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1.
Mol Med ; 29(1): 164, 2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-38049750

RESUMO

BACKGROUND: Lung ischemia-reperfusion (I/R) injury is a serious clinical problem without effective treatment. Enhancing branched-chain amino acids (BCAA) metabolism can protect against cardiac I/R injury, which may be related to bioactive molecules generated by BCAA metabolites. L-ß-aminoisobutyric acid (L-BAIBA), a metabolite of BCAA, has multi-organ protective effects, but whether it protects against lung I/R injury is unclear. METHODS: To assess the protective effect of L-BAIBA against lung I/R injury, an animal model was generated by clamping the hilum of the left lung, followed by releasing the clamp in C57BL/6 mice. Mice with lung I/R injury were pre-treated or post-treated with L-BAIBA (150 mg/kg/day), given by gavage or intraperitoneal injection. Lung injury was assessed by measuring lung edema and analyzing blood gases. Inflammation was assessed by measuring proinflammatory cytokines in bronchoalveolar lavage fluid (BALF), and neutrophil infiltration of the lung was measured by myeloperoxidase activity. Molecular biological methods, including western blot and immunofluorescence, were used to detect potential signaling mechanisms in A549 and BEAS-2B cells. RESULTS: We found that L-BAIBA can protect the lung from I/R injury by inhibiting ferroptosis, which depends on the up-regulation of the expressions of GPX4 and SLC7A11 in C57BL/6 mice. Additionally, we demonstrated that the Nrf-2 signaling pathway is key to the inhibitory effect of L-BAIBA on ferroptosis in A549 and BEAS-2B cells. L-BAIBA can induce the nuclear translocation of Nrf-2. Interfering with the expression of Nrf-2 eliminated the protective effect of L-BAIBA on ferroptosis. A screening of potential signaling pathways revealed that L-BAIBA can increase the phosphorylation of AMPK, and compound C can block the Nrf-2 nuclear translocation induced by L-BAIBA. The presence of compound C also blocked the protective effects of L-BAIBA on lung I/R injury in C57BL/6 mice. CONCLUSIONS: Our study showed that L-BAIBA protects against lung I/R injury via the AMPK/Nrf-2 signaling pathway, which could be a therapeutic target.


L-BAIBA upregulates the expression of GPX4 and SLC7A11 by activating the AMPK/Nrf-2/GPX4/SLC7A11 signaling pathway, thereby protecting against I/R-induced increase in ROS and ferroptosis in the lung.


Assuntos
Ferroptose , Traumatismo por Reperfusão , Camundongos , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Camundongos Endogâmicos C57BL , Pulmão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
2.
Acta Pharm Sin B ; 13(9): 3756-3769, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37719375

RESUMO

Myocardial dysfunction is the most serious complication of sepsis. Sepsis-induced myocardial dysfunction (SMD) is often associated with gastrointestinal dysfunction, but its pathophysiological significance remains unclear. The present study found that patients with SMD had higher plasma gastrin concentrations than those without SMD. In mice, knockdown of the gastrin receptor, cholecystokinin B receptor (Cckbr), aggravated lipopolysaccharide (LPS)-induced cardiac dysfunction and increased inflammation in the heart, whereas the intravenous administration of gastrin ameliorated SMD and cardiac injury. Macrophage infiltration plays a significant role in SMD because depletion of macrophages by the intravenous injection of clodronate liposomes, 48 h prior to LPS administration, alleviated LPS-induced cardiac injury in Cckbr-deficient mice. The intravenous injection of bone marrow macrophages (BMMs) overexpressing Cckbr reduced LPS-induced myocardial dysfunction. Furthermore, gastrin treatment inhibited toll-like receptor 4 (TLR4) expression through the peroxisome proliferator-activated receptor α (PPAR-α) signaling pathway in BMMs. Thus, our findings provide insights into the mechanism of the protective role of gastrin/CCKBR in SMD, which could be used to develop new treatment modalities for SMD.

3.
Biochem Biophys Res Commun ; 676: 149-157, 2023 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-37517217

RESUMO

Glioblastoma (GBM) has a high degree of invasiveness, which is largely attributed to the invalidation of current therapy and the unclear tumor growth mechanism. Ras related GTP binding B (RRAGB) is a family member of the Ras-homologous GTPases. The effect of RRAGB on tumor growth has been recognized, but its influences on GBM progression are ill-defined. Here, in our research, a significantly decreased expression of RRAGB in GBM tissues by using TCGA databases and glioma samples is observed. According to Kaplan-Meier (KM) analysis, RRAGB low expression leads to a significant decrease of overall survival rate of patients, and is associated with the classification of WHO grade, histological type and age increase. Functional enrichment analysis reveals that the pathway of enrichment includes cell cycle arrest, extracellular matrix (ECM) processes and PI3K/AKT signal. Thereafter, our cell experiments confirm an obvious decrease of RRAGB in several GBM cell lines. It should be noted that RRAGB promotion strongly reduces the proliferation, migration and invasion of GBM cells and induces cell cycle arrest in G0/G1 phase. RRAGB up-regulation significantly decreases the expression of PI3K, phosphorylated AKT, mTOR and S6K in GBM cell lines. Surprisingly, we further find that RRAGB-restrained proliferative, migratory and invasive properties of GBM cells are markedly offset after promoting AKT activation, accompanied with restored phosphorylation of mTOR and S6K, elucidating that AKT signaling blockage is partially indispensable for RRAGB to play its anti-cancer role in GBM. Animal studies confirmed that RRAGB over-expression obviously inhibits the tumor growth both in the xenograft and orthotopic mouse glioma models, along with improved overall survival rates. In short, we provide evidence that RRAGB is a potential therapeutic target and prognostic marker for GBM treatment.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Proteínas Monoméricas de Ligação ao GTP , Camundongos , Animais , Humanos , Glioblastoma/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células , Linhagem Celular Tumoral , Apoptose , Serina-Treonina Quinases TOR/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Monoméricas de Ligação ao GTP/metabolismo
4.
Kidney Int ; 103(4): 719-734, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36669643

RESUMO

Ischemia/reperfusion injury of the kidney is associated with high morbidity and mortality, and treatment of this injury remains a challenge. G protein-coupled receptor kinase 4 (GRK4) plays a vital role in essential hypertension and myocardial infarction, but its function in kidney ischemia/reperfusion injury remains undetermined. Among the GRK subtypes (GRK2-6) expressed in kidneys, the increase in GRK4 expression was much more apparent than that of the other four GRKs 24 hours after injury and was found to accumulate in the nuclei of injured mouse and human renal tubule cells. Gain- and loss-of-function experiments revealed that GRK4 overexpression exacerbated acute kidney ischemia/reperfusion injury, whereas kidney tubule-specific knockout of GRK4 decreased injury-induced kidney dysfunction. Necroptosis was the major type of tubule cell death mediated by GRK4, because GRK4 significantly increased receptor interacting kinase (RIPK)1 expression and phosphorylation, subsequently leading to RIPK3 and mixed lineage kinase domain-like protein (MLKL) phosphorylation after kidney ischemia/reperfusion injury, but was reversed by necrostatin-1 pretreatment (an RIPK1 inhibitor). Using co-immunoprecipitation, mass spectrometry, and siRNA screening studies, we identified signal transducer and activator of transcription (STAT)1 as a GRK4 binding protein, which co-localized with GRK4 in the nuclei of renal tubule cells. Additionally, GRK4 phosphorylated STAT1 at serine 727, whose inactive mutation effectively reversed GRK4-mediated RIPK1 activation and tubule cell death. Kidney-targeted GRK4 silencing with nanoparticle delivery considerably ameliorated kidney ischemia/reperfusion injury. Thus, our findings reveal that GRK4 triggers necroptosis and aggravates kidney ischemia/reperfusion injury, and its downregulation may provide a promising therapeutic strategy for kidney protection.


Assuntos
Injúria Renal Aguda , Traumatismo por Reperfusão , Animais , Humanos , Camundongos , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/complicações , Morte Celular , Regulação para Baixo , Rim/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores Acoplados a Proteínas G/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/prevenção & controle
5.
Contrast Media Mol Imaging ; 2022: 7855576, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36159172

RESUMO

Objective: To explore the effect of CT/MRI image fusion on cerebrovascular protection, postoperative complications and limb function recovery in patients with anterior and middle skull base tumors. Methods: During January 2019 to December 2021, a retrospective study was conducted on 50 patients who underwent anterior and middle skull base tumor resection in the same surgeon group in our hospital. According to the different surgical approaches, the patients were assigned to the fusion group (n = 29) and the routine group (n = 21). The routine group was operated with traditional operation, and the fusion group was operated with CT/MRI image fusion technique. The operation time, wound volume, resection rate and Karnofsky performance status (KPS), blood transfusion (vascular protection), tumor resection rate, and postoperative complications were compared. Results: The time of operation in the fusion group was shorter compared to the routine group, and the volume of the wound cavity in the fusion group was smaller compared to the routine group, and the difference was statistically significant (P < 0.05). Following treatment, the KPS score of the fusion group was remarkably higher compared to the routine group, and the difference was statistically significant (P < 0.05). The intraoperative blood transfusion rate in the fusion group was 17.24%, and the intraoperative blood transfusion rate in the routine group was 47.62%, and the difference was statistically significant (P < 0.05). The resection rate in the fusion group (89.66%) was remarkably higher compared to the routine group (61.90%, P < 0.05). The incidence of postoperative complications in the fusion group (6.90%) was remarkably lower compared to the control group (33.33%, P < 0.05). Conclusion: The application of CT/MRI image-fusion technology can effectively enhance the clinical symptoms of patients with tumors in the anterior and middle region of the skull base, which can promote the prognosis, shorten the operation time, reduce unnecessary cerebral neurovascular injuries, and retain more brain functions.


Assuntos
Neoplasias da Base do Crânio , Humanos , Imageamento por Ressonância Magnética , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Recuperação de Função Fisiológica , Estudos Retrospectivos , Neoplasias da Base do Crânio/diagnóstico por imagem , Neoplasias da Base do Crânio/cirurgia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
7.
J Hepatol ; 76(3): 558-567, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34736969

RESUMO

BACKGROUND & AIMS: Drug-induced liver injury (DILI) remains challenging to treat and is still a leading cause of acute liver failure. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream and whose physiological role in protection against DILI has not been examined. METHODS: Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of Mg53 or Ripk3. Live-cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection. RESULTS: Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen, tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation. CONCLUSIONS: Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI. LAY SUMMARY: Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver cell protection. Thus, MG53 is a potential treatment option for patients with drug-induced liver injury.


Assuntos
Hepatócitos/citologia , Proteínas de Membrana/metabolismo , Substâncias Protetoras/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas , Citosol/metabolismo , Modelos Animais de Doenças , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Proteínas de Membrana/análise , Proteínas de Membrana/sangue , Camundongos , Fatores de Proteção
8.
Oxid Med Cell Longev ; 2021: 2999296, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712381

RESUMO

Calorie restriction (CR) extends lifespan and increases resistance to multiple forms of stress, including renal ischemia-reperfusion (I/R) injury. However, whether CR has protective effects on contrast-induced nephropathy (CIN) remains to be determined. In this study, we evaluated the therapeutic effects of CR on CIN and investigated the potential mechanisms. CIN was induced by the intravenous injection of iodinated contrast medium (CM) iopromide (1.8 g/kg) into Sprague Dawley rats with normal food intake or 40% reduced food intake, 4 weeks prior to iopromide administration. We found that CR was protective of CIN, assessed by renal structure and function. CM increased apoptosis, reactive oxygen species (ROS), and inflammation in the renal outer medulla, which were decreased by CR. The silent information regulator 1 (SIRT1) participated in the protective effect of CR on CIN, by upregulating glutathione peroxidase 4 (GPX4), a regulator of ferroptosis, because this protective effect was reversed by EX527, a specific SIRT1 antagonist. Our study showed that CR protected CIN via SIRT1/GPX4 activation. CR may be used to mitigate CIN.


Assuntos
Restrição Calórica , Nefropatias/prevenção & controle , Rim/enzimologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Sirtuína 1/metabolismo , Animais , Apoptose , Meios de Contraste , Citocinas/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Ferroptose , Mediadores da Inflamação/metabolismo , Iohexol/análogos & derivados , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/enzimologia , Nefropatias/patologia , Masculino , Estresse Oxidativo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
9.
Clin Sci (Lond) ; 135(2): 409-427, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33458737

RESUMO

Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin. However, the relationship between gastrin and renal fibrosis in HN is still unknown. We, now, report that mice with angiotensin II (Ang II)-induced HN had increased renal cholecystokinin receptor B (CCKBR) expression. Knockout of CCKBR in mice aggravated, while long-term subcutaneous infusion of gastrin ameliorated the renal injury and interstitial fibrosis in HN and unilateral ureteral obstruction (UUO). The protective effects of gastrin on renal fibrosis can be independent of its regulation of blood pressure, because in UUO, gastrin decreased renal fibrosis without affecting blood pressure. Gastrin treatment decreased Ang II-induced renal tubule cell apoptosis, reversed Ang II-mediated inhibition of macrophage efferocytosis, and reduced renal inflammation. A screening of the regulatory factors of efferocytosis showed involvement of peroxisome proliferator-activated receptor α (PPAR-α). Knockdown of PPAR-α by shRNA blocked the anti-fibrotic effect of gastrin in vitro in mouse renal proximal tubule cells and macrophages. Immunofluorescence microscopy, Western blotting, luciferase reporter, and Cut&tag-qPCR analyses showed that CCKBR may be a transcription factor of PPAR-α, because gastrin treatment induced CCKBR translocation from cytosol to nucleus, binding to the PPAR-α promoter region, and increasing PPAR-α gene transcription. In conclusion, gastrin protects against HN by normalizing blood pressure, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis. Gastrin-mediated CCKBR nuclear translocation may make it act as a transcription factor of PPAR-α, which is a novel signaling pathway. Gastrin may be a new potential drug for HN therapy.


Assuntos
Gastrinas/farmacologia , Hipertensão Renal/fisiopatologia , Nefrite/fisiopatologia , PPAR alfa/metabolismo , Receptores da Colecistocinina/metabolismo , Angiotensina II/administração & dosagem , Animais , Apoptose , Fibrose , Humanos , Hipertensão/complicações , Células Jurkat , Túbulos Renais Proximais/patologia , Camundongos , Camundongos Knockout , PPAR alfa/genética , Fagocitose , RNA Interferente Pequeno , Receptores da Colecistocinina/genética , Transdução de Sinais/efeitos dos fármacos , Obstrução Ureteral/fisiopatologia
10.
J Oncol ; 2021: 1827992, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34976054

RESUMO

Glioma is the most common malignant primary brain tumor with an inferior survival period and unsatisfactory prognoses. Identification of novel biomarkers is important for the improvements of clinical outcomes of glioma patients. In recent years, more and more biomarkers were identified in many types of tumors. However, the sensitive markers for diagnoses and prognoses of patients with glioma remained unknown. In the present research, our team intended to explore the expression and clinical significance of ABCC3 in glioma patients. Sequential data filtration (survival analyses, independent prognosis analyses, ROC curve analyses, and clinical association analyses) was completed, which gave rise to the determination of the relationship between glioma and the ABCC3 gene. Clinical assays on the foundation of CGGA and TCGA datasets unveiled that ABCC3 expression was distinctly upregulated in glioma and predicted a shorter overall survival. In the multivariable Cox analysis, our team discovered that the expression of ABCC3 was an independent prognosis marker for both 5-year OS (HR = 1.118, 95% CI: 1.052-1.188; P < 0.001). Moreover, our team also studied the association between ABCC3 expression and clinical features of glioma patients, finding that differential expression of ABCC3 was remarkably related to age, 1p19q codeletion, PRS type, chemo status, grade, IDH mutation state, and histology. Overall, our findings suggested ABCC3 might be a novel prognosis marker in glioma.

11.
Oncol Rep ; 36(5): 2689-2696, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27633091

RESUMO

Glioblastoma multiforme (GBM), which is associated with a high rate of morbidity and mortality, is among the most malignant and treatment-refractory neoplasms in human adults. As GBM is highly resistant to conventional therapies, immunotherapies are a promising treatment candidate. HER2 is an attractive target for GBM immunotherapy, as its expression is highly associated with various types of GBM. We previously reported that a novel HER2-targeted recombinant protein e23sFv-Fdt-casp6 has an antitumor effect on HER2-positive gastric cancer cells. In this study, we established a genetically modified Chinese hamster ovary cell line, which produced and secreted e23sFv-Fdt-casp6 proteins. Following specific binding to and internalization into HER2-overexpressing tumor cells, the e23sFv-Fdt-casp6 protein induced tumor cell apoptosis and inhibited the proliferation of HER2-overexpressing A172 and U251MG cells in vitro, but not in U87MG cells with undetectable HER2. The e23sFv-Fdt-casp6 gene was introduced into severe combined immunodeficient mice bearing human glioblastoma xenografts by using intramuscular injections of a liposome-encapsulated vector. The recombinant protein e23sFv-Fdt-casp6 specifically targeted tumor cells and induced apoptosis, thereby leading to potent inhibition of tumor growth and prolonged the survival time of tumor-bearing mice. We concluded that e23sFv­Fdt­casp6 represents a promising HER2-targeted treatment option for human gliomas.


Assuntos
Caspase 6/genética , Glioblastoma/genética , Receptor ErbB-2/genética , Proteínas Recombinantes de Fusão/genética , Animais , Apoptose/genética , Células CHO , Cricetinae , Cricetulus , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Humanos , Camundongos , Receptor ErbB-2/biossíntese , Ensaios Antitumorais Modelo de Xenoenxerto
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