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1.
Am J Pathol ; 193(12): 1936-1952, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37673330

RESUMO

Renal fibrosis is a pathologic process that leads to irreversible renal failure without effective treatment. Epithelial-to-mesenchymal transition (EMT) plays a key role in this process. The current study found that aberrant expression of IL-11 is critically involved in tubular EMT. IL-11 and its receptor subunit alpha-1 (IL-11Rα1) were significantly induced in renal tubular epithelial cells (RTECs) in unilateral ureteral obstruction (UUO) kidneys, co-localized with transforming growth factor-ß1. IL-11 knockdown ameliorated UUO-induced renal fibrosis in vivo and transforming growth factor-ß1-induced EMT in vitro. IL-11 intervention directly induced the transdifferentiation of RTECs to the mesenchymal phenotype and increased the synthesis of profibrotic mediators. The EMT response induced by IL-11 was dependent on the sequential activation of STAT3 and extracellular signal-regulated kinase 1/2 signaling pathways and the up-regulation of metadherin in RTECs. Micheliolide (MCL) competitively inhibited the binding of IL-11 with IL-11Rα1, suppressing the activation of STAT3 and extracellular signal-regulated kinase 1/2-metadherin pathways, ultimately inhibiting renal tubular EMT and interstitial fibrosis induced by IL-11. In addition, treatment with dimethylaminomicheliolide, a pro-drug of MCL for in vivo use, significantly ameliorated renal fibrosis exacerbated by IL-11 in the UUO model. These findings suggest that IL-11 is a promising target in renal fibrosis and that MCL/dimethylaminomicheliolide exerts its antifibrotic effect by suppressing IL-11/IL-11Rα1 interaction and blocking its downstream effects.


Assuntos
Transição Epitelial-Mesenquimal , Nefropatias , Obstrução Ureteral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Interleucina-11/metabolismo , Interleucina-11/farmacologia , Interleucina-11/uso terapêutico , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Nefropatias/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/farmacologia , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia , Animais , Camundongos
2.
BMC Infect Dis ; 23(1): 777, 2023 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-37946099

RESUMO

BACKGROUND: Patients presenting to the emergency department with community-acquired pneumonia (CAP) are characterized by advanced age, comorbidities, critical illness and less-than-typical symptoms, posing a diagnostic challenge. Plasma heparin-binding protein (HBP) and the heparin-binding protein-to-albumin ratio (HBP/Alb) have not been adequately studied in the early diagnosis of CAP. This study assessed the diagnostic value of plasma HBP, HBP/Alb, and conventional inflammatory markers in emergency department patients with CAP. METHODS: We enrolled 103 patients with CAP, retrospectively analyzed the patients' clinical data, and divided the CAP patients into antibiotic (n = 79) and non-antibiotic (n = 24) groups based on whether antibiotics were administered prior to blood sampling and laboratory tests. The control group was comprised of 52 non-infected patients admitted during the same period. Within 24 h of admission, plasma HBP, serum procalcitonin (PCT), white blood cell count (WBC), neutrophil-to-lymphocyte ratio (NLR) and HBP/Alb levels were collected separately and compared. The receiver operating characteristic (ROC) curve was plotted to assess the diagnostic value of each indicator for CAP patients. Utilizing the Kappa test, the consistency of each indicator used to evaluate CAP and clinical diagnosis was analyzed. Spearman correlation was used to analyze the correlation between plasma HBP and clinical indicators of CAP patients. RESULTS: Plasma HBP, serum PCT, WBC, NLR and HBP/Alb were all elevated in the CAP group in comparison to the control group (P < 0.001). Plasma HBP, serum PCT, WBC, NLR and HBP/Alb levels did not differ statistically between antibiotic and non-antibiotic groups (P > 0.05). Plasma HBP and HBP/Alb had the highest diagnostic accuracy for CAP, the area under the ROC curve (AUC) were 0.931 and 0.938 (P < 0.0001), and the best cut-off values were 35.40 ng/mL and 0.87, respectively. In evaluating the consistency between CAP and clinical diagnosis, the Kappa values for HBP, PCT, WBC, NLR and HBP/Alb were 0.749, 0.465, 0.439, 0.566 and 0.773, respectively. Spearman correlation analysis showed that plasma HBP was positively correlated with serum PCT, WBC, NLR and HBP/Alb in CAP patients (P < 0.001). CONCLUSIONS: Plasma HBP and HBP/Alb have a high clinical diagnostic value for CAP and can be used as good and reliable novel inflammatory markers in the emergency department for the early diagnosis of CAP patients.


Assuntos
Infecções Comunitárias Adquiridas , Pneumonia , Humanos , Estudos Retrospectivos , Proteína C-Reativa/análise , Pneumonia/diagnóstico , Pró-Calcitonina , Infecções Comunitárias Adquiridas/diagnóstico , Albuminas , Antibacterianos
3.
J Biol Chem ; 294(41): 15052-15067, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31431501

RESUMO

Peritoneal fibrosis is a common complication of long-term peritoneal dialysis (PD) and the principal cause of ultrafiltration failure during PD. The initial and reversible step in PD-associated peritoneal fibrosis is the epithelial-mesenchymal transition (EMT). Although the mechanisms in the EMT have been the focus of many studies, only limited information is currently available concerning microRNA (miRNA) regulation in peritoneal fibrosis. In this study, we aimed to characterize the roles of microRNA-145 (miR-145) and fibroblast growth factor 10 (FGF10) in peritoneal fibrosis. After inducing EMT with transforming growth factor-ß1 (TGF-ß1) in vitro, we found that miR-145 is significantly up-regulated, whereas FGF10 is markedly down-regulated, suggesting a close link between miR-145 and FGF10 in peritoneal fibrosis, further confirmed in luciferase reporter experiments. Furthermore, in human peritoneal mesothelial cells (i.e. HMrSV5 cells), miR-145 mimics induced EMT, whereas miR-145 inhibition suppressed EMT, and we also observed that miR-145 suppressed FGF10 expression. In vivo, we found that the exogenous delivery of an miR-145 expression plasmid both blocked FGF10 and intensified the EMT, whereas miR-145 inhibition promoted the expression of FGF10 and reversed the EMT. In conclusion, miR-145 promotes the EMT during the development of peritoneal fibrosis by suppressing FGF10 activity, suggesting that miR-145 represents a potential therapeutic target for managing peritoneal fibrosis.


Assuntos
Transição Epitelial-Mesenquimal/genética , Fator 10 de Crescimento de Fibroblastos/genética , MicroRNAs/genética , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/genética , Fibrose Peritoneal/patologia , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Linhagem Celular , Fator 10 de Crescimento de Fibroblastos/deficiência , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
Lab Invest ; 100(5): 786-787, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31420584

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

5.
Mediators Inflamm ; 2020: 3934769, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879619

RESUMO

Chronic kidney disease is a common disease closely related to renal tubular inflammation and oxidative stress, and no effective treatment is available. Activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important factor in renal inflammation, but the mechanism remains unclear. Micheliolide (MCL), which is derived from parthenolide, is a new compound with antioxidative and anti-inflammatory effects and has multiple roles in tumors and inflammatory diseases. In this study, we investigated the effect of MCL on lipopolysaccharide- (LPS-) induced inflammation in renal tubular cells and the related mechanism. We found that MCL significantly suppressed the LPS-induced NF-κB signaling and inflammatory expression of cytokines, such as tumor necrosis factor-α and monocyte chemoattractant protein-1 in a rat renal proximal tubular cell line (NRK-52E). MCL also prevented LPS- and adenosine triphosphate-induced NLRP3 inflammasome activation in vitro, as evidenced by the inhibition of NLRP3 expression, caspase-1 cleavage, and interleukin-1ß and interleukin-18 maturation and secretion. Additionally, MCL inhibited the reduction of mitochondrial membrane potential and decreases the release of reactive oxygen species (ROS). Moreover, MCL can prevent NLRP3 inflammasome activation induced by rotenone, a well-known mitochondrial ROS (mROS) agonist, indicating that the mechanism of MCL's anti-inflammatory effect may be closely related to the mROS. In conclusion, our study indicates that MCL can inhibit LPS-induced renal inflammation through suppressing the mROS/NF-κB/NLRP3 axis in tubular epithelial cells.


Assuntos
Lipopolissacarídeos/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio , Sesquiterpenos de Guaiano/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Proteínas de Transporte/metabolismo , Linhagem Celular , Citocinas/metabolismo , Células Epiteliais/metabolismo , Inflamassomos , Inflamação , Túbulos Renais/citologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Sais de Tetrazólio/química , Tiazóis/química
6.
Lab Invest ; 99(8): 1092-1106, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30976056

RESUMO

Micheliolide (MCL), derived from parthenolide (PTL), is known for its antioxidant and anti-inflammatory effects and has multiple roles in inflammatory diseases and tumours. To investigate its effect on renal disease, we intragastrically administrated DMAMCL, a dimethylamino Michael adduct of MCL for in vivo use, in two renal fibrosis models-the unilateral ureteral occlusion (UUO) model and an ischaemia-reperfusion injury (IRI) model and used MCL in combination with transforming growth factor beta 1 (TGF-ß1) on mouse tubular epithelial cells (mTEC) in vitro. The expression of fibrotic markers (fibronectin and α-SMA) was remarkably reduced, while the expression of the epithelial marker E-cadherin was restored after DMAMCL treatment both in the UUO and IRI mice. MCL function in TGF-ß1-induced epithelial-mesenchymal transition (EMT) in mTEC was consistent with the in vivo results. Metadherin (Mtdh) was activated in the fibrotic condition, suggesting that it might be involved in fibrogenesis. Interestingly, we found that while Mtdh was upregulated in the fibrotic condition, DMAMCL/MCL could suppress its expression. The overexpression of Mtdh exerted a pro-fibrotic effect by modulating the BMP/MAPK pathway in mTECs, and MCL could specifically reverse this effect. In conclusion, DMAMCL/MCL treatment represents a novel and effective therapy for renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway.


Assuntos
Nefropatias/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Substâncias Protetoras/farmacologia , Proteínas de Ligação a RNA/metabolismo , Sesquiterpenos de Guaiano/farmacologia , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Células Cultivadas , Fibrose/metabolismo , Fibrose/patologia , Rim/citologia , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Traumatismo por Reperfusão/metabolismo , Obstrução Ureteral/metabolismo
7.
Pharmacol Res ; 150: 104506, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31669149

RESUMO

Diabetic kidney disease (DKD) is the principal cause of end-stage renal disease worldwide and few treatments are available. Because immunomodulators are pivotal to DKD pathophysiology, anti-inflammatory agents may be useful for treating DKD. This study was conducted to investigate the effect of micheliolide (MCL), a novel guaianolide sesquiterpene lactone with well-known anti-inflammatory effects, on DKD. Treatment with dimethylaminomicheliolide (DMAMCL), the pro-drug of MCL currently under clinical trial in oncology, protected the kidneys against proteinuria, renal failure, histopathological injury, and inflammation in db/db mice. This effect was associated with metadherin (Mtdh) downregulation. We observed aberrant upregulation of Mtdh in the kidneys of db/db mice and high-glucose (HG)-induced mouse tubular epithelial cells (mTECs). Downregulation of Mtdh obviously inhibited nuclear factor-κB signaling activation and suppressed its downstream inflammatory cytokines, such as monocyte chemotactic peptide-1, interleukin-1ß, tumor necrosis factor-α, and interleukin-6 in HG-induced mTECs, which was similar to the effect of MCL. Mtdh overexpression largely reversed the anti-inflammatory role of MCL. Moreover, MCL downregulated Mtdh by both inhibiting the transcription level and promoting ubiquitin-mediated degradation. These findings suggest that DMAMCL is a promising anti-inflammatory agent useful for preventing renal injury in DKD by inhibiting Mtdh-mediated renal inflammation.


Assuntos
Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Sesquiterpenos de Guaiano/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Regulação para Baixo , Células Epiteliais/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , NF-kappa B/metabolismo , Pró-Fármacos/farmacologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Sesquiterpenos de Guaiano/farmacologia
8.
Cell Mol Biol (Noisy-le-grand) ; 64(6): 58-64, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29808802

RESUMO

To examine the exact role of flavored Guilu Erxian decoction, a Traditional Chinese Medicine (TCM) in the treatment of cisplatin-induced side-effects in bone marrow mesenchymal stem cells (BM-MSCs). BM-MSCs were isolated from bone marrow collected from SD rats and identified by flow cytometry. Cells were cultivated in MEM alpha medium containing 5% (TCM-L), 10% (TCM-M) and 20% (TCM-H) dosages of flavored Guilu Erxian decoction with or without cisplatin. Cell viability was determined through CCK-8 and thymidine analog 5-ethynyl-2'-deoxyuridine (EdU) staining assay. Flow cytometry was used to determine cell cycle and apoptosis. The expression of p21 and cleaved-caspase-3 were examined using Western blot assay. The PI3K-AKT-mTOR pathway associated proteins, including p-PI3K, p-AKT and p-mTOR, were also examined by Western blot assay. CCK-8 and EdU staining assay demonstrated that cisplatin could inhibit cell proliferation in BM-MSCs in a dose and time dependent manner. Further, cisplatin could induce apoptosis through increasing G0/G1 cell cycle arrest, p21 and cleaved-caspase-3 expression. However, these phenomena would be significantly alleviated when adding the serum containing flavored Guilu Erxian decoction. Furthermore, the PI3K-AKT-mTOR pathway activation could be inhibited by cisplatin in BM-MSCs, while flavored Guilu Erxian decoction treatment successfully abrogated this effect. Combination of flavored Guilu Erxian decoction and cisplatin could reduce the damage to BM-MSCs. This indicates that the flavored Guilu Erxian decoction can enhance the possibility of BM-MSCs repairing and rehabilitating the normal function of injured tissues induced by cisplatin, which could provide a new direction for therapeutic applications.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Cisplatino/toxicidade , Medicamentos de Ervas Chinesas/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Caspase 3/biossíntese , Caspase 3/genética , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Separação Celular , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia
9.
BMC Cancer ; 17(1): 138, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28202053

RESUMO

BACKGROUND: Cisplatin (DDP)-based chemotherapy is the common first-line therapy for lung cancer. However, their efficacy is often limited by primary drug resistance and/or acquired drug resistance. The aim of this study was to investigate the function of miRNA-146a (miR-146a) in DDP-resistant non-small cell lung cancer (NSCLC), as well as the underlying mechanisms. METHODS: The effect of overexpression of miR-146a and/or knockdown of cyclin J (CCNJ) in A549/DDP and SPC-A1/DDP cells were investigated as follows. The cellular sensitivity to DDP, cell apoptosis, cell cycle and cell mobility were detected by CCK-8, flow cytometry, hoechst staining and cell invasion/migration assay, respectively. The effects of miR-146a overexpression in NSCLC resistant cells were further analyzed in a nude mouse xenograft model. RESULTS: Overexpression of miR-146a and/or knockdown of CCNJ significantly increased the sensitivity to DDP in A549/DDP and SPC-A1/DDP cells compared to NC group via arresting cell cycle, enhancing cell apoptosis, inhibiting cell viability and motility in vitro and in vivo. Furthermore, miR-146a could specially degrade the mRNA of CCNJ, as examined by dual luciferase report assay. CONCLUSION: The study indicates a crucial role of miR-146a in the development of acquired drug resistance to DDP in NSCLC cells. Further understanding of miR-146a mediated crosstalk networks may promote the clinical use of miR-146a analogue in NSCLC therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/farmacologia , Ciclinas/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/genética , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclinas/genética , Ciclinas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Mediators Inflamm ; 2016: 1405924, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26880862

RESUMO

The receptor activator of NF-κB ligand (RANKL) and its receptor RANK are overexpressed in focal segmental glomerular sclerosis (FSGS), IgA nephropathy (IgAN), and membranous nephropathy (MN). However, the expression and the potential roles of RANKL and RANK in diabetic nephropathy (DN) remain unclear. Irbesartan (Irb) has beneficial effects against diabetes-induced renal damage, but its mechanisms are poorly understood. Our present study investigated the effects of Irb in DN and whether the renal protective effects of Irb are mediated by RANKL/RANK and the downstream NF-κB pathway in db/db mice. Our results showed that db/db mice revealed severe metabolic abnormalities, renal dysfunction, podocyte injury, and increased MCP-1; these symptoms were reversed by Irb. At the molecular level, RANKL and RANK were overexpressed in the kidneys of db/db mice and Irb downregulated RANKL and RANK and inhibited the downstream NF-κB pathway. Our study suggests that Irb can ameliorate DN by suppressing the RANKL-RANK-NF-κB pathway.


Assuntos
Compostos de Bifenilo/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Tetrazóis/uso terapêutico , Animais , Anti-Hipertensivos/uso terapêutico , Western Blotting , Diabetes Mellitus Tipo 2/metabolismo , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Irbesartana , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão
12.
J Org Chem ; 80(11): 5730-6, 2015 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-25955879

RESUMO

A novel visible-light-induced trifluoromethylarylation/1,4-aryl shift/desulfonylation cascade reaction using CF3SO2Cl as CF3 source was described. The protocol provides an efficient approach for the synthesis of α-aryl-ß-trifluoromethyl amides and/or CF3-containing oxindoles as well as the isoquinolinediones under benign conditions.


Assuntos
Alcenos/química , Hidrocarbonetos Fluorados/síntese química , Compostos de Sulfidrila/química , Catálise , Hidrocarbonetos Fluorados/química , Indóis/síntese química , Indóis/química , Isoquinolinas/síntese química , Isoquinolinas/química , Luz , Estrutura Molecular , Oxindóis
13.
Cell Prolif ; 52(6): e12699, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31599032

RESUMO

OBJECTIVES: The chemotherapy drug resistance is a major challenge for non-small-cell lung cancer (NSCLC) treatment. Combination of immunotherapy and chemotherapy has shown promise for cancer. The goal of this study was to evaluate the anti-tumour efficacy of interleukin-7 (IL-7) combining cisplatin against NSCLC. MATERIALS AND METHODS: Cell proliferation was analysed using CCK-8 assay, EdU proliferation assay and colony-forming assay. Cell apoptosis was evaluated using HOECHST 33342 assay and flow cytometry. The protein expression levels were analysed by Western blot. The blocking antibody against the IL-7 receptor and the inhibitors of STAT5 and JAK3 were used to investigate the pathway involved. A xenograft model was established to assess the anti-tumour efficacy of IL-7 combining cisplatin in vivo. RESULTS: Here we found IL-7R was increased in A549/DDP cells compared with A549 cells. The block of IL-7R reversed the inhibitory effects of IL-7 combined with cisplatin and decreased the numbers of apoptosis cells induced by treatment of IL-7 combined with cisplatin. The JAK3 inhibitor and STAT5 inhibitor were used to identify the pathway involved. The results showed that JAK3/STAT5 pathway was involved in enhancing role of cisplatin sensitivity of NSCLC cells by IL-7. In vivo, cisplatin significantly inhibited tumour growth and IL-7 combined with cisplatin achieved the best therapeutic effect. CONCLUSION: Together, IL-7 promoted the sensitivity of NSCLC cells to cisplatin via IL-7R-JAK3/STAT5 signalling pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interleucina-7/farmacologia , Células A549/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Janus Quinase 3/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Fator de Transcrição STAT5/efeitos dos fármacos , Proteínas Supressoras de Tumor/efeitos dos fármacos
14.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(2): 156-161, 2019 02 28.
Artigo em Zh | MEDLINE | ID: mdl-30890502

RESUMO

OBJECTIVE: To explore the effect of telmisartan on the expression of metadherin in the kidney of mice with unilateral ureter obstruction. METHODS: Eighteen male C57 mice were randomized into sham-operated group, model group and telmisartan treatment group. In the latter two groups, renal interstitial fibrosis as the result of unilateral ureter obstruction (UUO) was induced by unilateral ureteral ligation with or without telmisartan intervention. Renal pathological changes of the mice were assessed using Masson staining, and immunohistochemistry and Western blotting were used to detect the expression of extracellular matrix proteins and metadherin in the kidney of the mice. In the in vitro experiment, cultured mouse renal tubular epithelial cells (mTECs) were stimulated with transforming growth factor-ß1 (TGF-ß1) and transfected with a siRNA targeting metadherin, and the changes in the expressions of extracellular matrix proteins and metadherin were detected using Western blotting. RESULTS: The expressions of extracellular matrix proteins and metadherin increased significantly in the kidney of mice with UUO (P < 0.05). Intervention with telmisartan significantly lowered the expressions of extracellular matrix proteins and metadherin and alleviated the pathology of renal fibrosis in mice with UUO (P < 0.05). In cultured mTECs, siRNA-mediated knockdown of metadherin obviously reversed TGF-ß1-induced increase in the expressions of extracellular matrix proteins and metadherin. CONCLUSIONS: Telmisartan can suppress the production of extracellular matrix proteins and the expression of metadhein to attenuate UUO-induced renal fibrosis in mice.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Rim/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Telmisartan/farmacologia , Obstrução Ureteral/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Animais , Anti-Hipertensivos , Fibrose , Rim/metabolismo , Rim/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno , Proteínas de Ligação a RNA , Distribuição Aleatória , Fator de Crescimento Transformador beta1/farmacologia , Obstrução Ureteral/complicações
15.
Medicine (Baltimore) ; 98(28): e16244, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305403

RESUMO

RATIONALE: The incidence exercise-induced rhabdomyolysis is increasing in the healthy general population. Rhabdomyolysis can lead to the life-threatening systemic complications of acute kidney injury (AKI), compartment syndrome, and disseminated intravascular coagulopathy. PATIENT CONCERNS: A 21-year-old man had bilateral lower limb pain and soreness, dark brown urine after lower exremity training. Laboratory results showed that creatinine kinase (CK) and myoglobin (Mb) increased to 140,500 IU/L and 8632 µg/L respectively, with elevated liver enzymes, Scr, and proteinuria. DIAGNOSES: Exercise-induced rhabdomyolysis with AKI. INTERVENTIONS: The patient was hospitalized and treated with vigorous hydration and sodium bicarbonate for 6 days. OUTCOMES: After 6 days of treatment, the patient had a significant decrease in the CK and Mb levels. His renal function returned to normal. His laboratory tests had completely normalized during 2-week follow-up. LESSONS: Exercise-induced rhabdomyolysis can cause serious complications such as AKI. Delayed diagnosis can be critical, so timely manner should be taken to achieve a favorable prognosis.


Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/fisiopatologia , Exercício Físico , Extremidade Inferior , Rabdomiólise/etiologia , Rabdomiólise/fisiopatologia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/tratamento farmacológico , Diagnóstico Diferencial , Exercício Físico/fisiologia , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Rabdomiólise/diagnóstico , Rabdomiólise/tratamento farmacológico , Adulto Jovem
16.
J Mol Med (Berl) ; 97(5): 659-674, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30854581

RESUMO

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in patients receiving long-term peritoneal dialysis (PD), and effective prevention and treatment strategies are urgently needed. The dimethylamino Michael adduct of a natural product-derived micheliolide (MCL), dimethylaminomicheliolide (DMAMCL), is a new lead compound with the advantages of high stability, low toxicity, and sustainable release of MCL. This study aimed to investigate the protective effect of DMAMCL against PD-related PF and the mechanisms involved. In this study, we found that DMAMCL significantly decreased PD-induced extracellular matrix (ECM) deposition in a mouse model of PD, and that delayed DMAMCL administration halted the progression of PF in an established PD model. In addition, rapamycin administration induced autophagy and significantly ameliorated PF. The protective effect of DMAMCL against PF was weakened when co-administered with DMAMCL and 3-methyladenine. Inducing autophagy by rapamycin decreased transforming growth factor-ß1-induced ECM accumulation in vitro. MCL promoted autophagy and inhibited ECM deposition. The anti-fibrotic effect of MCL was eliminated when knocking down ATG7 by siRNA. Taken together, DMAMCL might prevent against PF through activating autophagy. The anti-fibrotic effect of DMAMCL may be a new candidate for the treatment in patients with PD-related PF. KEY MESSAGES: Dimethylaminomicheliolide, the pro-drug of micheliolide, protects against peritoneal fibrosis in a mouse peritoneal dialysis model. Micheliolide inhibits TGF-ß1-induced extracellular matrix accumulation in vitro. Autophagy plays a protective role against peritoneal fibrosis. The antifibrogenic effect of dimethylaminomicheliolide may be due to the activation of autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Fibrose Peritoneal/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Sesquiterpenos de Guaiano/uso terapêutico , Animais , Feminino , Masculino , Camundongos Endogâmicos C57BL , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/etiologia , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/prevenção & controle , Substâncias Protetoras/farmacologia , Sesquiterpenos de Guaiano/farmacologia , Fator de Crescimento Transformador beta1/metabolismo
17.
Int Immunopharmacol ; 59: 197-208, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29656210

RESUMO

The anti-inflammatory, immunomodulatory, and anticancer effects of micheliolide (MCL) isolated from Michelia champaca were previously reported, but its role and underlying mechanisms in relieving liver steatosis remain unclear. Herein, we investigated the effects of MCL on hepatic steatosis using a db/db mouse model and lipid mixture (LM)-induced AML12 and LO2 cells. The body and liver weights, food consumption, lipid content and liver aminotransferase levels in serum, the lipid content and inflammatory cytokine levels in liver tissue, and the extent of hepatic steatosis in db/db mice were increased compared with those in db/m mice, and these increases were reversed by MCL treatment. Similarly, MCL also attenuated the inflammatory responses and lipid accumulation in LM-treated AML12 and L02 cells by upregulating PPAR-γ and decreasing p-IкBα and p-NF-κB/p65, thereby inhibiting the NF-κB pathway and reducing lipotoxicity. Furthermore, MCL administration increased LC3B, Atg7 and Beclin-1 expression and the LC3B-II/I ratio in db/db mouse livers and LM-treated AML12 and L02 cells, and these MCL-induced increases were mediated by the activation of PPAR-γ and p-AMPK and inhibition of p-mTOR and induce autophagy. These effects were blocked by PPAR-γ and AMPK inhibitors. Our findings suggest that MCL ameliorates liver steatosis by upregulating PPAR-γ expression, thereby inhibiting NF-κB-mediated inflammation and activating AMPK/mTOR-dependent autophagy.


Assuntos
Anti-Inflamatórios , Fígado Gorduroso/tratamento farmacológico , NF-kappa B/metabolismo , PPAR gama/metabolismo , Proteínas Quinases/metabolismo , Sesquiterpenos de Guaiano , Serina-Treonina Quinases TOR/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Autofagia/efeitos dos fármacos , Linhagem Celular , Fígado Gorduroso/metabolismo , Humanos , Interleucina-1beta/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Sesquiterpenos de Guaiano/farmacologia , Sesquiterpenos de Guaiano/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo
18.
Cell Death Dis ; 7(11): e2477, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27882943

RESUMO

Apoptosis, one of the major causes of podocyte loss, has been reported to have a vital role in diabetic nephropathy (DN) pathogenesis, and understanding the mechanisms underlying the regulation of podocyte apoptosis is crucial. Metadherin (MTDH) is an important oncogene, which is overexpressed in most cancers and responsible for apoptosis, metastasis, and poor patient survival. Here we show that the expression levels of Mtdh and phosphorylated p38 mitogen-activated protein kinase (MAPK) are significantly increased, whereas those of the microRNA-30 family members (miR-30s) are considerably reduced in the glomeruli of DN rat model and in high glucose (HG)-induced conditionally immortalized mouse podocytes (MPC5). These levels are positively correlated with podocyte apoptosis rate. The inhibition of Mtdh expression, using small interfering RNA, but not Mtdh overexpression, was shown to inhibit HG-induced MPC5 apoptosis and p38 MAPK pathway, and Bax and cleaved caspase 3 expression. This was shown to be similar to the effects of p38 MAPK inhibitor (SB203580). Furthermore, luciferase assay results demonstrated that Mtdh represents the target of miR-30s. Transient transfection experiments, using miR-30 microRNA (miRNA) inhibitors, led to the increase in Mtdh expression and induced the apoptosis of MPC5, whereas the treatment with miR-30 miRNA mimics led to the reduction in Mtdh expression and apoptosis of HG-induced MPC5 cells in comparison with their respective controls. Our results demonstrate that Mtdh is a potent modulator of podocyte apoptosis, and that it represents the target of miR-30 miRNAs, facilitating podocyte apoptosis through the activation of HG-induced p38 MAPK-dependent pathway.


Assuntos
Apoptose , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Proteínas de Membrana/metabolismo , Podócitos/metabolismo , Podócitos/patologia , Animais , Apoptose/efeitos dos fármacos , Sequência de Bases , Linhagem Celular , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Glucose/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Modelos Biológicos , Podócitos/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
J Diabetes Complications ; 30(5): 760-9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27052152

RESUMO

AIMS: The aim of this research was to investigate the effects of cyclopropanyldehydrocostunolide (also named LJ), a derivative of sesquiterpene lactones (SLs), on high glucose (HG)-induced podocyte injury and the associated molecular mechanisms. METHODS: Differentiated mouse podocytes were incubated in different treatments. The migration and albumin filtration of podocytes were examined by Transwell filters. The protein and mRNA levels of MCP-1 were measured using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (q-PCR). Protein expression and phosphorylation were detected by western blot, and the nuclear translocation of NF-κB was performed with a confocal microscope. The gene expression of the receptor activator for NF-κB (RANK) was silenced by small interfering RNA (siRNA). RESULTS: Our results showed that HG enhanced migration, albumin filtration and MCP-1 expression in podocytes. At the molecular level, HG promoted the phosphorylation of NF-κB/p65, IKKß, IκBα, mitogen-activated protein kinase (MAPK) and the nuclear translocation of p65. LJ reversed the effects of HG in a dose-dependent manner. Furthermore, our data provided the first demonstration that the receptor activator for NF-κB ligand (RANKL) and its cognate receptor RANK were overexpressed in HG-induced podocytes and were downregulated by LJ. RANK siRNA also attenuated HG-induced podocyte injury and markedly inhibited the activation of NF-κB and MAPK signaling pathways. CONCLUSIONS: LJ attenuates HG-induced podocyte injury by suppressing RANKL/RANK-mediated NF-κB and MAPK signaling pathways.


Assuntos
Hipoglicemiantes/farmacologia , Lactonas/farmacologia , Podócitos/efeitos dos fármacos , Ligante RANK/antagonistas & inibidores , Receptor Ativador de Fator Nuclear kappa-B/antagonistas & inibidores , Sesquiterpenos/farmacologia , Fator de Transcrição RelA/antagonistas & inibidores , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Linhagem Celular Transformada , Movimento Celular/efeitos dos fármacos , Quimiocina CCL2/agonistas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Nefropatias Diabéticas/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/agonistas , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Podócitos/metabolismo , Podócitos/patologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ligante RANK/metabolismo , Interferência de RNA , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Fator de Transcrição RelA/metabolismo
20.
Nan Fang Yi Ke Da Xue Xue Bao ; 34(9): 1265-71, 2014 Aug.
Artigo em Zh | MEDLINE | ID: mdl-25263356

RESUMO

OBJECTIVE: To investigate the effect of the serum of rats fed with Shenkang pill in regulating monocyte chemoattractant protein 1 (MCP-1) expression induced by advanced oxidation protein products (AOPP) in mouse podocyte clone 5 (MPC5) and explore the underlying mechanism. METHODS: MPC5 cultured in vitro were incubated for different time lengths in the presence of different concentrations of serum of rats medicated with Shenkang pill, and the cell proliferation was assessed using MTT assay. In MPC5 treated with AOPP prior to exposure to the rat serum, the changes in the protein expressions of p38MAPK and IκBα were examined with Western blotting, NF-κB p65 nuclear translocation was analyzed with immunofluorescence assay, and MCP-1 expression in the supernatant was determined using ELISA kits. RESULTS: The medicated rat serum time- and concentration-dependently promoted the proliferation of MPC5, with the optimal serum concentration of 5% and incubation time of 24 h. AOPP significantly increased MCP-1 expression in the cell supernatant in a time-and concentration-dependent manner; pretreatment with SB203580 (a p38 inhibitor) or parthenolide (a NF-κB inhibitor) significantly decreased MCP-1 expression, and treatment with the medicated serum significantly decreased AOPP-induced MCP-1 expression. AOPP concentration-dependently increased the protein expression of P-p38 but decreased that of IκBα. Both the medicated serum and SB203580 increased IκBα protein in AOPP-induced cells, but the effect was more obvious with the medicated serum. The medicated serum also decreased NF-κB p65 nuclear translocation in AOPP-induced MPC5. CONCLUSION: Shenkang pill-medicated serum can decrease AOPP-induced expression of MPC-1 in MPC5 by regulating p38MAPK/NF-κB to mediate its anti-inflammatory effect. This finding provides a new theoretical basis for the application of Shenkang pill to treat diabetic nephropathy.


Assuntos
Produtos da Oxidação Avançada de Proteínas/farmacologia , Quimiocina CCL2/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular , Proliferação de Células , Regulação para Baixo , Proteínas I-kappa B/metabolismo , Imidazóis , Camundongos , Inibidor de NF-kappaB alfa , Piridinas , Ratos , Soro/química , Sesquiterpenos
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