RESUMO
Telomerase is a basic reverse transcriptase that maintains the telomere length in cells, and accurate and specific sensing of telomerase in living cells is critical for medical diagnostics and disease therapeutics. Herein, we demonstrate for the first time the construction of an enzymatically controlled DNA nanomachine with endogenous apurinic/apyrimidinic endonuclease 1 (APE1) as a driving force for one-step imaging of telomerase in living cells. The DNA nanomachine is designed by rational engineering of substrate probes and reporter probes embedded with an enzyme-activatable site (i.e., AP site) and their subsequent assembly on a gold nanoparticle (AuNP). Upon recognition and cleavage of the AP site in the substrate probe by APE1, the loop of the substrate probe unfolds, exposing telomeric primer (TP) with the 3'-OH end. Subsequently, the TP is elongated by telomerase at the 3'-OH end to generate a long telomeric product. The resultant telomeric product acts as a swing arm that can hybridize with a reporter probe to initiate the APE1-powered walking reaction, ultimately generating a significantly enhanced fluorescence signal. Notably, endogenous APE1 is used as the driving force of the DNA nanomachine, avoiding the introduction of exogenous auxiliary cofactors into the cellular microenvironment. Owing to the high kinetics and high amplification efficiency of the APE1-powered DNA nanomachine, this strategy enables one-step sensitive sensing of telomerase in vitro and in vivo. It can successfully discriminate telomerase activity between cancer cells and normal cells, screen telomerase inhibitors, and monitor the variations of telomerase activity in living cells, offering a prospective platform for molecular diagnostics and drug discovery.
Assuntos
Nanopartículas Metálicas , Telomerase , Humanos , Telomerase/metabolismo , Ouro/química , Nanopartículas Metálicas/química , DNA/química , Células HeLa , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismoRESUMO
The process of parturition is associated with inflammation within the uterine tissues, and IL-1ß is a key proinflammatory cytokine involved. Autophagy is emerging as an important pathway to remove redundant cellular components. However, it is not known whether IL-1ß employs the autophagy pathway to degrade collagen, thereby participating in membrane rupture at parturition. In this study, we investigated this issue in human amnion. Results showed that IL-1ß levels were significantly increased in human amnion obtained from deliveries with spontaneous labor and membrane rupture, which was accompanied by decreased abundance of COL1A1 and COL1A2 protein but not their mRNA, the two components of collagen I. Consistently, IL-1ß treatment of cultured primary human amnion fibroblasts reduced COL1A1 and COL1A2 protein but not their mRNA abundance along with increased abundance of autophagy activation markers, including the microtubule-associated protein L chain 3ß II/I ratio and autophagy-related 7 (ATG7) in the cells. The reduction in COL1A1 and COL1A2 protein abundance induced by IL-1ß could be blocked by the lysosome inhibitor chloroquine or small interfering RNA-mediated knockdown of ATG7 or ER-phagy receptor FAM134C, suggesting that FAM134C-mediated ER-phagy was involved in IL-1ß-induced reduction in COL1A1 and COL1A2 protein in amnion fibroblasts. Consistently, levels of L chain 3ß II/I ratio, ATG7, and FAM134C were significantly increased in human amnion obtained from deliveries with spontaneous labor and membrane rupture. Conclusively, increased IL-1ß abundance in human amnion may stimulate ER-phagy-mediated COL1A1 and COL1A2 protein degradation in amnion fibroblasts, thereby participating in membrane rupture at parturition.
RESUMO
The process of parturition is associated with inflammation within the uterine tissues, and IL-1ß is a key proinflammatory cytokine involved. Autophagy is emerging as an important pathway to remove redundant cellular components. However, it is not known whether IL-1ß employs the autophagy pathway to degrade collagen, thereby participating in membrane rupture at parturition. In this study, we investigated this issue in human amnion. Results showed that IL-1ß levels were significantly increased in human amnion obtained from deliveries with spontaneous labor and membrane rupture, which was accompanied by decreased abundance of COL1A1 and COL1A2 protein but not their mRNA, the two components of collagen I. Consistently, IL-1ß treatment of cultured primary human amnion fibroblasts reduced COL1A1 and COL1A2 protein but not their mRNA abundance along with increased abundance of autophagy activation markers, including the microtubule-associated protein L chain 3ß II/I ratio and autophagy-related 7 (ATG7) in the cells. The reduction in COL1A1 and COL1A2 protein abundance induced by IL-1ß could be blocked by the lysosome inhibitor chloroquine or small interfering RNA-mediated knockdown of ATG7 or ER-phagy receptor FAM134C, suggesting that FAM134C-mediated ER-phagy was involved in IL-1ß-induced reduction in COL1A1 and COL1A2 protein in amnion fibroblasts. Consistently, levels of L chain 3ß II/I ratio, ATG7, and FAM134C were significantly increased in human amnion obtained from deliveries with spontaneous labor and membrane rupture. Conclusively, increased IL-1ß abundance in human amnion may stimulate ER-phagy-mediated COL1A1 and COL1A2 protein degradation in amnion fibroblasts, thereby participating in membrane rupture at parturition.
RESUMO
Liposomes decorated with tumour-targeting cell-penetrating peptides can enhance specific drug delivery at the tumour site. The TR peptide, c(RGDfK)-AGYLLGHINLHHLAHL(Aib)HHIL, is pH-sensitive and actively targets tumour cells that overexpress integrin receptor αvß3, such as B16F10 melanoma cells. Liposomes can be modified with the TR peptide by two different methods: utilization of the cysteine residue on TR to link DSPE-PEG2000-Mal contained in the liposome formula (LIPTR) or decoration of TR with a C18 stearyl chain (C18-TR) for direct insertion into the liposomal phospholipid bilayer through electrostatic and hydrophobic interactions (LIPC18-TR). We found that both TR and C18-TR effectively reversed the surface charge of the liposomes when the systems encountered the low pH of the tumour microenvironment, but LIPC18-TR exhibited a greater increase in the charge, which led to higher cellular uptake efficiency. Correspondingly, the IC50 values of PTX-LIPTR and PTX-LIPC18-TR in B16F10 cells in vitro were 2.1-fold and 2.5-fold lower than that of the unmodified PTX-loaded liposomes (PTX-LIP), respectively, in an acidic microenvironment (pH 6.3). In B16F10 tumour-bearing mice, intravenous administration of PTX-LIPTR and PTX-LIPC18-TR (8 mg/kg PTX every other day for a total of 4 injections) caused tumour reduction ratios of 39.4% and 56.1%, respectively, compared to 20.8% after PTX-LIP administration. Thus, we demonstrated that TR peptide modification could improve the antitumour efficiency of liposomal delivery systems, with C18-TR presenting significantly better results. After investigating different modification methods, our data show that selecting an adequate method is vital even when the same molecule is used for decoration.
Assuntos
Lipossomos , Neoplasias , Camundongos , Animais , Lipossomos/química , Paclitaxel/química , Sistemas de Liberação de Medicamentos/métodos , Peptídeos/química , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Network Meta-analysis was used to compare the efficacy and safety of Chinese patent medicines in the treatment of unstable angina pectoris. PubMed, Cochrane Library, CNKI, Wanfang, VIP and other databases were retrieved by computers from the establishment of the databases to June 2020. Randomized controlled trials(RCTs) of Chinese patent medicines for the treatment of unstable angina pectoris were collected. Two investigators independently screened out the literatures, and extracted data according to the inclusion and exclusion criteria. The quality of the included RCTs was evaluated according to the bias risk assessment tool recommended by the Cochrane System Reviewer Manual, and the Stata 13.0 software was used for data analysis and mapping. Through screening, 28 eligible studies were finally included, with the sample size of 2 885 cases, involving 8 Chinese patent medicines. The results of the network Meta-analysis showed that in terms of total effective rate for angina symptom improvement, the order was as follows: Shenshao Capsules > Naoxintong Capsules > Ginkgo Ketone Ester Dripping Pills > Compound Danshen Dripping Pills > Ginkgo Leaf Tablets > Shexiang Baoxin Pills > Tongxinluo Capsules > Yindan Xinnaotong Soft Capsules; in terms of total effective rate for ECG curative effect, the order was as follows: Ginkgo Ketone Ester Dripping Pills>Compound Danshen Dripping Pills > Tongxinluo Capsules > Shenshao Capsules > Shexiang Baoxin Pills > Yindan Xinnaotong Soft Capsules; in terms of hypersensitivity-C-reactive protein curative effect, the order was as follows: Tongxinluo Capsules > Shenshao Capsules > Ginkgo Leaf Tablets>Compound Danshen Dropping Pills> Shexiang Baoxin Pills > Naoxintong Capsules > Yindan Xinnaotong Soft Capsules > Ginkgo Ketone Ester Dropping Pills. Chinese patent medicine combined with conventional therapy can improve the clinical efficacy of unstable angina pectoris. Due to the differences in the quantity and quality of the included studies, the order results of Chinese patent medicines need to be further verified.
Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional do Leste Asiático , Angina Instável/tratamento farmacológico , China , Humanos , Metanálise em Rede , Medicamentos sem PrescriçãoRESUMO
We had previously demonstrated that the calcitonin gene-related peptide (CGRP) suppresses the oxidative stress and vascular smooth muscle cell (VSMC) proliferation induced by vascular injury. A recent study also indicated that CGRP protects against the onset and development of angiotensin II (Ang II)-induced hypertension, vascular hypertrophy and oxidative stress. However, the mechanism behind the effects of CGRP on Ang II-induced oxidative stress is unclear. CGRP significantly suppressed the level of reactive oxygen species (ROS) generated by NADPH oxidase in Ang II-induced VSMCs. The Ang II-stimulated activation of both Src and the downstream transcription factor, STAT3, was abrogated by CGRP. However, the antioxidative effect of CGRP was lost following the expression of constitutively activated Src or STAT3. Pre-treatment with H-89 or CGRP8-37 also blocked the CGRP inhibitory effects against Ang II-induced oxidative stress. Additionally, both in vitro and in vivo analyses show that CGRP treatment inhibited Ang II-induced VSMC proliferation and hypertrophy, accompanied by a reduction in ROS generation. Collectively, these results demonstrate that CGRP exhibits its antioxidative effect by blocking the Src/STAT3 signalling pathway that is associated with Ang II-induced VSMC hypertrophy and hyperplasia.
Assuntos
Angiotensina II/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Quinases da Família src/metabolismo , Animais , Antioxidantes/metabolismo , Calcitonina/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Apoptosis is associated with various cardiovascular diseases. CGRP exerts a variety of effects within the cardiovascular system, and protects against the onset and development of angiotensin (Ang) II-induced vascular dysfunction and remodelling. However, it is not known whether CGRP has a direct effect on Ang II-induced apoptosis in vascular smooth muscle cells (VSMCs), and the mechanism underlying the anti-apoptotic role remains unclear. In this study, CGRP significantly suppressed reactive oxygen species (ROS) and apoptosis in Ang II-induced VSMCs. In VSMCs pre-treated with a CGRP receptor antagonist (CGRP8-37), the CGRP-mediated inhibition of Ang II-induced ROS and apoptosis was completely abolished. Moreover, pre-treatment with N-acetyl-L cysteine (NAC), an ROS scavenger, blocked the effects of CGRP on Ang II-induced apoptosis. In addition, the activation of CaMKII and the downstream transcription factor CREB stimulated by Ang II was abrogated by CGRP. Importantly, in both CGRP and NAC-treated VSMCs, CGRP failed to further attenuate CaMKII and CREB activation. The results demonstrate that CGRP attenuated Ang II-induced ROS-dependent apoptosis in VSMCs by inhibiting the CaMKII/CREB signalling pathway.
Assuntos
Angiotensina II/farmacologia , Apoptose , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Músculo Liso Vascular/citologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , HumanosRESUMO
Preterm premature rupture of fetal membranes precedes 30-40% of preterm births. Activation of matrix metalloproteases (MMPs) is the one of the major causes of extracellular matrix (ECM) degradation in membrane rupture. Increased cortisol, regenerated by 11ß-hydroxysteroid dehydrogenase 1 in the amnion at parturition, is known to participate in a number of parturition-pertinent events. However, whether cortisol has a role in the regulation of MMPs in the membranes is not known. Here, we addressed this issue using human amnion tissue, the most tensile layer of the membranes. RNA-sequencing revealed that cortisol induced MMP7 expression dramatically in amnion fibroblasts, which was confirmed by real-time quantitative RT-PCR and Western blotting analysis in cortisol-treated amnion explants and fibroblasts. Measurement of collagen IV α5 chain (COL4A5), a substrate for MMP-7, showed that cortisol reduced its extracellular abundance, which was blocked by an antibody against MMP-7. Moreover, increased MMP-7 but decreased COL4A5 abundance was observed in the amnion tissue following labor-initiated spontaneous rupture of membranes. Mechanistic studies showed that cortisol increased the phosphorylation of c-Jun and the expression of c-Fos, the 2 major components of activated protein 1 (AP-1), respectively. The knocking down of c-Fos or c-Jun significantly attenuated the induction of MMP7 expression by cortisol. Chromatin immunoprecipitation assays showed that cortisol stimulated the enrichment of c-Fos and c-Jun at the AP-1 binding site in the MMP7 promoter. The data suggest that induction of MMP7 by cortisol via AP-1 may be a contributing factor to ECM degradation in membrane rupture at parturition.-Wang, L.-Y., Wang, W.-S., Wang, Y.-W., Lu, J.-W., Lu, Y., Zhang, C.-Y., Li, W.-J., Sun, K., Ying, H. Drastic induction of MMP-7 by cortisol in the human amnion: implications for membrane rupture at parturition.
Assuntos
Âmnio/enzimologia , Ruptura Prematura de Membranas Fetais/patologia , Fibroblastos/enzimologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hidrocortisona/efeitos adversos , Metaloproteinase 7 da Matriz/metabolismo , Parto , Âmnio/efeitos dos fármacos , Anti-Inflamatórios/efeitos adversos , Células Cultivadas , Ativação Enzimática , Feminino , Ruptura Prematura de Membranas Fetais/induzido quimicamente , Ruptura Prematura de Membranas Fetais/enzimologia , Fibroblastos/efeitos dos fármacos , Humanos , GravidezRESUMO
The de novo synthesis of serum amyloid A1 (SAA1) is augmented in human fetal membranes at parturition. However, its role in parturition remains largely unknown. Here, we investigated whether SAA1 was involved in the rupture of fetal membranes, a crucial event in parturition accompanied with extensive degradation of collagens. Results showed that SAA1 decreased both intracellular and extracellular COL1A1 and COL1A2 abundance, the two subunits of collagen I, without affecting their mRNA levels in human amnion fibroblasts. These reductions were completely blocked only with inhibition of both matrix metalloproteases (MMPs) and autophagy. Consistently, SAA1 increased MMP-2/9 abundance and the markers for autophagic activation including autophagy related (ATG) 7 (ATG7) and the microtubule-associated protein light chain 3 ß (LC3B) II/I ratio with the formation of LC3 punctas and autophagic vacuoles in the fibroblasts. Moreover, the autophagic degradation of COL1A1/COL1A2 and activation of MMP-2/9 by SAA1 were blocked by inhibitors for the toll-like receptors 2/4 (TLR2/4) or NF-κB. Finally, reciprocal corresponding changes of SAA1 and collagen I were observed in the amnion following spontaneous rupture of membranes (ROM) at parturition. Conclusively, SAA1 may participate in membrane rupture at parturition by degradating collagen I via both autophagic and MMP pathways. These effects of SAA1 appear to be mediated by the TLR2/4 receptors and the NF-κB pathway.
Assuntos
Âmnio/metabolismo , Colágeno Tipo I/metabolismo , Parto/metabolismo , Proteína Amiloide A Sérica/metabolismo , Autofagia , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Parto/genética , Proteólise , Proteína Amiloide A Sérica/genética , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismoRESUMO
Rapid progress has been witnessed in the past decade in the fields of covalent organic frameworks (COFs) and dynamic nuclear polarization (DNP). In this contribution, we bridge these two fields by constructing radical-embedded COFs as promising DNP agents. Via polarization transfer from unpaired electrons to nuclei, DNP realizes significant enhancement of NMR signal intensities. One of the crucial issues in DNP is to screen for suitable radicals to act as efficient polarizing agents, the basic criteria for which are homogeneous distribution and fixed orientation of unpaired electrons. We therefore envisioned that the crystalline and porous structures of COFs, if evenly embedded with radicals, may work as a new "crystalline sponge" for DNP experiments. As a proof of concept, we constructed a series of proxyl-radical-embedded COFs (denoted as PR( x)-COFs) and successfully applied them to achieve substantial DNP enhancement. Benefiting from the bottom-up and multivariate synthetic strategies, proxyl radicals have been covalently reticulated, homogeneously distributed, and rigidly embedded into the crystalline and mesoporous frameworks with adjustable concentration ( x%). Excellent performance of PR( x)-COFs has been observed for DNP 1H, 13C, and 15N solid-state NMR enhancements. This contribution not only realizes the direct construction of radical COFs from radical monomers, but also explores the new application of COFs as DNP polarizing agents. Given that many radical COFs can therefore be rationally designed and facilely constructed with well-defined composition, distribution, and pore size, we expect that our effort will pave the way for utilizing radical COFs as standard polarizing agents in DNP NMR experiments.
Assuntos
Estruturas Metalorgânicas/química , Radicais Livres/química , Espectroscopia de Ressonância Magnética , Estruturas Metalorgânicas/síntese química , Estrutura MolecularRESUMO
Cotton cultivars have evolved to produce extensive, long, seed-born fibers important for the textile industry, but we know little about the molecular mechanism underlying spinnable fiber formation. Here, we report how PACLOBUTRAZOL RESISTANCE 1 (PRE1) in cotton, which encodes a basic helix-loop-helix (bHLH) transcription factor, is a target gene of spinnable fiber evolution. Differential expression of homoeologous genes in polyploids is thought to be important to plant adaptation and novel phenotypes. PRE1 expression is specific to cotton fiber cells, upregulated during their rapid elongation stage and A-homoeologous biased in allotetraploid cultivars. Transgenic studies demonstrated that PRE1 is a positive regulator of fiber elongation. We determined that the natural variation of the canonical TATA-box, a regulatory element commonly found in many eukaryotic core promoters, is necessary for subgenome-biased PRE1 expression, representing a mechanism underlying the selection of homoeologous genes. Thus, variations in the promoter of the cell elongation regulator gene PRE1 have contributed to spinnable fiber formation in cotton. Overexpression of GhPRE1 in transgenic cotton yields longer fibers with improved quality parameters, indicating that this bHLH gene is useful for improving cotton fiber quality.
Assuntos
Fibra de Algodão , Regulação da Expressão Gênica de Plantas , Variação Genética , Genoma de Planta , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/genética , Sequência de Bases , Modelos Biológicos , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Poliploidia , Deleção de Sequência/genética , TATA Box/genética , Fatores de Transcrição/metabolismoRESUMO
Sorafenib, a small inhibitor of tyrosine protein kinases, is currently the standard chemotherapy drug for the treatment of advanced hepatocellular carcinoma (HCC). Although sorafenib improves the survival of HCC patients, its efficacy is not optimal and requires further improvement. Capsaicin, the major active component of chili peppers from the genus Capsicum, is not only the agonist of TRPV1 channel, but also displays antitumor activity and enhances the sensitivity of cancer cells to cytotoxic drugs. In this study, we investigated the antitumor effects of combined sorafenib and capsaicin on HCC cells in vitro and xenograft tumors. Treatment with capsaicin alone dose-dependently inhibited the proliferation of the HCC cell lines PLC/PRF/7, HuH7 and HepG2 with IC50 values of 137, 108 and 140.7 µmol/L, respectively. No obvious expression of TRPV1 channel was detected in the 3 HCC cell lines and TRPV1 channel blockers did not alleviate the cytotoxicity of capsaicin. By contrast, combining capsaicin and sorafenib significantly enhanced the suppression on cell proliferation, achieving a high-level synergistic effect (inhibition rates over 50%) and promoting HCC cell apoptosis. In nude mice with PLC/PRF/5 xenografts, combined administration of capsaicin and sorafenib significantly enhanced the suppression on tumor growth without apparent gross toxicity compared to either agent alone. Mechanistically, capsaicin (10-200 µmol/L) dose-dependently increased the levels of phosphorylated ERK (p-ERK) in PLC/PRF/5 cells, thus leading to enhanced sorafenib sensitivity and a synergistic suppression on the tumor cells. Taken together, our results suggest that capsaicin-increased phosphorylation of ERK contributes to the enhanced antitumor activity of sorafenib, and capsaicin may be useful in improving the efficacy of sorafenib for the treatment of HCC.
Assuntos
Antineoplásicos/farmacologia , Capsaicina/farmacologia , Sinergismo Farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Niacinamida/farmacologia , Sorafenibe , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The cytotoxic activity of camptothecin derivatives is so high that these compounds need to be further modified before their successful application as anti-cancer agents clinically. In this study, we reported the synthesis and biological evaluation of a novel camptothecin derivative called compound 2-47. The changes in structure did not reduce its activity to inhibit DNA topoisomerase I. Compound 2-47 induced apoptosis of many tumor cells including leukemia cells K562, Jurkat, HL-60, breast cancer cell BT-549, colon cancer cell HT-29 and liver cancer cell HepG2 with a half maximal inhibitory concentration (IC50) of 2- to 3-fold lower than HCPT as a control. In particular, 2-47 inhibited the proliferation of Jurkat cells with an IC50 of as low as 40 nM. By making use of Jurkat cell as a model, following treatment of Jurkat cells, compound 2-47 activated caspase-3 and PARP, resulting in a decreased Bcl-2/Bax ratio. These data showed that compound 2-47 induces Jurkat cell death through the mitochondrial apoptotic pathway. In addition, compound 2-47 showed a decreased cytotoxic activity against normal cells and an improved solubility in low-polar solvent. For example, compound 2-47 solutes in CHCl3 130-fold higher than HCPT. Taken together, our data demonstrated that camptothecin derivative 2-47 notably inhibits the tumor cell proliferation through mitochondrial-mediated apoptosis in vitro.
Assuntos
Apoptose/efeitos dos fármacos , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Camptotecina/toxicidade , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Solubilidade , Resultado do TratamentoRESUMO
PURPOSE: This scoping review aimed to understand the advances in radiomics in esophagogastric junction (EGJ) cancer and assess the current status of radiomics in EGJ cancer. METHODS: We conducted systematic searches of PubMed, Embase, and Web of Science databases from January 18, 2012, to January 15, 2023, to identify radiomics articles related to EGJ cancer. Two researchers independently screened the literature, extracted data, and assessed the quality of the studies using the Radiomics Quality Score (RQS) and the METhodological RadiomICs Score (METRICS) tool, respectively. RESULTS: A total of 120 articles were retrieved from the three databases, and after screening, only six papers met the inclusion criteria. These studies investigated the role of radiomics in differentiating adenocarcinoma from squamous carcinoma, diagnosing T-stage, evaluating HER2 overexpression, predicting response to neoadjuvant therapy, and prognosis in EGJ cancer. The median score percentage of RQS was 34.7% (range from 22.2% to 38.9%). The median score percentage of METRICS was 71.2% (range from 58.2% to 84.9%). CONCLUSION: Although there is a considerable difference between the RQS and METRICS scores of the included literature, we believe that the research value of radiomics in EGJ cancer has been revealed. In the future, while actively exploring more diagnostic, prognostic, and biological correlation studies in EGJ cancer, greater emphasis should be placed on the standardization and clinical application of radiomics.
Assuntos
Neoplasias Esofágicas , Junção Esofagogástrica , Neoplasias Gástricas , Humanos , Junção Esofagogástrica/diagnóstico por imagem , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Gástricas/diagnóstico por imagem , Prognóstico , RadiômicaRESUMO
Standard multidetector computed tomography (MDCT) uses a single X-ray tube to emit a mixed energy X-ray beam, which is received by a single detector. The difference is that dual-energy CT (DECT), a new equipment in recent years, employs a single X-ray tube or two X-ray tubes to emit two single-energy X-ray beams, which are received by a single or two detectors. The application of dual-energy technology to portal venography has become one of the research hotspots. This paper will elaborate on the clinical application values of DECT portal venography in improving portal vein image quality, distinguishing the nature of portal vein thrombus, reducing contrast agent dose and radiation dose, and will discuss the possibility of its movement from research to routine practice and future development opportunities.
RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum cassia Presl (Cinnamomum cassia) is a common traditional Chinese medicine, which can promote the secretion and digestion of gastric juice, improve the function of gastrointestinal tract. Cinnamaldehyde (CA) is a synthetic food flavoring in the Chinese Pharmacopoeia. AIM OF THE STUDY: This study aimed to search for the active ingredient (CA) of inhibiting H. pylori from Cinnamomum cassia, and elucidate mechanism of action, so as to provide the experimental basis for the treatment of H. pylori infection with Cinnamomum cassia. MATERIALS AND METHODS: It's in vitro and in vivo pharmacological properties were evaluated based on minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and an acute gastric inflammation model in mice infected with H. pylori. Drug safety was evaluated using the CCK8 method and high-dose administration in mice. The advantageous characteristics of CA in inhibiting H. pylori were confirmed using acidic conditions and in combination with the antibiotics. The mechanism underlying the action of CA on H. pylori was explored using scanning electron microscopy (SEM), adhesion experiments, biofilm inhibition tests, ATP and ROS release experiments, and drug affinity responsive target stability (DARTS) screening of target proteins. The protein function and target genes were verified by molecular docking and Real-Time quantitative reverse transcription PCR (qRT-PCR). RESULTS: The results demonstrated that CA was found to be the main active ingredient against H. pylori in Cinnamomum cassia in-vitro tests, with a MIC of 8-16 µg/mL. Moreover, CA effectively inhibited both sensitive and resistant H. pylori strains. The dual therapy of PPI + CA exhibited remarkable in vivo efficacy in the acute gastritis mouse model, superior to the standard triple therapy. DARTS, molecular docking, and qRT-PCR results suggested that the target sites of action were closely associated with GyrA, GyrB, AtpA, and TopA, which made DNA replication and transcription impossible, then leading to inhibition of bacterial adhesion and colonization, suppression of biofilm formation, and inhibition ATP and enhancing ROS. CONCLUSIONS: This study demonstrated the suitability of CA as a promising lead drug against H. pylori, The main mechanisms can target GyrA ect, leading to reduce ATP and produce ROS, which induces the apoptosis of bacterial.
Assuntos
Acroleína , Antibacterianos , Cinnamomum aromaticum , Infecções por Helicobacter , Helicobacter pylori , Testes de Sensibilidade Microbiana , Animais , Acroleína/análogos & derivados , Acroleína/farmacologia , Helicobacter pylori/efeitos dos fármacos , Cinnamomum aromaticum/química , Antibacterianos/farmacologia , Camundongos , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Masculino , Simulação de Acoplamento Molecular , Biofilmes/efeitos dos fármacosRESUMO
A base-promoted olefin skeletal rearrangement strategy from para-quinone methides (p-QMs) and N-fluoroarenesulfonamides is reported, enabling direct nitrogen insertion of olefins to produce a series of multiarylated (Z)-N-sulfonyl amidines with complete stereoselectivity and generally good yields. Using p-QMs without o-hydroxy substituents gave triarylated N-sulfonyl amidines, whereas tetraarylated N,N'-disulfonyl amidines were synthesized with the existence of o-hydroxy groups.
RESUMO
OBJECTIVE: Hepatolenticular degeneration (HLD) is an autosomal recessive disorder that manifests as multiorgan damage due to impaired copper (Cu) metabolism. Female patients with HLD often experience reproductive impairments. This study investigated the protective effect of berberine against ovarian damage in toxic-milk (TX) mice, a murine model for HLD. METHODS: Mice were categorized into control group, HLD TX group (HLD group), penicillamine (Cu chelator)-treated TX group and berberine-treated TX group. Body weight, ovary weight and the number of ovulated eggs were recorded. Follicular morphology and cellular ultrastructure were examined. Total iron, ferrous iron (Fe2+) and trivalent iron (Fe3+) levels, as well as malondialdehyde (MDA), glutathione (GSH) and oxidized glutathione (GSSG), were measured in the ovaries. Western blot analysis was used to analyze the expression of proteins related to ferroptosis and endoplasmic reticulum (ER) stress. RESULTS: Ovarian tissue damage was evident in the HLD group, with a significant increase in ferroptosis and ER stress compared to the control group. This damage was inhibited by treatment with penicillamine, a Cu chelator. Compared with the HLD group, berberine increased the number of ovulations, and improved ovarian morphology and ultrastructure. Further, we found that berberine reduced total iron, Fe2+, MDA and GSSG levels, elevated GSH levels, decreased the expression of the ferroptosis marker protein prostaglandin-endoperoxide synthase 2 (PTGS2), and increased glutathione peroxidase 4 (GPX4) expression. Furthermore, berberine inhibited the expression of ER stress-associated proteins mediated by the protein kinase RNA-like ER kinase (PERK) pathway. CONCLUSION: Ferroptosis and ER stress are involved in Cu-induced ovarian damage in TX mice. Berberine ameliorates ovarian damage in HLD TX mice by inhibiting ferroptosis and ER stress. Please cite this article as: Liu QZ, Han H, Fang XR, Wang LY, Zhao D, Yin MZ, Zhang N, Jiang PY, Ji ZH, Wu LM. Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress. J Integr Med. 2024; 22(4): 494-503.
Assuntos
Berberina , Estresse do Retículo Endoplasmático , Ferroptose , Degeneração Hepatolenticular , Ovário , Animais , Feminino , Ferroptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Berberina/farmacologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/metabolismo , Degeneração Hepatolenticular/genética , Modelos Animais de Doenças , Cobre , Glutationa/metabolismo , Ferro/metabolismo , Malondialdeído/metabolismoRESUMO
Black carbon (BC) and brown carbon (BrC) over the high-altitude Tibetan Plateau (TP) can significantly influence regional and global climate change as well as glacial melting. However, obtaining plateau-scale in situ observations is challenging due to its high altitude. By integrating reanalysis data with on-site measurements, the spatial distribution of BC and BrC can be accurately estimated using the random forest algorithm (RF). In our study, the on-site observations of BC and BrC were successively conducted at four sites from 2018 to 2021. Ground-level BC and BrC concentrations were then obtained at a spatial resolution of 0.25° × 0.25° for three periods (including Periods-1980, 2000, and 2020) using RF and multi-source data. The highest annual concentrations of BC (1363.9 ± 338.7 ng/m3) and BrC (372.1 ± 96.2 ng/m3) were observed during Period-2000. BC contributed a dominant proportion of carbonaceous aerosol, with concentrations 3-4 times higher than those of BrC across the three periods. The ratios of BrC to BC decreased from Period-1980 to Period-2020, indicating the increasing importance of BC over the TP. Spatial distributions of plateau-scale BC and BrC concentrations showed heightened levels in the southeastern TP, particularly during Period-2000. These findings significantly enhance our understanding of the spatio-temporal distribution of light-absorbing carbonaceous aerosol over the TP.
RESUMO
Isobavachalcone (IBC) is a natural small molecule with various biological activities; however, its inhibitory effects on Cryptococcus neoformans remain unclear. In our study, IBC showed a good antifungal effect. Through in vitro experiments, its minimum inhibitory concentration was 0.5-1 µg/mL. It exhibited the same antifungal effect as Amphotericin B in brain and lung infections in in vivo experiments. IBC also showed a synergistic antifungal effect with emodin with lower toxicity, and C. neoformans did not develop drug resistance to IBC. In the mechanistic study, significantly damaged mitochondria of C. neoformans, a significant reduction in mitochondrial membrane potential and adenosine triphosphate production, and an increase in hydrogen peroxide (H2O2) caused by IBC were observed using transmission electron microscopy. Through drug affinity-responsive target stability combined with phenotype detection, riboflavin synthases of aconitase and succinate dehydrogenase were screened. Molecular docking, quantitative polymerase chain reaction experiments, target inhibitor and agonist intervention, molecular interaction measurements, and minimum inhibitory concentration detection of the constructed expression strains revealed that IBC targeted the activity of these two enzymes, interfered by the tricarboxylic acid cycle, inhibited the production of adenosine triphosphate, blocked electron transport, reduced mitochondrial membrane potential, and induced antioxidation imbalance and reactive oxygen species accumulation, thus producing an antifungal effect. Therefore, IBC is a promising lead drug and redox antifungal agent for C. neoformans.