism , Sirolimus/pharmacology , Tunicamycin/pharmacology
2.
Frontiers of Medicine ; (4): 467-482, 2022.
Article in English | WPRIM | ID: wpr-939878

ABSTRACT

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.


Subject(s)
Anilides/pharmacology , Animals , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Cell Proliferation , Endothelial Cells/metabolism , Humans , Liver Neoplasms/drug therapy , Pyridines/pharmacology , Sirolimus/pharmacology , Xenograft Model Antitumor Assays
3.
Chinese Journal of Oncology ; (12): 673-692, 2022.
Article in Chinese | WPRIM | ID: wpr-939499

ABSTRACT

Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway (PAM pathway) plays an important role in the development of breast cancer and are closely associated with the resistance to endocrine therapy in advanced breast cancer. Therefore, anti-cancer treatment targeting key molecules in this signaling pathway has become research hot-spot in recent years. Randomized clinical trials have demonstrated that PI3K/AKT/mTOR inhibitors bring significant clinical benefit to patients with advanced breast cancer, especially to those with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER) 2-negative advanced breast cancer. Alpelisib, a PI3K inhibitor, and everolimus, an mTOR inhibitor, have been approved by Food and Drug Administration. Based on their high efficacy and relatively good safety profile, expanded indication of everolimus in breast cancer have been approved by National Medical Products Administration. Alpelisib is expected to be approved in China in the near future. The members of the consensus expert panel reached this consensus to comprehensively define the role of PI3K/AKT/mTOR signaling pathway in breast cancer, efficacy and clinical applications of PI3K/AKT/mTOR inhibitors, management of adverse reactions, and PIK3CA mutation detection, in order to promote the understanding of PI3K/AKT/mTOR inhibitors for Chinese oncologists, improve clinical decision-making, and prolong the survival of target patient population.


Subject(s)
Breast Neoplasms/metabolism , Consensus , Everolimus/therapeutic use , Female , Humans , MTOR Inhibitors , Phosphatidylinositol 3-Kinase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/metabolism
4.
Chinese Journal of Burns ; (6): 462-470, 2022.
Article in Chinese | WPRIM | ID: wpr-936033

ABSTRACT

Objective: To investigate the role and mechanism of Vγ4 T cells in impaired wound healing of rapamycin-induced full-thickness skin defects in mice. Methods: The experimental research methods were applied. Eighty-six C57BL/6J male mice (hereinafter briefly referred to as wild-type mice) aged 8-12 weeks were selected for the following experiments. Vγ4 T cells were isolated from axillary lymph nodes of five wild-type mice for the following experiments. Intraperitoneal injection of rapamycin for 42 mice was performed to establish rapamycin-treated mice model for the following experiments. Eighteen wild-type mice were divided into normal control group without any treatment, trauma only group, and trauma+CC chemokine ligand 20 (CCL20) inhibitor group according to the random number table (the same grouping method below), with 6 mice in each group. The full-thickness skin defect wound was made on the back of mice in the latter two groups (the same wound model below), and mice in trauma+CCL20 inhibitor group were continuously injected subcutaneously with CCL20 inhibitor at the wound edge for 3 days after injury. Another 6 rapamycin-treated mice were used to establish wound model as rapamycin+trauma group. On post injury day (PID) 3, the epidermal cells of the skin tissue around the wound of each trauma mice were extracted by enzyme digestion, and the percentage of Vγ4 T cells in the epidermal cells was detected by flow cytometry. In normal control group, the epidermal cells of the normal skin tissue in the back of mice were taken at the appropriate time point for detection as above. Five wild-type mice were used to establish wound models. On PID 3, the epidermal cells were extracted from the skin tissue around the wound. The cell populations were divided into Vγ4 T cells, Vγ3 T cells, and γδ negative cells by fluorescence-activated cell sorter, which were set as Vγ4 T cell group, Vγ3 T cell group, and γδ negative cell group (with cells in each group being mixed with B16 mouse melanoma cells), respectively. B16 mouse melanoma cells were used as melanoma cell control group. The expression of interleukin-22 (IL-22) mRNA in cells of each group was detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-PCR), with the number of samples being 6. Thirty rapamycin-treated mice were used to establish wound models, which were divided into Vγ4 T cell only group and Vγ4 T cell+IL-22 inhibitor group performed with corresponding injections and rapamycin control group injected with phosphate buffer solution (PBS) immediately after injury, with 10 mice in each group. Another 10 wild-type mice were taken to establish wound models and injected with PBS as wild-type control group. Mice in each group were injected continuously for 6 days. The percentage of wound area of mice in the four groups was calculated on PID 1, 2, 3, 4, 5, and 6 after injection on the same day. Six wild-type mice and 6 rapamycin-treated mice were taken respectively to establish wound models as wild-type group and rapamycin group. On PID 3, the mRNA and protein expressions of IL-22 and CCL20 in the peri-wound epidermis tissue of mice in the two groups were detected by real-time fluorescence quantitative RT-PCR and Western blotting, respectively. The Vγ4 T cells were divided into normal control group without any treatment and rapamycin-treated rapamycin group. After being cultured for 24 hours, the mRNA and protein expressions of IL-22 of cells in the two groups were detected by real-time fluorescence quantitative RT-PCR and Western blotting, respectively, with the number of samples being 6. Data were statistically analyzed with independent sample t test, analysis of variance for repeated measurement, one-way analysis of variance, Bonferroni method, Kruskal-Wallis H test, and Wilcoxon rank sum test. Results: The percentage of Vγ4 T cells in the epidermal cells of the skin tissue around the wound of mice in trauma only group on PID 3 was 0.66% (0.52%, 0.81%), which was significantly higher than 0.09% (0.04%, 0.14%) in the epidermal cells of the normal skin tissue of mice in normal control group (Z=4.31, P<0.01). The percentages of Vγ4 T cells in the epidermal cells of the skin tissue around the wound of mice in rapamycin+trauma group and trauma+CCL20 inhibitor group on PID 3 were 0.25% (0.16%, 0.37%) and 0.24% (0.17%, 0.35%), respectively, which were significantly lower than that in trauma only group (with Z values of 2.27 and 2.25, respectively, P<0.05). The mRNA expression level of IL-22 of cells in Vγ4 T cell group was significantly higher than that in Vγ3 T cell group, γδ negative cell group, and melanoma cell control group (with Z values of 2.96, 2.45, and 3.41, respectively, P<0.05 or P<0.01). Compared with that in wild-type control group, the percentage of wound area of mice in rapamycin control group increased significantly on PID 1-6 (P<0.01), the percentage of wound area of mice in Vγ4 T cell+IL-22 inhibitor group increased significantly on PID 1 and PID 3-6 (P<0.05 or P<0.01). Compared with that in rapamycin control group, the percentage of wound area of mice in Vγ4 T cell only group decreased significantly on PID 1-6 (P<0.05 or P<0.01). Compared with that in Vγ4 T cell only group, the percentage of wound area of mice in Vγ4 T cell+IL-22 inhibitor group increased significantly on PID 3-6 (P<0.05 or P<0.01). On PID 3, compared with those in wild-type group, the expression levels of IL-22 protein and mRNA (with t values of -7.82 and -5.04, respectively, P<0.01) and CCL20 protein and mRNA (with t values of -7.12 and -5.73, respectively, P<0.01) were decreased significantly in the peri-wound epidermis tissue of mice in rapamycin group. After being cultured for 24 hours, the expression levels of IL-22 protein and mRNA in Vγ4 T cells in rapamycin group were significantly lower than those in normal control group (with t values of -7.75 and -6.04, respectively, P<0.01). Conclusions: In mice with full-thickness skin defects, rapamycin may impair the CCL20 chemotactic system by inhibiting the expression of CCL20, leading to a decrease in the recruitment of Vγ4 T cells to the epidermis, and at the same time inhibit the secretion of IL-22 by Vγ4 T cells, thereby slowing the wound healing rate.


Subject(s)
Animals , Male , Melanoma , Mice , Mice, Inbred C57BL , RNA, Messenger , Sirolimus/pharmacology , T-Lymphocytes , Wound Healing
5.
Acta Physiologica Sinica ; (6): 225-236, 2022.
Article in Chinese | WPRIM | ID: wpr-927598

ABSTRACT

This study was to investigate the changes of autophagy in pancreatic tissue cells from hyperlipidemic acute pancreatitis (HLAP) rats and the molecular mechanism of autophagy to induce inflammatory injury in pancreatic tissue cells. Male Sprague Dawley (SD) rats were intraperitoneally injected with caerulein to establish acute pancreatitis (AP) model and then given a high fat diet to further prepare HLAP model. The HLAP rats were treated with autophagy inducer rapamycin or inhibitor 3-methyladenine. Pancreatic acinar (AR42J) cells were treated with caerulein to establish HLAP cell model. The HLAP cell model were treated with rapamycin or transfected with vascular endothelial growth factor (VEGF) siRNA. The inflammatory factors in serum and cell culture supernatant were detected by ELISA method. The histopathological changes of pancreatic tissue were observed by HE staining. The changes of ultrastructure and autophagy in pancreatic tissue were observed by electron microscopy. The expression levels of Beclin-1, microtubule- associated protein light chain 3-II (LC3-II), mammalian target of rapamycin complex 1 (mTORC1), and VEGF were measured by immunohistochemistry and Western blot. The results showed that, compared with control group, the autophagy levels and inflammatory injury of pancreatic tissue cells from HLAP model rats were obviously increased, and these changes were aggravated by rapamycin treatment, but alleviated by 3-methyladenine treatment. In HLAP cell model, rapamycin aggravated the autophagy levels and inflammatory injury, whereas VEGF siRNA transfection increased mTORC1 protein expression, thus alleviating the autophagy and inflammatory injury of HLAP cell model. These results suggest that VEGF-induced autophagy plays a key role in HLAP pancreatic tissue cell injury, and interference with VEGF-mTORC1 pathway can reduce the autophagy levels and alleviate the inflammatory injury. The present study provides a new target for prevention and treatment of HLAP.


Subject(s)
Acute Disease , Animals , Autophagy , Ceruletide/adverse effects , Male , Mammals/metabolism , Mechanistic Target of Rapamycin Complex 1 , Microtubule-Associated Proteins/metabolism , Pancreatitis , RNA, Small Interfering/genetics , Rats , Rats, Sprague-Dawley , Sirolimus/adverse effects , Vascular Endothelial Growth Factor A/genetics
6.
Chinese Medical Journal ; (24): 837-848, 2022.
Article in English | WPRIM | ID: wpr-927571

ABSTRACT

BACKGROUND@#Pulmonary microvascular endothelial cells (PMVECs) were not complex, and the endothelial barrier was destroyed in the pathogenesis progress of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Previous studies have demonstrated that hepatocyte growth factor (HGF), which was secreted by bone marrow mesenchymal stem cells, could decrease endothelial apoptosis. We investigated whether mTOR/STAT3 signaling acted in HGF protective effects against oxidative stress and mitochondria-dependent apoptosis in lipopolysaccharide (LPS)-induced endothelial barrier dysfunction and ALI mice.@*METHODS@#In our current study, we introduced LPS-induced PMEVCs with HGF treatment. To investigate the effects of mammalian target of rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3) pathway in endothelial oxidative stress and mitochondria-dependent apoptosis, mTOR inhibitor rapamycin and STAT3 inhibitor S3I-201 were, respectively, used to inhibit mTOR/STAT3 signaling. Moreover, lentivirus vector-mediated mTORC1 (Raptor) and mTORC2 (Rictor) gene knockdown modifications were introduced to evaluate mTORC1 and mTORC1 pathways. Calcium measurement, reactive oxygen species (ROS) production, mitochondrial membrane potential and protein, cell proliferation, apoptosis, and endothelial junction protein were detected to evaluate HGF effects. Moreover, we used the ALI mouse model to observe the mitochondria pathological changes with an electron microscope in vivo.@*RESULTS@#Our study demonstrated that HGF protected the endothelium via the suppression of ROS production and intracellular calcium uptake, which lead to increased mitochondrial membrane potential (JC-1 and mitochondria tracker green detection) and specific proteins (complex I), raised anti-apoptosis Messenger Ribonucleic Acid level (B-cell lymphoma 2 and Bcl-xL), and increased endothelial junction proteins (VE-cadherin and occludin). Reversely, mTOR inhibitor rapamycin and STAT3 inhibitor S3I-201 could raise oxidative stress and mitochondria-dependent apoptosis even with HGF treatment in LPS-induced endothelial cells. Similarly, mTORC1 as well as mTORC2 have the same protective effects in mitochondria damage and apoptosis. In in vivo experiments of ALI mouse, HGF also increased mitochondria structural integrity via the mTOR/STAT3 pathway.@*CONCLUSION@#In all, these reveal that mTOR/STAT3 signaling mediates the HGF suppression effects to oxidative level, mitochondria-dependent apoptosis, and endothelial junction protein in ARDS, contributing to the pulmonary endothelial survival and barrier integrity.


Subject(s)
Animals , Apoptosis , Calcium/metabolism , Endothelial Cells/metabolism , Endothelium/metabolism , Hepatocyte Growth Factor/metabolism , Lipopolysaccharides/pharmacology , Mammals/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 2/metabolism , Mice , Mitochondria/metabolism , Oxidative Stress , Reactive Oxygen Species/metabolism , Respiratory Distress Syndrome, Newborn , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/metabolism
7.
Article in English | WPRIM | ID: wpr-929019

ABSTRACT

OBJECTIVES@#Genetic mutation is one of the important causes for tumor genesis and development, but genetic mutation in nasopharyngeal carcinoma (NPC) has rarely been reported. This study explored the role of phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt), mammalian target of rapamycin (mTOR), and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway in the efficacy and prognosis in patients with NPC.@*METHODS@#A total of 31 patients with advanced NPC, who came from the Affiliated Cancer Hospital of Xiangya School of Medicine of Central South University/Hunan Provincial Cancer Hospital, were enrolled. All of the exons of 288 genes, introns of 38 genes and promoters or fusion breakpoint regions from the nasopharyngeal biopsy tissues before treatment were detected by the gene sequencing platform Illumina NextSeq CN500. The coding regions of 728 genes were carried out a high-depth sequencing of target region capture, and the 4 variant types of tumor genes (including point mutations, insertion deletions of small fragments, copy number variations, and currently known fusion genes) were detected. All of 31 patients received platinum-based induction chemotherapy combined with concurrent chemoradiotherapy and were followed up for a long time.@*RESULTS@#The 3-year regional failure-free survival (RFFS) and disease-free survival (DFS) in patients with PI3K-Akt pathway mutation were significantly lower than those in unmutated patients (χ2=6.647, P<0.05). The 3-year RFFS and DFS in patients with mTOR pathway mutations were significantly lower than those in unmutated patients, and there was significant difference (χ2=5.570, P<0.05). The rate of complete response (CR) in patients with unmutated AMPK pathway was significantly higher than that in patients with mutation at 3 months after treatment (P<0.05), and the 3-year RFFS and DFS in patients with AMPK pathway mutation were significantly lower than those in unmutated patients (χ2=4.553, P<0.05). PI3K-Akt/mTOR/AMPK signaling pathway mutations and pre-treatment EB virus DNA copy numbers were independent prognostic factors for 3-year RFFS and DFS in patients with NPC (both P<0.05).@*CONCLUSIONS@#The NPC patients with PI3K-Akt/mTOR/AMPK signaling pathway mutation have poor prognosis, and the detection of PI3K-Akt, mTOR, AMPK driver genes and signaling pathways by next-generation sequencing is expected to provide new idea for basic research and targeted therapy of NPC.


Subject(s)
AMP-Activated Protein Kinases/metabolism , DNA Copy Number Variations , Humans , Mutation , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Prognosis , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Sirolimus , TOR Serine-Threonine Kinases/metabolism
8.
In. Soeiro, Alexandre de Matos; Leal, Tatiana de Carvalho Andreucci Torres; Accorsi, Tarso Augusto Duenhas; Gualandro, Danielle Menosi; Oliveira Junior, Múcio Tavares de; Caramelli, Bruno; Kalil Filho, Roberto. Manual da residência em cardiologia / Manual residence in cardiology. Santana de Parnaíba, Manole, 2 ed; 2022. p.377-382, tab, ilus.
Monography in Portuguese | LILACS | ID: biblio-1352599
9.
Cienc. Salud (St. Domingo) ; 6(1): [81-85], ene.-abr. 2022.
Article in English | LILACS | ID: biblio-1366938

ABSTRACT

Las malformaciones linfáticas y su manejo no han sido bien descritas en República Dominicana. Es por ello, que el objetivo de este artículo es la presentación de tres casos, con diferentes patrones y necesidades de tratamiento, de modo que sirva como referencia para trabajadores de la salud en países en vías de desarrollo.


Lymphatic malformations and its management are not well described in the Dominican Republic. That is why this article's objective is to present 3 cases, with different patterns and treatment needs, so it will work as a reference for healthcare workers in developing countries.


Subject(s)
Humans , Male , Female , Child , Lymphangioma, Cystic , Sclerotherapy , Sirolimus
10.
Arch. argent. pediatr ; 119(3): e264-e268, Junio 2021. ilus
Article in Spanish | LILACS, BINACIS | ID: biblio-1248231

ABSTRACT

La linfangiomatosis pulmonar difusa es una enfermedad rara caracterizada por una marcada proliferación y dilatación de los vasos linfáticos en los pulmones, la pleura y el mediastino. Se desconoce la prevalencia, y la etiología no se comprende completamente.Una niña de 22 meses ingresó por poliserositis, con derrame pericárdico y pleural. Requirió pericardiocentesis y avenamiento pleural, y presentó drenaje de quilo (1,5-4 litros/día) sin respuesta al tratamiento médico (ayuno, nutrición parenteral y octreotide). Se realizó biopsia pulmonar. La anatomía patológica mostró hallazgos compatibles con linfangiomatosis difusa pulmonar. Comenzó tratamiento con sirolimus y propanolol, que disminuyeron las pérdidas por el drenaje pleural a la semana. Presentó buena evolución; suspendió aporte de oxígeno y se retiró el drenaje pleural. Se externó al cuarto mes de internación. El diagnóstico temprano de la linfangiomatosis pulmonar difusa es difícil de lograr, pero permite aplicar terapéuticas que evitan la progresión de enfermedad y disminuir la morbimortalida


Diffuse pulmonary lymphangiomatosis is a rare disease characterized by marked proliferation and dilation of lymphatic vessels in the lungs, pleura, and mediastinum. The prevalence is unknown and the etiology is not fully understood.A 22-month-old girl was admitted for polyserositis, with pericardial and pleural effusion. She required pericardiocentesis and pleural drainage, presenting chyle drainage (1.5-4 liters/day) without response to medical treatment (fasting, parenteral nutrition and octreotide). A lung biopsy was performed. The pathological anatomy showed findings compatible with diffuse pulmonary lymphangiomatosis. Treatment with sirolimus and propanolol began, decreasing losses due to pleural drainage one week after treatment. She progressed well, discontinued oxygen supply and pleural drainage was removed, leaving the patient after the fourth month of hospitalization.Early diagnosis of diffuse pulmonary lymphangiomatosis is difficult to achieve, but it allows the application of therapies that prevent disease progression, reducing morbidity and mortality.


Subject(s)
Humans , Female , Infant , Lung Diseases/congenital , Lymphangiectasis/congenital , Pleural Effusion , Propranolol/therapeutic use , Biopsy , Sirolimus/therapeutic use , Lung Diseases/pathology , Lung Diseases/diagnostic imaging , Lymphangiectasis/pathology , Lymphangiectasis/diagnostic imaging
11.
Journal of Experimental Hematology ; (6): 1667-1670, 2021.
Article in Chinese | WPRIM | ID: wpr-922314

ABSTRACT

Autoimmune cytopenia is a general term for all hemocytopenia diseases caused by humoral or cellular immunity abnormalities, and its common immune mechanism determines the importance of immunosuppressive therapy. Sirolimus, as an immunosuppressant against of mTOR, induces immune tolerance by adjusting Treg cells, which has application prospect in the treatment of refractory autoimmune cytopenia. This article reviews the mechanism, application, and possible adverse reactions of sirolimus in the treatment of idiopathic autoimmune cytopenia.


Subject(s)
Humans , Immunosuppressive Agents , Sirolimus , T-Lymphocytes, Regulatory , Thrombocytopenia
12.
Article in English | WPRIM | ID: wpr-922250

ABSTRACT

To investigate the mechanism of rapamycin in promoting asthmatic regulatory T cell differentiation . Asthma model was prepared by sensitization and challenge of ovalbumin in mice. Spleen CD4CD25 T cells were sorted from the asthmatic mice and normal mice by ultrahigh speed flow cytometer, and divided into three groups. Transforming growth factor-β and interleukin-2, or combined with rapamycin (final concentration of 500 nmol/L) were given in the model group or the rapamycin group. The levels of Treg cells and CD4CD25 T cells were detected by flow cytometry. The phosphorylation level of downstream proteins of S6 and Akt in the mTORC1/2 signaling pathway were examined by Western blotting. Compared with the model group, the differentiation level of Treg cells in the rapamycin group was significantly increased, the proliferation level of CD4CD25 T cells was decreased, and the phosphorylations of the mTORC1/2 substrates, S6 protein and Akt were decreased (all <0.05). Rapamycin can promote the differentiation and function of Treg cells via inhibition of the mTORC1/2 signaling pathway.


Subject(s)
Animals , Asthma , Cell Differentiation , Mice , Phosphorylation , Signal Transduction , Sirolimus/pharmacology , T-Lymphocytes, Regulatory
13.
Journal of Experimental Hematology ; (6): 1911-1916, 2021.
Article in Chinese | WPRIM | ID: wpr-922223

ABSTRACT

OBJECTIVE@#To investigate the clinical efficacy of calcitriol combined with sirolimus in the treatment of chronic primary immune thrombocytopenia (cITP) patients.@*METHODS@#A total of 146 adult cITP patients reated in the First Affiliated Hospital of Hebei North University from March 2017 to March 2020 were randomly divided into observation group (73 cases) and control group (73 cases) according to random number table. The control group was treated with oral sirolimus capsule, the observation group was treated with oral calcitriol capsule combined with sirolimus capsule, and the curative effect of the 2 groups was evaluated after continuous treatment for 6 weeks. The changes of World Health Organization (WHO) bleeding grade, laboratory related index, including peripheral blood regulatory T cell (Treg), serum 1,25-dihydroxy-vitamin D@*RESULTS@#The total effective rate of the observation group was 79.5% (58/73), which was significantly higher than 64.4% (47/73) of the control group (P<0.05). The revised WHO bleeding grades after treatment were significantly better than those before treatment in the 2 groups (P<0.05), but the observation group was improved more significantly than the control group (P<0.05). After treatment, platelet count (PLT), peripheral blood Treg cell ratio, and serum 1,25(OH)@*CONCLUSION@#The overall efficacy of calcitriol combined with sirolimus in the treatment of cITP in adults is satisfactory, which can effectively alleviate patient's condition, improve the quality of life, further increase the platelet level and decrease the expression of VDR in peripheral blood lymphocyte, the mechanism may be related to increasing the level of serum 1,25(OH)


Subject(s)
Calcitriol , Humans , Platelet Count , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Quality of Life , Sirolimus
14.
Chinese Journal of Cardiology ; (12): 128-135, 2021.
Article in Chinese | WPRIM | ID: wpr-941248

ABSTRACT

Objective: To evaluate the 4-year clinical outcomes of patients following Firesorb bioresorbable scaffold (BRS) implantation. Methods: The study reported the 4-year follow-up results of the FUTURE I study. FUTURE I was a prospective, single-center, open-label, first-in-man study which evaluated the feasibility, preliminary safety, and efficacy of Firesorb stent in the treatment of coronary artery stenosis. A total of 45 patients with single de novo lesions in native coronary arteries ,who hospitalized in Fuwai Hospital from January to March 2016 were enrolled. After successfully stent implantation these patients were randomized in a 2∶1 ratio into cohort 1 (n=30) or cohort 2 (n=15). The patients in cohort 1 underwent angiographic, IVUS or OCT examination at 6 months and 2 years; and cohort 2 underwent angiographic, IVUS or OCT at 1 and 3 years. All patients underwent clinical follow-up at 1, 6 months and 1 year and annually thereafter up to 5 years. The primary endpoint was target lesion failure (TLF, including cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization). Secondary endpoints included patient-oriented composite endpoint (PoCE, defined as composite of all death, all miocardial infarction, or any revascularization). Results: A total of 45 patients were enrolled and implanted with Firesorb BRS, including 35 males (77.8%), and the age was (54.4±9.3) years. At 4 years, 10 patients in cohort 1 were reexamined by coronary angiography and OCT examination. Among them, 2 patients' stents were completely degraded and absorbed. Compared with the OCT images of the other 8 patients in cohort 2 at 3 years, the degree of stent degradation was increased, and no stent adherence was found. The 4-year clinical follow-up rate was 100%. In 4-year clinical following up, 2 patients suffered PoCE (4.4%): 1 patient underwent non-target vessel revascularization the day after index procedure and target vessel revascularization (Non-target lesion revascularization) at 2-year imaging follow-up; the other patient underwent target lesion revascularization during imaging follow-up at 4 years but not due to ischemic driven. There was no scaffold thrombosis or TLF events through 4 years. Conclusions: Four years after the implantation, complete degradation and absorption of the Firsorb stent are evidenced in some patients. Firesorb stent is feasible and effective in the treatment of patients with non-complex coronary lesions.


Subject(s)
Absorbable Implants , Cardiovascular Agents , Coronary Artery Disease/surgery , Drug-Eluting Stents , Humans , Male , Middle Aged , Percutaneous Coronary Intervention , Prospective Studies , Sirolimus , Treatment Outcome
15.
Chinese Journal of Cardiology ; (12): 121-127, 2021.
Article in Chinese | WPRIM | ID: wpr-941247

ABSTRACT

Objective: To evaluate the five-year safety and efficacy of the second generation biodegradable polymer sirolimus-eluting stent (EXCROSSAL) in treating patients with de novo coronary artery diseases. Methods: Patients with coronary artery disease (CAD)who were implanted with EXTROSSAL stents in CREDIT Ⅱ and CREDIT Ⅲ study were included. CREDIT Ⅱ was a randomized trial, and CREDIT Ⅲ was a single-arm study. From November 2013 to December 2014, 833 CAD patients with de novo coronary lesions implanted with EXTROSSAL stents were selected from 33 centers in China. The primary outcome was 5-year target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction and clinically indicated target lesion revascularization. Secondary endpoints was patient-oriented composite endpoint (PoCE), including all-cause death, all myocardial infarction, or any revascularization within 5 years post stenting and stent thrombosis according to Academic Research Consortium's (ARC) definition. Kaplan Meier method was used to calculate the incidence of TLF and PoCE within 5 years after operation. Univariate Cox regression analysis was used to analyze the impacts of diabetes, small vessel disease (vessel diameter ≤ 2.74 mm), lesion length ≥ 16.7 mm and multivessel disease on the incidence of TLF within 5 years after operation. Results: A total of 833 patients were included in this study including 579 males (69.5%), the age was (59.3±9.1) years. And 832 (99.9%) patients completed 5-year clinical follow-up. The incidence of TLF and PoCE in the 5-year follow-up were 10.6%(86/811) and 15.5%(126/811), respectively. Stent thrombosis occurred in 1.0%(8/811) of patients. Univariate Cox regression analysis showed that vessel diameter ≤ 2.74 mm (HR=3.20,95%CI 1.90-5.39,P<0.001), lesion length ≥ 16.7 mm (HR=1.88,95%CI 1.18-2.99,P=0.007) and multivessel disease (HR=2.44,95%CI 1.60-3.72,P<0.001) were related factors of TLF within 5 years after operation. Conclusion: EXCROSSAL stent is effective and safe in treating CAD patients with de novo coronary lesions, with low incidence of TLF and PoCE within 5 years after operation.


Subject(s)
Aged , Cardiovascular Agents , China , Coronary Artery Disease/surgery , Drug-Eluting Stents , Humans , Male , Middle Aged , Percutaneous Coronary Intervention , Polymers , Risk Factors , Sirolimus/therapeutic use , Time Factors , Treatment Outcome
16.
Acta Physiologica Sinica ; (6): 137-142, 2021.
Article in Chinese | WPRIM | ID: wpr-878243

ABSTRACT

Rapamycin (Rap) is an immunosuppressant, which is mainly used in the anti-rejection of organ transplantation. Meanwhile, it also shows great potential in the fields of anticancer, neuroprotection and anti-aging. Rap can inhibit the activity of mammalian target of Rap (mTOR). It activates the transcription factor EB (TFEB) to up-regulate lysosomal function and eliminates the inhibitory effect of mTOR on ULK1 (unc-51 like autophagy activating kinase 1) to promote autophagy. Recent research showed that Rap can directly activate the lysosomal cation channel TRPML1 in an mTOR-independent manner. TRPML1 activation releases lysosomal calcium. Calcineurin functions as the sensor of the lysosomal calcium signal and activates TFEB, thus promoting lysosome function and autophagy. This finding has greatly broadened and deepened our understanding of the pharmacological roles of Rap. In this review, we briefly introduce the canonical Rap-mTOR-ULK1/TFEB signaling pathway, and then discuss the discovery of TRPML1 as a new target of Rap and the pharmacological potential of this novel Rap-TRPML1-Calcineurin-TFEB pathway.


Subject(s)
Autophagy , Calcium/metabolism , Calcium Channels , Lysosomes/metabolism , Signal Transduction , Sirolimus
17.
Rev. bras. anestesiol ; 70(6): 627-634, Nov.-Dec. 2020. graf
Article in English | LILACS | ID: biblio-1155766

ABSTRACT

Abstract Background and objectives The mechanisms by which local anesthetics cause neurotoxicity are very complicated. Apoptosis and autophagy are highly coordinated mechanisms that maintain cellular homeostasis against stress. Studies have shown that autophagy activation serves as a protective mechanism in vitro. However, whether it also plays the same role in vivo is unclear. The aim of this study was to explore the role of autophagy in local anesthetic-induced neurotoxicity and to elucidate the mechanism of neurotoxicity in an intrathecally injected rat model. Methods Eighteen healthy adult male Sprague-Dawley rats were randomly divided into three groups. Before receiving an intrathecal injection of 1% bupivacaine, each rat received an intraperitoneal injection of vehicle or rapamycin (1 mg.kg-1) once a day for 3 days. The pathological changes were examined by Haematoxylin and Eosin (HE) staining. Apoptosis was analysed by TdT-mediated dUTP Nick-End Labelling (TUNEL) staining. Caspase-3, Beclin1 and LC3 expression was examined by Immunohistochemical (IHC) staining. Beclin1 and LC3 expression and the LC3-II/LC3-I ratio were detected by western blot analysis. Results After bupivacaine was injected intrathecally, pathological damage occurred in spinal cord neurons, and the levels of apoptosis and caspase-3 increased. Enhancement of autophagy with rapamycin markedly alleviated the pathological changes and decreased the levels of apoptosis and caspase-3 while increasing the expression of LC3 and Beclin1 and the ratio of LC3-II to LC3-I. Conclusions Enhancement of autophagy decreases caspase-3-dependent apoptosis and improves neuronal survivalin vivo. Activation of autophagy may be a potential therapeutic strategy for local anaesthetic-induced neurotoxicity.


Resumo Introdução e objetivos Os mecanismos de neurotoxicidade dos anestésicos locais são complexos. A apoptose e a autofagia são mecanismos altamente organizados que mantêm a homeostase celular durante o estresse. Estudos revelam que a ativação da autofagia atua como mecanismo de proteção in vitro. Não está claro se a autofagia também desempenha essa função in vivo. O objetivo deste estudo foi analisar o papel da autofagia na neurotoxicidade induzida por anestésico local e esclarecer o mecanismo dessa neurotoxicidade utilizando um modelo de injeção intratecal em ratos. Métodos Dezoito ratos Sprague‐Dawley machos adultos saudáveis foram divididos aleatoriamente em três grupos. Antes de receber a injeção intratecal de bupivacaína a 1%, cada rato recebeu injeção intraperitoneal de veículo ou rapamicina (1 mg.kg‐1) uma vez ao dia durante 3 dias. As alterações patológicas foram examinadas por coloração com Hematoxilina e Eosina (HE). A apoptose foi analisada por coloração com o método dUTP Nick‐End Labeling (TUNEL) mediado por TdT. A expressão de caspase‐3, Beclin1 e LC3 foram examinadas por coloração Imunohistoquímica (IHQ). A expressão de Beclin1 e LC3 e a razão LC3‐II/LC3‐I foram detectadas por análise de western blot. Resultados Após a injeção intratecal de bupivacaína, ocorreu lesão patológica nos neurônios da medula espinhal e os níveis de apoptose e caspase‐3 aumentaram. A ativação da autofagia causada pela rapamicina mitigou de forma expressiva as alterações patológicas e diminuiu os níveis de apoptose e caspase‐3, aumentando a expressão de LC3 e Beclin1 e a razão LC3‐II/LC3‐I. Conclusões O aumento da autofagia diminui a apoptose dependente da caspase‐3 e melhora a sobrevivência neuronal in vivo. A ativação da autofagia pode ser uma estratégia terapêutica potencial para a neurotoxicidade induzida por anestésicos locais.


Subject(s)
Animals , Male , Rats , Autophagy/drug effects , Bupivacaine/toxicity , Neurotoxicity Syndromes/prevention & control , Caspase 3/metabolism , Anesthetics, Local/toxicity , Neurons/drug effects , Spinal Cord/drug effects , Autophagy/physiology , Bupivacaine/administration & dosage , Random Allocation , Rats, Sprague-Dawley , Apoptosis/drug effects , Sirolimus/administration & dosage , In Situ Nick-End Labeling , Beclin-1/metabolism , Microtubule-Associated Proteins/metabolism , Neurons/pathology
18.
Gac. méd. Méx ; 156(4): 276-282, Jul.-Aug. 2020. graf
Article in English | LILACS | ID: biblio-1249911

ABSTRACT

Abstract Introduction: A drug-eluting coronary stent is being developed at the National Institute of Cardiology of Mexico for the treatment of ischemic heart disease. Objective: To establish the best animal model for the tests, to show the advances in the drug-eluting stent prototype, to assess two drugs’ antiproliferative activity and histological results. Method: Smooth muscle cell culture tests were performed in order to assess sirolimus and paclitaxel antiproliferative properties. The drugs were encapsulated inside the polymeric matrix of the stents. Rabbits and pigs were used as animal models. Results: Sirolimus and paclitaxel showed an inhibitory effect, which was higher for the latter. Infrared spectroscopy and light and optical microscopy showed that the drug/polymer layer properly adhered to the stent. At a four-week follow-up, both animal models showed satisfactory clinical evolution and adequate histological response, although the porcine model was shown to be more suitable for future protocols. Conclusions: Preliminary tests of the drug-eluting stent provided bases for the development of a study protocol with an adequate number of pigs and with clinical angiographic and histopathological three-month follow-up.


Resumen Introducción: En el Instituto Nacional de Cardiología de México se desarrolla una endoprótesis (stent) coronaria liberadora de fármacos para el tratamiento de la cardiopatía isquémica. Objetivo: Establecer el mejor modelo animal para las pruebas, mostrar los avances en el prototipo del stent liberador de fármacos, evaluar la actividad antiproliferativa de dos fármacos y los resultados histológicos. Método: Se realizaron cultivos de células de músculo liso para evaluar las propiedades antiproliferativas de sirolimus y paclitaxel. Los fármacos fueron encapsulados en el interior de la matriz polimérica de los stents. Se emplearon conejos y cerdos como modelos animales. Resultados: Sirolimus y paclitaxel mostraron efecto inhibitorio, mayor en el segundo. La espectroscopia infrarroja y la microscopia óptica y electrónica mostraron que la capa del polímero con el fármaco se adhería adecuadamente al stent. A las cuatro semanas de seguimiento, ambos modelos animales mostraron evolución clínica satisfactoria y adecuada respuesta histológica, si bien el modelo porcino resultó más conveniente para protocolos futuros. Conclusiones: Las pruebas preliminares del stent liberador de fármaco brindó bases para desarrollar el protocolo con un número adecuado en cerdos y con seguimiento clínico angiográfico e histopatológico a tres meses.


Subject(s)
Animals , Male , Female , Rabbits , Paclitaxel/administration & dosage , Sirolimus/administration & dosage , Drug-Eluting Stents , Prosthesis Design , Spectrophotometry, Infrared , Swine , Follow-Up Studies , Disease Models, Animal , Microscopy
19.
Chinese Journal of Cardiology ; (12): 111-117, 2020.
Article in Chinese | WPRIM | ID: wpr-941069

ABSTRACT

Objective: To evaluate the long-term prognosis of coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI) by risk stratification with American College of Cardiology (ACC)/American Heart Association (AHA) classification of coronary lesions. Methods: Data used in this study derived from the I-LOVE-IT 2 trial. I-LOVE-IT 2 trial was a prospective, multicenter, randomized, assessor-blinded, noninferiority study. A total of 1 255 patients in I-LOVE-IT 2 trial with only one lesion and underwent biodegradable polymer drug-eluting stent implantation were included and grouped according to ACC/AHA classification of coronary lesions, namely type A/B1 lesion group (n=184), type B2 lesion group (n=457) and type C lesion group (n=614). The primary endpoint was 48-month patient-oriented composite endpoint (PoCE), a composite of all-cause mortality, all myocardial infarction, stroke, and/or any revascularization. The secondary endpoints were target lesion failure (TLF), components of PoCE, major bleeding (bleeding academic research consortium(BARC) type 3-5) and definite/probable stent thrombosis within 48 months. The incidences of endpoint events were compared in the three groups. The multivariable Cox hazard ratio model was used to analyze the independent predictors of PoCE and TLF at 48 months. Results: Incidences of PoCE at 48 months were significantly higher in patients with type C lesion compared with patients with type A/B1 (24.43%(150/614) vs. 14.13%(26/184), P<0.05) or B2 lesion (24.43%(150/614) vs. 15.97%(73/457), P<0.05). The multivariable Cox hazard ratio model showed that the type C lesion were the independent predictors of 48-month PoCE (HR=1.59, 95%CI 1.21-2.08, P<0.001) and TLF (HR=2.31, 95%CI 1.53-3.49, P<0.001). After multivariable adjustment, the HRs of PoCE for patients with type C lesion versus type A/B1 and type B2 were 1.91 (95%CI 1.25-2.92, P=0.003) and 1.64 (95%CI 1.23-2.20, P<0.001), respectively. Meanwhile, the HRs of TLF for patients with type C lesion versus type A/B1 and type B2 were 2.45 (95%CI 1.29-4.64, P=0.006) and 2.55 (95%CI 1.62-4.02, P=0.001), respectively. Conclusions: The ACC/AHA classification of coronary lesions has good discrimination with long-term outcomes for CAD patients undergoing PCI. The type C lesion is associated with a worse prognosis, enough attention should be paid in these patients during routine clinical management.


Subject(s)
Cardiovascular Agents , Coronary Artery Disease , Drug-Eluting Stents , Humans , Percutaneous Coronary Intervention , Prognosis , Prospective Studies , Risk Assessment , Risk Factors , Sirolimus , Treatment Outcome
20.
Article in Chinese | WPRIM | ID: wpr-828628

ABSTRACT

To study the clinical effect of oral sirolimus in the treatment of children with blue rubber bleb nevus syndrome (BRBNS) in the gastrointestinal tract, a retrospective analysis was performed on the clinical data and follow-up results of two children with BRBNS treated by sirolimus. The two children with BRBNS had gastrointestinal bleeding and anemia and were treated with sirolimus at a dose of 1 mg/day as part of treatment. The plasma concentration of the drug was maintained between 2.5-12.0 ng/mL. The children showed disappearance of gastrointestinal bleeding and improvements in anemia and coagulation function, and blood transfusion could be stopped during treatment, with no obvious adverse drug reactions. PubMed, Wanfang Data, and CNKI were searched for related articles on sirolimus in the treatment of BRBNS. A total of 26 cases of children with BRBNS, aged 0-18 years, were obtained. With the addition of the 2 cases in this study, sirolimus treatment achieved a satisfactory clinical effect in all 28 cases. Sirolimus may be effective and safe in the treatment of children with BRBNS, and further prospective studies are needed to evaluate the long-term efficacy of this drug.


Subject(s)
Adolescent , Child , Child, Preschool , Gastrointestinal Neoplasms , Drug Therapy , Humans , Infant , Infant, Newborn , Nevus, Blue , Drug Therapy , Prospective Studies , Retrospective Studies , Sirolimus , Therapeutic Uses , Skin Neoplasms , Drug Therapy
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