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BACKGROUND: Genetic factors contribute to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Advances in genetic testing have enabled the identification of hereditary kidney diseases, including those caused by LMX1B mutations. LMX1B mutations can lead to nail-patella syndrome (NPS) or nail-patella-like renal disease (NPLRD) with only renal manifestations. CASE PRESENTATION: The proband was a 13-year-old female who was diagnosed with nephrotic syndrome at the age of 6. Then she began intermittent hormone and drug therapy. When she was 13 years old, she was admitted to our hospital due to sudden chest tightness, which progressed to end-stage kidney disease (ESRD), requiring kidney replacement therapy. Whole-Exome Sequencing (WES) results suggest the presence of LMX1B gene mutation, c.737Gâ >â T, p.Arg246Leu. Tracing her family history, we found that her father, grandmother, uncle and 2 cousins all had hematuria, or proteinuria. In addition to the grandmother, a total of 9 members of the family performed WES. The members with kidney involved all carry the mutated gene. Healthy members did not have the mutated gene. It is characterized by co-segregation of genotype and phenotype. We followed the family for 9 year, the father developed ESRD at the age of 50 and started hemodialysis treatment. The rest patients had normal renal function. No extra-renal manifestations associated with NPS were found in any member of the family. CONCLUSIONS: This study has successfully identified missense mutation, c.737Gâ >â T (p.Arg246Leu) in the homeodomain, which appears to be responsible for isolated nephropathy in the studied family. The arginine to leucine change at codon 246 likely disrupts the DNA-binding homeodomain of LMX1B. Previous research has documented 2 types of mutations at codon R246, namely R246Q and R246P, which are known to cause NPLRD. The newly discovered mutation, R246L, is likely to be another novel mutation associated with NPLRD, thus expanding the range of mutations at the crucial renal-critical codon 246 that contribute to the development of NPLRD. Furthermore, our findings suggest that any missense mutation occurring at the 246th amino acid position within the homeodomain of the LMX1B gene has the potential to lead to NPLRD.
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Falência Renal Crônica , Síndrome da Unha-Patela , Nefrite Hereditária , Humanos , Feminino , Adolescente , Fatores de Transcrição/genética , Proteínas com Homeodomínio LIM/genética , Nefrite Hereditária/genética , Mutação , Falência Renal Crônica/genética , Falência Renal Crônica/terapia , Códon , China , Proteínas de Homeodomínio/genéticaRESUMO
Ischemic stroke (IS) is a prominent type of cerebrovascular disease leading to death and disability in an aging society and is closely related to oxidative stress. Gene expression profiling (GSE222551) was derived from Gene Expression Omnibus (GEO), and 1934 oxidative stress (OS) genes were obtained from the GeneCards database. Subsequently, we identified 149 differentially expressed genes related to OS (DEOSGs). Finally, PTGS2, FOS, and RYR1 were identified as diagnostic markers of IS. Moreover, GSE16561 was used to validate the DEOSGs. Two diagnostic genes (PTGS2 and FOS) were significantly highly expressed, while RYR1 was significantly lowly expressed in the IS group. Remarkably, immune infiltration characteristics of these three genes were analyzed, and we found that PTGS2, FOS, and RYR1 were mainly correlated with Mast cells activated, Neutrophils, and Plasma cells, respectively. Next, we intersected three DEOSGs with the ferroptosis gene set, the findings revealed that only PTGS2 was a differentially expressed gene of ferroptosis. High PTGS2 expression levels in the infarcted cortex of middle cerebral artery occlusion (MCAO) rats were confirmed by immunofluorescence (IF), western blotting (WB), and Immunohistochemistry (IHC). Inhibition of PTGS2 clearly improved the neurological outcome of rats by decreasing infarct volume, neurological problems, and modified neurological severity scores following IS compared with the controls. The protective effect of silencing PTGS2 may be related to anti-oxidative stress and ferroptosis. In conclusion, this work may provide a new perspective for the research of IS, and further research based on PTGS2 may be a breakthrough.
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Ferroptose , AVC Isquêmico , Animais , Ratos , AVC Isquêmico/genética , Ciclo-Oxigenase 2/genética , Ferroptose/genética , Canal de Liberação de Cálcio do Receptor de Rianodina , Estresse Oxidativo , BiomarcadoresRESUMO
There is an urgent need to discover new antibacterial drugs and provide new treatment options for clinical antimicrobial resistance (AMR) pathogen infections. Inspired by the structural insights from analyzing the co-crystal structure of lefamulin with the ribosomes of S. aureus, a series of novel pleuromutilin derivatives of phenylene sulfide incorporated with urea moiety were designed and synthesized. The structure-activity relationship (SAR) study revealed that derivatives with urea in the meta position of phenylene sulfide had optimal antibacterial activities in vitro. Among them, 21h was the most potent one against Methicillin-resistant Staphylococcus aureus (MRSA) and clinical AMR Gram-positive bacteria with minimum inhibitory concentrations (MICs) in the range of 0.00195-0.250 µg/mL. And it possessed low resistance frequency, prolonged Post-Antibiotic Effect and the capability to overcome lefamulin-induced resistance. Furthermore, 21h exhibited potent antibacterial activity in vivo in both the thigh infection model and trauma infection model, representing a promising lead for the development of new antibiotics against Gram-positive pathogens, especially for AMR bacteria.
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Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Antibacterianos/farmacologia , Antibacterianos/química , Staphylococcus aureus , Relação Estrutura-Atividade , Testes de Sensibilidade Microbiana , Sulfetos/farmacologia , PleuromutilinasRESUMO
Metabolomics have been widely used in pregnancy-related diseases. However, physiological variations induced by chronic hypoxia during pregnancy are not well characterized. We aimed to investigate physiological variations induced by chronic hypoxia during pregnancy. A Sprague-Dawley (SD) pregnant rat model of chronic hypoxia was established. Plasma and urine metabolite profiles at different stages of the pregnancy were detected by 1H NMR (nuclear magnetic resonance). Multivariate statistical analysis was used to analyze changes in plasma and urine metabolic trajectories at different time-points. We identified hypoxia-induced changes in the levels of 30 metabolites in plasma and 29 metabolites in urine during different stages of pregnancy; the prominently affected metabolites included acetic acid, acetone, choline, citric acid, glutamine, isoleucine, lysine, and serine. Most significant hypoxia-induced changes in plasma and urine sample metabolites were observed on the 11th day of gestation. In summary, chronic hypoxia has a significant effect on pregnant rats, and may cause metabolic disorders involving glucose, lipids, amino acids, and tricarboxylic acid cycle. Metabolomics study of the effect of hypoxia during pregnancy may provide insights into the pathogenesis of obstetric disorders.
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Hipóxia , Metabolômica , Gravidez , Feminino , Animais , Ratos , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley , Espectroscopia de Ressonância MagnéticaRESUMO
Reactive oxygen species (ROS) play vital roles in intestinal inflammation. Therefore, eliminating ROS in the inflammatory site by antioxidant enzymes such as catalase and superoxide dismutase may effectively curb inflammatory bowel disease (IBD). Here, Escherichia coli Nissle 1917 (ECN), a kind of oral probiotic, was genetically engineered to overexpress catalase and superoxide dismutase (ECN-pE) for the treatment of intestinal inflammation. To improve the bioavailability of ECN-pE in the gastrointestinal tract, chitosan and sodium alginate, effective biofilms, were used to coat ECN-pE via a layer-by-layer electrostatic self-assembly strategy. In a mouse IBD model induced by different chemical drugs, chitosan/sodium alginate coating ECN-pE (ECN-pE(C/A)2) effectively relieved inflammation and repaired epithelial barriers in the colon. Unexpectedly, such engineered EcN-pE(C/A)2 could also regulate the intestinal microbial communities and improve the abundance of Lachnospiraceae_NK4A136 and Odoribacter in the intestinal flora, which are important microbes to maintain intestinal homeostasis. Thus, this study lays a foundation for the development of living therapeutic proteins using probiotics to treat intestinal-related diseases.
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Quitosana , Infecções por Escherichia coli , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Probióticos , Alginatos/química , Animais , Catalase/metabolismo , Quitosana/química , Escherichia coli/genética , Escherichia coli/metabolismo , Inflamação , Doenças Inflamatórias Intestinais/tratamento farmacológico , Camundongos , Probióticos/farmacologia , Probióticos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Inflammation mediates a variety of physiological and pathological events, prompting an importance of inflammation management for prevention and treatment of inflammatory diseases. This study formulated tripterine (Tri) into selenized phytosomes in an attempt to attenuate its cytotoxicity and potentiate its inflammation-regulating effect with selenium. Tri-loaded phytosomes (Tri-PTs) with selenium modification were prepared by a melting-hydration followed by in situ reduction technique. Then, selenized Tri-PTs (Se@Tri-PTs) were characterized by particle size, entrapment efficiency, and transmission electron microscope. The in vitro drug release and cellular uptake were performed to examine the formulation performance of Se@Tri-PTs. The cytotoxicity and anti-inflammatory efficacy through inhibiting NLRP3 inflammasome activation and pyroptosis were appreciated in murine J774A.1 macrophage cell line, respectively. The resultant Se@Tri-PTs presented a particle size of 125 nm around. Se@Tri-PTs exhibited attenuated cytotoxicity and improved cellular uptake in macrophages compared with free Tri or Tri-PTs. Also, Se@Tri-PTs inhibited the releases of caspase-1p20 and mature IL-1ß, resulting in restriction of NLRP3 inflammasome activation that inhibits the formation of GSDMD-NT whereby to initiate pyroptosis. Altogether, our findings suggest that Se@Tri-PTs can inhibit inflammatory response by regulating the NLRP3/caspase-1 pathway, which in turn reduces pyroptosis via suppressing the cleavage of GSDMD.
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Piroptose , Selênio , Animais , Caspases , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Triterpenos Pentacíclicos , Selênio/farmacologiaRESUMO
Shenmai injection is mainly used for the treatment of heart-related diseases, including coronary heart disease, viral myocarditis, chronic cor pulmonale, and shock in Asia. Medicinal materials from different origins produce Shenmai injections for clinical use, and their protective effects on cardiomyocytes may vary with the choice of raw materials. In this study, we compared the protective effects of Shenmai injections produced from different raw materials on cardiomyocytes. Results showed that the protective effects of various Shenmai injections on hypoxia-reoxygenation-induced cardiomyocyte injury were mainly attributed to total ginsenosides extract, with few differences between them. However, the protective effects of different Shenmai injections on doxorubicin and oxidative stress-induced cardiomyocyte injury were significantly different; the protective effects of Shenmai injection with Zhejiang Ophiopogon japonicus as raw material were significantly better than those with Sichuan Ophiopogon japonicus, consistent with our previous research results. Our study reveals the different cardiomyocyte protective effects of Shenmai injections produced by medicinal materials from different origins, laying a scientific foundation for their clinical selection.
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The survival of cancer stem cells is usually limited to a specific tumor microenvironment, and this microenvironment plays a vital role in the development of tumors. The mechanical properties of the microenvironment differ in different regions of solid tumors. However, in solid tumors, whether the distribution of cancer stem cells relates to the mechanical microenvironment of different regions is still unclear. In this study, we undertook a biophysical and biochemical assessment of the changes in the mechanical properties of liver tissue during the progression of liver cancer and explored the distribution of liver cancer stem cells in liver cancer tissues. Our analysis confirmed previous observations that the stiffness of liver tissue gradually increased with the progress of fibrosis. In liver cancer tissues, we found obvious mechanical heterogeneity: the core of the tumor was soft, the invasive front tissue was the hardest, and the para-cancer tissue was in an intermediate state. Interestingly, the greatest number of liver cancer stem cells was found in the invasive front part of the tumor. We finally established that stroma stiffness correlated with the number of liver cancer stem cells. These findings indicate that the distribution of liver cancer stem cells correlates with the mechanical heterogeneity of liver cancer tissue. This result provides a theoretical basis for the development of targeted therapies against the mechanical microenvironment of liver cancer stem cells.
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Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/patologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Microambiente TumoralRESUMO
BACKGROUND: Although gefitinib brings about tremendous advances in the treatment of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, most of patients become incurable due to drug resistance. JuBei oral liquid (JB) has been widely used to treat pneumonia in clinic. Components of JB were reported to induce apoptosis in NSCLC, which indicated that JB could be a potential antitumor agent for NSCLC patients. In this study, we investigated the effect of JB on gefitinib-sensitive PC-9 and gefitinib-resistant PC-9/GR, H1975 cells as well as its underlying molecular mechanisms. METHODS: PC-9, PC-9/GR and H1975 cells were treated with JB, LY294002, SCH772984, gefitinib alone or in combination. Then, cell viability, colony formation, cell death, expression of mitochondria-dependent pathway proteins, expression of EGFR, PI3K/AKT, MAPK signal pathway proteins, Bcl-2 mitochondrial translocation, ROS generation and cell apoptosis were examined by MTT, colony forming, live/dead cell staining, Western blot, immunofluorescence and flow cytometry assay. RESULTS: Our results showed that JB significantly induced cell growth inhibition and apoptotic cell death in PC-9, PC-9/GR and H1975 cells. JB activated mitochondria-mediated apoptotic pathway through inhibiting Bcl-2 mitochondrial translocation while inducing Bax translocated into mitochondria along with accumulated ROS production, thereby increasing the release of cytochrome c, subsequently cleaving procaspase9 into cleaved-caspase9 and then cleaving procaspase3 into cleaved-caspase3. Furthermore, the employment of protein kinase inhibitors LY294002 and SCH772984 revealed that the induction of mitochondria-mediated apoptosis by JB was reliant on inactivation of PI3K/AKT and MAPK signal pathways. Moreover, JB could synergize with gefitinib to induce apoptosis in PC-9, PC-9/GR and H1975 cells. CONCLUSION: These data indicated that JB could be a potential therapeutic agent for NSCLC patients harboring EGFR mutations as well as those under gefitinib resistance.
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Background: The clinical application of EGFR tyrosine kinase inhibitors is always accompanied by inevitable drug resistance. However, the mechanism remains elusive. In the present study, we investigate the involvement of MAPK/SREBP1 pathway in NSCLC gefitinib resistance and evaluate the synergistic effects of shenqi fuzheng injection (SFI) and gefitinib on NSCLC cells. Methods: To investigate the MAPK/SREBP1 pathway involved in gefitinib resistance, Western blotting was used to examine p-MEK, p-ERK and SREBP1 expression in PC-9 and PC-9/GR cells, MTT was used on cell proliferation, wound healing assay was used on cell migration. To detect the cooperative effects of SFI and gefitinib, clonogenic assay was used on cell proliferation. Apoptosis assay was analyzed by flow cytometry. Immunofluorescence was used to detect gefitinib binding to EGFR. Western blotting was used to detect whether SFI regulate the resistance to gefitinib via the suppression of MAPK/SREBP1 pathway. Results: Our results showed that MAPK/SREBP1 pathway mediated resistance to gefitinib in NSCLC cells. MAPK pathway was found to directly target SREBP1 and inhibition of SREBP1 increased gefitinib sensitivity. In addition, SFI showed cooperative anti-proliferation and pro-apoptosis impacts on gefitinib resistant cells via down-regulating MAPK/SREBP1 pathway. Moreover, the combination of SFI and gefitinib enhanced gefitinib binding to EGFR resulting in the restoration of sensitivity to gefitinib. Conclusions: Taken together, MAPK/SREBP1 pathway could be regarded as the potential treatment target for overcoming resistance to EGFR-TKIs in NSCLC and adjuvant therapy of SFI could be a potential therapeutic strategy for gefitinib resistant treatment.
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Amplifying intracellular oxidative stress effectively destroys cancer cells. In addition, iron-mediated Fenton reaction converts endogenous H2O2 to produce hypertoxic hydroxyl radical (â¢OH), resulting in irreversible oxidative damage to combat tumor cells. This method is known as chemodynamic therapy (CDT). Overexpressed glutathione (GSH) in tumor cells efficiently scavenges â¢OH, significantly reducing the curative effects of CDT. To overcome this challenge and enhance intracellular oxidative stress, iron oxide nanocarriers loaded with ß-lapachone (Lapa) drugs (Fe3O4-HSA@Lapa) were constructed and had both Fenton-like agents and GSH depletion properties to amplify intracellular oxidative stress. Release of Lapa selectively increases tumor site-specific generation of H2O2 via NAD(P)H: quinone oxidoreductase 1 (NQO1) catalysis. Subsequently, the iron ions released from the ionization of Fe3O4 in the acidic environment selectively convert H2O2 into highly toxic â¢OH by Fenton reaction, dramatically improving CDT with minimal systemic toxicity due to low NQO1 expression in normal tissues. Meanwhile, released Lapa consumes GSH in the tumor, amplifying oxidative stress and enhancing the efficacy of CDT. Designed Fe3O4-HSA@Lapa nanoparticles (NPs) exhibit perfect targeting capability, prolonged blood circulation, and increased tumor accumulation. Furthermore, Fe3O4-HSA@Lapa NPs effectively enhance the inhibition of tumor growth and reduce the side effects of anticancer drugs. This work establishes a remarkably enhanced tumor-selective CDT against NQO1-overexpressing tumors by significantly inducing intratumoral oxidative stress with minimal side effects.
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Antineoplásicos , Glutationa/metabolismo , Nanopartículas de Magnetita , Naftoquinonas , Neoplasias Experimentais , Estresse Oxidativo/efeitos dos fármacos , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Feminino , Humanos , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Camundongos , Camundongos Nus , Naftoquinonas/química , Naftoquinonas/farmacocinética , Naftoquinonas/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng (Panax ginseng C. A. Mey) has been widely used in Asian countries for thousands of years. It has auxiliary anticancer efficacy and its derived preparations (e.g. Shenmai injection) are prescribed for cancer patients as Traditional Chinese Medicines clinically in China. AIM OF THE STUDY: The involved adjuvant anticancer mechanisms of ginseng are still unknown. The present study evaluated the anti-cancer effect of total ginsenosides extract (TGS) and determined the anticancer mechanisms of TGS-induced cell death in human non-small cell lung cancer (NSCLC) cells. MATERIALS AND METHODS: The anti-cancer effect of TGS was evaluated in NSCLC by cell proliferation assay. The autophagy flux induction of TGS were tested and validated by Western blot, immunofluorescence and transmission electron microscope. The mechanisms of TGS in inducing autophagic cell death were validated by Western blot, gene knockdown and quantitative real time PCR assay. RESULTS: We found TGS could induce cell death in concentration and time dependent manners, and the cell morphology of NSCLC changed from cobblestone shape to elongated spindle shape after treated with TGS. In the study of cell autophagy, we confirm that TGS could upregulate autophagy flux and induce autophagic cell death through activation endoplasmic reticulum stress. Further investigations demonstrated this process was mediated by the ATF4-CHOP-AKT1-mTOR axis in NSCLC cells. CONCLUSION: Our findings suggested that TGS could induce autophagic cell death in NSCLC cells through activation of endoplasmic reticulum stress, disclosing another characteristic of TGS-induced cell death and a novel mechanism of TGS and its derived preparations in clinical treatment of cancer patients.
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Antineoplásicos/farmacologia , Morte Celular Autofágica/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ginsenosídeos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Fator 4 Ativador da Transcrição/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Transcrição CHOP/metabolismoRESUMO
AIM: To understand potential pro-oncological effects of lower dose paclitaxel treatment in cervical cancer cells, we investigated the potential roles of KRT17 on migration and proliferation of cervical cancer cells which might respond to cytoskeletal-based drugs treatments. MATERIALS AND METHODS: We extracted the clinic data of cervical cancer patients from TCGA database to investigate mRNA expression of different keratins. HPV genotypes were identified by reverse transcription PCR. krt17 mRNA and EMT markers were quantified by real-time PCR. krt17 and EMT markers protein were immunoblotted by western blot. Cell viability was detected by CCK8. Cell migration was performed by transwell migration assay. KEY FINDINGS: Our results showed that HPV16 infection correlated with the expression of KRT17 in cervical cancer cell lines. KRT17 knockdown would decrease Snail2 and elevate E-Cadherin to inhibit migration of Caski cells and SiHa cells. Lower dose of paclitaxel promoted SiHa proliferation, it also significantly promoted the migration of Caski cells. Otherwise, colchicine and higher dose of paclitaxel dose-dependently suppressed the proliferation and migration of Caski cells and SiHa cells. Moreover, KRT17 knockdown significantly facilitated cytoskeletal-based drugs to inhibit migration and induce cytotoxicity in cervical cancer cells. SIGNIFICANCE: KRT17 played pivotal oncogenic roles in cell survival, migration and paclitaxel-induced resistance of cervical cancer cells. Thus, KRT17 would serve as a promising target for compromising paclitaxel-induced resistance and metastasis.
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Antineoplásicos Fitogênicos/farmacologia , Movimento Celular , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Queratina-17/metabolismo , Paclitaxel/farmacologia , Neoplasias do Colo do Útero/patologia , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Queratina-17/genética , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genéticaRESUMO
Exposure to lead (Pb) poses a threat to human bone health, including changes in bone mineral composition and the inhibition of skeletal growth and bone maturation. However, little is known about how Pb directly affects osteoblasts. In this work, we found that sub-toxic Pb concentrations suppressed bone nodule formation and inhibited differentiation in MC3T3-E1 subclone 14â¯cells, as shown by decreased expression levels of the differentiation markers alkaline phosphatase (ALP), type 1 collagen (COL1), osteocalcin (OC), and runt-related transcription factor 2 (RUNX2). Moreover, Pb inactivated the canonical Wnt pathway by regulating key components, such as Wnt3a, Dkk-1, pGSK3ß, and ß-catenin. Icaritin (ICT), a hydrolytic product of icariin from the genus Epimedium, attenuates the inhibitory effect of Pb on osteoblastic differentiation, as well as activate the canonical Wnt signal pathway. Taken together, the results suggest ICT as a potential bone protectant that may be used to prevent bone damage caused by Pb and can activate the canonical Wnt signal pathway.
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Flavonoides/uso terapêutico , Chumbo/toxicidade , Via de Sinalização Wnt/efeitos dos fármacos , Células 3T3 , Animais , Osso e Ossos/patologia , Diferenciação Celular/efeitos dos fármacos , Epimedium/química , Camundongos , Osteoblastos/citologia , Substâncias Protetoras/farmacologiaRESUMO
Hypoxia plays vital roles in the development of tumor resistance against typical anticancer therapies and local reoxygenation has proved effective to overcome the hypoxia-induced chemoresistance. Perfluorocarbon (PFC) is an FDA approved oxygen carrier and currently vigorously investigated for oxygen delivery to tumors. This study reports a perfluorocarbon and etoposide (EP) loaded porous hollow Fe3O4-based theranostic nanoplatform capable of delivering oxygen to solid tumors to enhance their susceptibility against EP. Results show that oxygen could be released at a moderate rate from the porous hollow magnetic Fe3O4 nanoparticles (PHMNPs) over an extended period of time, therefore effectively reducing the hypoxia-induced EP resistance of tumor cells. Moreover, the surface of PHMNPs was modified with lactobionic acid (LA)-containing amphiphilic polymers via hydrophobic interaction, which could provide targeting effect against certain types of tumors. The hydrophilic moiety would be subsequently shed by the intratumoral GSH after cellular internalization and result in the agglomeration of nanocarriers inside tumor cells, consequently impeding the nanoparticle exocytosis to enhance their intracellular retention. The enhanced retention could elevate the intracellular EP level and effectively boost the tumor cell killing effect. In addition to the therapeutic benefits, the Fe3O4 nanocage could also be used for the magnetic resonance imaging of the tumor area. The assorted benefits of the composite nanosystem are anticipated to be advantageous for the treatment of drug-resistant hypoxic tumors.
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Antineoplásicos Fitogênicos/uso terapêutico , Substitutos Sanguíneos/uso terapêutico , Etoposídeo/uso terapêutico , Fluorocarbonos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Substitutos Sanguíneos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Etoposídeo/administração & dosagem , Fluorocarbonos/administração & dosagem , Células Hep G2 , Humanos , Hipóxia , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita/química , Camundongos Nus , Neoplasias/diagnóstico por imagem , Nanomedicina Teranóstica/métodos , Resultado do Tratamento , Hipóxia Tumoral/efeitos dos fármacosRESUMO
Modern molecular techniques have highlighted the presence of inflammation throughout the spectrum of tendinopathy. Previous studies have suggested that excessive inflammation in the tendon is a major factor leading to poor clinical treatment. Furthermore, the NLRP3 inflammasome, as a new term, is closely associated with the pathogenesis of many diseases. In the present study, we examined whether the NLRP3 inflammasome contributes to the development of tendinitis and whether cyclic stretching plays a prominent role in inflammation in the tendon. In the present study, we showed that hydrogen peroxide (H2O2) remarkably enhances the expression and release of IL-1ß, TNF-α, and IL-6. The maturation of IL-1ß, induced by H2O2, depends on the activation of the NLRP3 inflammasome. Cyclic stretching enhances the maturation of IL-1ß via promoting H2O2-induced NLRP3 inflammasome activation in tenocytes. Furthermore, we also found that the depolymerization of filamentous actin (F-actin) was required for cyclic stretching-enhanced NLRP3 inflammasome activation. The present study suggests that NLRP3 inflammasome plays an important regulatory role in the pathogenesis of tendinitis. Disruption of the cytoskeleton by cyclic stretching exerts a proinflammatory effect via further activating the NLRP3/IL-1ß pathway and hence contributes to tendinitis. These results may provide theoretical support for a new treatment strategy for preventing excessive inflammation in the tendon.
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Actinas/metabolismo , Fenômenos Biomecânicos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Tendinopatia/etiologia , Citoesqueleto de Actina/metabolismo , Animais , Humanos , Peróxido de Hidrogênio/farmacologia , Inflamação , Interleucina-1beta/metabolismo , PolimerizaçãoRESUMO
Tumor hypoxia is one of the major challenges for the treatment of tumors, as it may negatively affect the efficacy of various anticancer modalities. In this study, a tumor-targeted redox-responsive composite biocatalyst is designed and fabricated, which may combine tumor starvation therapy and low-temperature photothermal therapy for the treatment of oxygen-deprived tumors. The nanosystem was prepared by loading porous hollow Prussian Blue nanoparticles (PHPBNs) with glucose oxidase (GOx) and then coating their surface with hyaluronic acid (HA) via redox-cleavable linkage, therefore allowing the nanocarrier to bind specifically with CD44-overexpressing tumor cells while also exerting control over the cargo release profile. The nanocarriers are designed to enhance the efficacy of the hypoxia-suppressed GOx-mediated starvation therapy by catalyzing the decomposition of intratumoral hydroperoxide into oxygen with PHPBNs, and the enhanced glucose depletion by the two complementary biocatalysts may consequently suppress the expression of heat shock proteins (HSPs) after photothermal treatment to reduce their resistance to the PHPBN-mediated low-temperature photothermal therapies.
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Ferrocianetos/uso terapêutico , Glucose Oxidase/uso terapêutico , Hipertermia Induzida/métodos , Nanopartículas/uso terapêutico , Neoplasias/terapia , Animais , Sistemas de Liberação de Medicamentos , Glucose/metabolismo , Células Hep G2 , Humanos , Peróxido de Hidrogênio/metabolismo , Camundongos , Camundongos Nus , Nanopartículas/ultraestrutura , Neoplasias/metabolismo , Neoplasias/patologia , Oxigênio/metabolismo , Fototerapia/métodos , TemperaturaRESUMO
BACKGROUND: Circulating cell-free DNA (cfDNA) isolated from plasma or serum by noninvasive procedures can serve as a "liquid biopsy" and has potential as a biomarker for the tumor burden and survival prediction of breast cancer (BC). However, its prognostic value in patients with BC is currently under debate. The aim of this meta-analysis was to investigate the relationship between cfDNA and survival outcome. METHODS: We systematically searched PubMed, Embase, and Science Citation Index electronic databases for studies about the prognostic utility of cfDNA in patients with BC. The clinical characteristics, relapse/disease-free survival (RFS/DFS), and overall survival (OS) data were extracted from the eligible studies. The hazard ratios (HR) and 95% confidence intervals (CI) were calculated and pooled with a fixed-effects model using the Stata12.0 software. Subgroup and sensitivity analyses were also performed. RESULTS: This meta-analysis included a total of 10 eligible studies and 1127 patients with BC. The pooled HR with 95% CI showed strong associations between cfDNA and OS (HRâ=â2.41, 95% CI, 1.83-3.16) along with DFS/RFS (HRâ=â2.73, 95% CI, 2.04-3.67) in patients with BC. Although publication bias was found in the studies regarding RFS/DFS, further trim and fill analysis revealed that the adjusted HR would be 2.53 (95% CI, 1.83-3.51), which is close to the original HR. Subgroup analyses confirmed the role of cfDNA as a strong prognostic marker in patients with BC, regardless of cfDNA analysis, sampling time, sample source, detection method, tumor stage, sample size, or area. CONCLUSIONS: Our meta-analysis indicates that cfDNA is a strong predictive and prognostic marker in patients with BC.
Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Ácidos Nucleicos Livres/sangue , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Análise de SobrevidaRESUMO
Thrombin has long been suggested as a desirable antithrombotic target, but anti-thrombin therapy without anti-platelet thereby has never achieved the ideal effect. HY023016 is a novel compound, in our previous study, it exerted better anti-thrombotic than dabigatran etexilate. The present study aims to illustrate the excess anti-thrombotic molecular mechanisms of HY023016 through thrombin anion exosites and the platelet membrane receptor subunit glycoprotein Ibα (GPIbα). HY023016 strongly inhibited the conversion of fibrinogen to fibrous may via blocking thrombin exosite I. We also discovered that HY023016 remarkably inhibited exosite II by a loss of affinity for the γ'-peptide of fibrinogen and for heparin. Furthermore, a solid phase binding assay revealed that HY023016 inhibited ristocetin-induced washed platelets bind to von Willebrand factor (vWF). In GST pull-down assay, HY023016 decreased the binding of recombinant vWF-A1 to GPIbα N-terminal. Thus, HY023016 provides an innovative idea for designing multi-targeted anti-thrombotic drugs and laying a scientific foundation for reducing "total thrombosis risk" in a clinical drug treatment.
Assuntos
Dabigatrana/farmacologia , Fibrinolíticos/farmacologia , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Trombina/química , Trombina/metabolismo , Sítios de Ligação , Humanos , Complexo Glicoproteico GPIb-IX de Plaquetas/química , Glicoproteínas da Membrana de Plaquetas/metabolismo , Ligação Proteica/efeitos dos fármacos , Domínios ProteicosRESUMO
Overcoming EGFR-TKI resistant which has the initial enthusiasm over substantial clinical responses is a formidable challenge on nowadays. In this study, we showed that cholesterol level in lipid rafts in gefitinib resistant non-small cell lung cancer (NSCLC) cell lines was remarkably higher than gefitinib sensitive cell line, and depletion of cholesterol increased gefitinib sensitivity. Furthermore, cholesterol-depleted enhanced gefitinib inhibit phosphorylation of EGFR, Akt-1, MEK1/2, and ERK1/2 and these were reversed in cholesterol add-back experiments. Gefitinib resistant cell lines showed high affinity of gefitinib and EGFR when cholesterol was depleted. Therefore, targeting cholesterol combined with EGFR-TKI is potentially a novel therapeutic strategy for gefitinib resistant treatment.