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The advent of nanotechnology has opened new possibilities for bioimaging. Metal nanoparticles (such as gold, silver, iron, copper, etc.) hold tremendous potential and offer enormous opportunities for imaging and diagnostics due to their broad optical characteristics, ease of manufacturing technique, and simple surface modification. The arginine-glycine-aspartate (RGD) peptide is a three-amino acid sequence that seems to have a considerably greater ability to adhere to integrin adhesion molecules that exclusively express on tumour cells. RGD peptides act as the efficient tailoring ligand with a variety of benefits including non-toxicity, greater precision, rapid clearance, etc. This review focuses on the possibility of non-invasive cancer imaging using metal nanoparticles with RGD assistance.
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Nanopartículas del Metal , Neoplasias , Humanos , Secuencia de Aminoácidos , Glicina , OligopéptidosRESUMEN
Fibrosis is caused by extensive deposition of extracellular matrix (ECM) components, which play a crucial role in injury repair. Fibrosis attributes to ~45% of all deaths worldwide. The molecular pathology of different fibrotic diseases varies, and a number of bioactive factors are involved in the pathogenic process. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that have promising therapeutic effects in the treatment of different diseases. Current updates of fibrotic pathogenesis reveal that residential MSCs may differentiate into myofibroblasts which lead to the fibrosis development. However, preclinical and clinical trials with autologous or allogeneic MSCs infusion demonstrate that MSCs can relieve the fibrotic diseases by modulating inflammation, regenerating damaged tissues, remodeling the ECMs, and modulating the death of stressed cells after implantation. A variety of animal models were developed to study the mechanisms behind different fibrotic tissues and test the preclinical efficacy of MSC therapy in these diseases. Furthermore, MSCs have been used for treating liver cirrhosis and pulmonary fibrosis patients in several clinical trials, leading to satisfactory clinical efficacy without severe adverse events. This review discusses the two opposite roles of residential MSCs and external MSCs in fibrotic diseases, and summarizes the current perspective of therapeutic mechanism of MSCs in fibrosis, through both laboratory study and clinical trials.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Fibrosis Pulmonar , Animales , Fibrosis , Cirrosis Hepática/terapia , Cirrosis Hepática/patología , Fibrosis Pulmonar/terapia , Fibrosis Pulmonar/patología , Inflamación/patologíaRESUMEN
KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90 N (Hsp90N). Absence of complex crystal structure of Hsp90N-KW-2478, however, hampered further structure optimization of KW-2478 and understanding on the molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90N-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59 Å; PDB ID: 6LT8) and their molecular interaction was analyzed in detail, which suggested that KW-2478 perfectly bound in the N-terminal ATP-binding pocket of Hsp90 to disable its molecular chaperone function, therefore suppressed or killed cancer cells. The results from thermal shift assay (TSA, ΔTm, 18.82 ± 0.51 °C) and isothermal titration calorimetry (ITC, Kd, 7.30 ± 2.20 nM) suggested that there is an intense binding force and favorable thermodynamic changes during the process of KW-2478 binding with Hsp90N. Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC50, 8.16 µM for A549; 14.29 µM for H1975) and migration, induced cell cycle arrest and promoted apoptosis. Thirty-six novel KW-2478 derivatives were designed, based on the complex crystal structure and molecular interaction analysis of Hsp90N-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90N evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478.
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Antineoplásicos/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/química , Morfolinas/química , Morfolinas/farmacología , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptosis/efectos de los fármacos , Calorimetría , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Cristalografía por Rayos X , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Enlace de Hidrógeno , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Simulación del Acoplamiento Molecular , Morfolinas/metabolismo , Estabilidad Proteica , Relación Estructura-ActividadRESUMEN
This study aimed to investigate the association between red blood cell distribution width (RDW) and the risk of coronary artery lesions (CALs) in patients with Kawasaki disease (KD). A total of 1355 patients who met the diagnostic criteria for KD were reviewed between January 2018 and December 2019, including 636 patients with CALs and 719 patients without CALs. Blood samples for RDW were obtained at admission (before intravenous immunoglobulin treatment). A logistic regression analysis was performed, and a receiver operating characteristic curve was constructed to determine the prognostic value of RDW standard deviation (RDW-SD) and RDW coefficient of variation (RDW-CV). The study was registered at www.chictr.org.cn , No.: ChiCTR 2000040980. The results showed that RDW-SD increased in patients with complete KD and CALs compared with patients with complete KD without CALs (39 fL vs. 38 fL, respectively; p = 0.000). RDW-CV in patients with complete KD and CALs was significantly higher compared with patients with completed KD without CALs (p = 0.000). Further multivariate logistic regression analysis revealed that RDW-SD was an independent marker of CALs in patients with complete KD (p = 0.001), but no association was found between RDW-CV and CALs. The area under the curve of RDW-SD for predicting CALs in patients with complete KD was 0.606 (95% confidence interval 0.572-0.640; p = 0.000) with a sensitivity and specificity of 61% and 55%, respectively, when the optimal cut-off value of RDW-SD was 38.5 fL. RDW-CV increased in patients with incomplete KD and CALs compared with patients without CALs (13.55% vs 13.3%, respectively; p = 0.004), and multivariate logistic regression analysis revealed that RDW-CV was an independent marker of CALs in patients with incomplete KD (p = 0.021). The area under the curve of RDW-CV for predicting CALs in patients with incomplete KD was 0.597 (95% confidence interval 0.532-0.661; p = 0.004) with a sensitivity and specificity of 40% and 77%, respectively, when the optimal cut-off value of RDW-SD was 13.85%. Conclusion: RDW can be used as an independent predictive marker of CALs in patients with KD, but the type of KD should be considered. RDW-SD was an independent marker of CALs in patients with complete KD, while RDW-CV was a predictor of incomplete KD.
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Enfermedad de la Arteria Coronaria , Síndrome Mucocutáneo Linfonodular , Vasos Coronarios , Índices de Eritrocitos , Eritrocitos , Humanos , Inmunoglobulinas Intravenosas , Síndrome Mucocutáneo Linfonodular/complicacionesRESUMEN
BACKGROUND: To investigate the drug resistant gene profiles and molecular typing of Acinetobacter baumannii isolates collected from clinical specimens in a comprehensive hospital, Jiangsu province. METHODS: This study included 120 patients in a comprehensive hospital with drug-resistant A. baumannii infections on clinical specimens from October 2011 to December 2013. Antibiotic susceptibility test was determined by Vitek 2 Compact system. OXA-51, OXA-23, OXA-24, OXA-58, VIM, IMP, SHV, GES, TEM, AmpC, qacEΔ1-sul1, intI l, CarO, aac(6')-Ib, and aac(6')-II were analyzed by PCR. The analysis of molecular typing for 50 multidrug resistant A. baumannii isolates was performed by PFGE. RESULTS: A total of 64(53%) isolates were multidrug-resistant A.baumannii. The antibiotic susceptibility tests showed that the resistant rates to common antibiotics of mutidrug-resistant A. baumannii were extremely high, most of which over 60%. One hundred and ten isolates harbored OXA-51 (91.7%), 100 for OXA-23(83.3%), 103 for VIM-1(85.8%), 90 for AmpC(75.00%), 50 for aac(6')-Ib(41.7%), 77 for the loss of CarO (64.2%), 85 for intl1(70.8%), and 64 for qacEΔ1-sul1(53.33%), while OXA-24 was undetected. Fifty multidrug-resistant A. baumannii isolates belong to 14 clones according to the PFGE DNA patterns. Main clone A includes 24 isolates, while clone B and clone C includes 6 and 9 isolates, respectively and others with no common source identified. CONCLUSION: There is high morbidity of A. baumannii infections in the hospital, especially in ICU and sputum is the most common sample type.The mainly drug-resistant genes of A. baumannii are OXA-51, OXA-23, and VIM-1 in the hospital. Clonal dissemination provides evidence for the prevalence of multidrug-resistant A. baumannii among clinical isolates. It is suggested that there is an urgent need for effective control and prevention measures.
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Infecciones por Acinetobacter/microbiología , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Infección Hospitalaria/microbiología , Farmacorresistencia Bacteriana Múltiple , Infecciones por Acinetobacter/epidemiología , Acinetobacter baumannii/clasificación , Acinetobacter baumannii/genética , Acinetobacter baumannii/aislamiento & purificación , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Bacterianas/genética , China/epidemiología , Infección Hospitalaria/epidemiología , Femenino , Hospitales/estadística & datos numéricos , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Adulto JovenRESUMEN
Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely ß-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.
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Inhibidores de la Enzima Convertidora de Angiotensina , Antihipertensivos , Hipertensión , Humanos , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Hipertensión/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Bloqueadores de los Canales de Calcio/farmacología , Animales , Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas Adrenérgicos beta/farmacología , Diuréticos/uso terapéutico , Diuréticos/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéuticoRESUMEN
High-quality crystals are key to obtaining accurate three-dimensional structures of proteins using X-ray diffraction techniques. However, obtaining such protein crystals is often a challenge. Several containerless crystallization techniques have been reported to have the ability to improve crystal quality, but it is unknown which is the most favourable way to grow high-quality protein crystals. In this paper, a quality comparison of protein crystals which were grown under three containerless conditions provided by diamagnetic levitation, silicone oil and agarose gel was conducted. A control experiment on a vessel wall was also simultaneously carried out. Seven different proteins were crystallized under the four conditions, and the crystal quality was assessed in terms of the resolution limit, the mosaicity and the Rmerge. It was found that the crystals grown under the three containerless conditions demonstrated better morphology than those of the control. X-ray diffraction data indicated that the quality of the crystals grown under the three containerless conditions was better than that of the control. Of the three containerless crystallization techniques, the diamagnetic levitation technique exhibited the best performance in enhancing crystal quality. This paper is to our knowledge the first report of improvement of crystal quality using a diamagnetic levitation technique. Crystals obtained from agarose gel demonstrated the second best improvement in crystal quality. The study indicated that the diamagnetic levitation technique is indeed a favourable method for growing high-quality protein crystals, and its utilization is thus potentially useful in practical efforts to obtain well diffracting protein crystals.
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Cristalografía por Rayos X , Gravitación , Espectroscopía de Resonancia Magnética , Espectroscopía de Fotoelectrones , Proteínas/química , Sefarosa/normas , Aceites de Silicona/normas , Animales , Pollos , Cristalización/métodos , Cristalización/normas , Cristalografía por Rayos X/métodos , Cristalografía por Rayos X/normas , Proteínas de Escherichia coli/química , Proteínas/normas , Control de Calidad , Trichosanthes , Difracción de Rayos X/métodos , Difracción de Rayos X/normasRESUMEN
Most protein crystallisation begins from heterogeneous nucleation; in practice, crystallisation typically occurs in the presence of a solid surface in the solution. The solid surface provides a nucleation site such that the energy barrier for nucleation is lower on the surface than in the bulk solution. Different types of solid surfaces exhibit different surface energies, and the nucleation barriers depend on the characteristics of the solid surfaces. Therefore, treatment of the solid surface may alter the surface properties to increase the chance to obtain protein crystals. In this paper, we propose a method to modify the glass cover slip using a self-assembled monolayer (SAM) of functional groups (methyl, sulfydryl and amino), and we investigated the effect of each SAM on protein crystallisation. The results indicated that both crystallisation success rate in a reproducibility study, and crystallisation hits in a crystallisation screening study, were increased using the SAMs, among which, the methyl-modified SAM demonstrated the most significant improvement. These results illustrated that directly modifying the crystallisation plates or glass cover slips to create surfaces that favour heterogeneous nucleation can be potentially useful in practical protein crystallisation, and the utilisation of a SAM containing a functional group can be considered a promising technique for the treatment of the surfaces that will directly contact the crystallisation solution.
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Proteínas/química , Adsorción , Precipitación Química , Cristalización , Microscopía de Fuerza Atómica , Modelos Moleculares , Espectroscopía de Fotoelectrones , Reproducibilidad de los Resultados , Silanos/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Receptor chromatography involves high-throughput separation and accurate drug screening based on specific drug-receptor recognition and affinity, which has been widely used to screen active compounds in complex samples. This review summarizes the immobilization methods for receptors from three aspects: random covalent immobilization methods, site-specific covalent immobilization methods and dual-target receptor chromatography. Meanwhile, it focuses on its applications from three angles: screening active compounds in natural products, in natural-product-derived DNA-encoded compound libraries and drug-receptor interactions. This review provides new insights for the design and application of receptor chromatography, high-throughput and accurate drug screening, drug-receptor interactions and more.
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Productos Biológicos , Descubrimiento de Drogas , Descubrimiento de Drogas/métodos , Cromatografía , Productos Biológicos/química , Biblioteca de Genes , Evaluación Preclínica de Medicamentos/métodosRESUMEN
The mechanical environment is important for tumorigenesis and progression. Tumor cells can sense mechanical signals by mechanosensitive receptors, and these mechanical signals can be converted to biochemical signals to regulate cell behaviors, such as cell differentiation, proliferation, migration, apoptosis, and drug resistance. Here, we summarized the effects of the mechanical microenvironment on breast cancer cell activity, and mechanotransduction mechanism from cellular microenvironment to cell membrane, and finally to the nucleus, and also relative mechanosensitive proteins, ion channels, and signaling pathways were elaborated, therefore the mechanical signal could be transduced to biochemical or molecular signal. Meanwhile, the mechanical models commonly used for biomechanics study in vitro and some quantitative descriptions were listed. It provided an essential theoretical basis for the occurrence and development of mechanosensitive breast cancer, and also some potential drug targets were proposed to treat such disease.
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Neoplasias de la Mama , Mecanotransducción Celular , Humanos , Femenino , Mecanotransducción Celular/fisiología , Canales Iónicos/metabolismo , Transducción de Señal , Fenómenos Biomecánicos , Microambiente TumoralRESUMEN
This paper reports on an ultrasonic levitation system developed for crystallization from solution in a containerless condition. The system has been proven to be able to levitate droplets stably and grow crystals rapidly and freely from a levitated droplet. Crystals of four samples, including NaCl, NH(4)Cl, lysozyme, and proteinase K, were obtained successfully utilizing the system. The studies showed that the crystals obtained from the acoustically levitated droplets all exhibited higher growth rates, larger sizes, better shapes, fewer crystals, as well as fewer twins and shards, compared with the control on a vessel wall. The results indicated that containerless ultrasonic levitation could play a key role in improving the crystallization of both inorganic salts and proteins. The ultrasonic levitation system could be used as a ground-based microgravity simulation platform, which could swiftly perform crystallization and screening of crystallization conditions for space crystallization and other ground-based containerless techniques. Moreover, the approach could also be conveniently applied to researching the dynamics and mechanism of crystallization. In addition, the device could be used for the preparation of high-purity materials, analysis of minute or poisonous samples, study of living cells, environmental monitoring, and so on.
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The effect of magnetic fields on water is still a highly controversial topic despite the vast amount of research devoted to this topic in past decades. Enhanced water evaporation in a magnetic field, however, is less disputed. The underlying mechanism for this phenomenon has been investigated in previous studies. In this paper, we present an investigation of the evaporation of water in a large gradient magnetic field. The evaporation of pure water at simulated gravity positions (0 gravity level (ab. g), 1 g, 1.56 g and 1.96 g) in a superconducting magnet was compared with that in the absence of the magnetic field. The results showed that the evaporation of water was indeed faster in the magnetic field than in the absence of the magnetic field. Furthermore, the amount of water evaporation differed depending on the position of the sample within the magnetic field. In particular, the evaporation at 0 g was clearly faster than that at other positions. The results are discussed from the point of view of the evaporation surface area of the water/air interface and the convection induced by the magnetization force due to the difference in the magnetic susceptibility of water vapor and the surrounding air.
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Campos Magnéticos , Modelos Químicos , Agua/químicaRESUMEN
Incorporation of highly selective and stable adsorbent with facile extraction technology is desired in practical analysis. Here we show the rational preparation of a urea-linked covalent organic framework functionalized polytetrafluoroethylene film (COF-117-PTFE) with ordered porous structure, rich functional groups, and large surface area-to-volume ratio as the effective adsorbent for convenient, selective and rapid thin film microextraction (TFME) of rhodamine B (RB). The COF-117-PTFE based TFME coupled with high performance liquid chromatography-fluorescence detector (HPLC-FLD) successfully realized the determination of RB with the limit of detection of 0.007 µg L-1, the linear range of 0.1 - 100 µg L-1. The relative standard deviation (RSD) of intraday (n = 5) and interday (n = 5) for the determination of 10 µg L-1 RB were 2.3% and 6.8%, respectively. The absolute recoveries were 80.3%, 71.2% and 67.9% in river water, chili powder and Sichuan pepper powder, respectively. The recoveries for RB spiking in complicated real samples (dry chili, chili powder, dry Sichuan pepper, Sichuan pepper powder and river water) ranged from 90.4% to 107.5%. The developed COF-117-PTFE based TFME-HPLC-FLD method is promising in practical application. This work reveals the high potential of functionalized COF film as the adsorbent for effective extraction of trace contaminants in complicated samples.
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Estructuras Metalorgánicas , Límite de Detección , Estructuras Metalorgánicas/química , Politetrafluoroetileno , Polvos , Rodaminas , Urea , AguaRESUMEN
New targeted chemotherapy agents greatly improved five-year survival in NSCLC patients, but which were susceptible to drug resistance. NVP-AUY922, terminated in phase II clinical trials, exhibited promising anti-NSCLC (non-small-cell lung cancer) activity targeting to Hsp90N (heat shock protein), which demonstrated advantages in overcoming drug resistance as a broad-spectrum anti-cancer target. It was expected to develop novel anti-NSCLC drugs to overcome drug resistance by the structural optimization of NVP-AUY922. However, the absence of high-resolution complex crystal structure of Hsp90N-NVP-AUY922 blocked the way. Herein, 1.59 Å-resolution complex crystal structure of Hsp90N-NVP-AUY922 (PDB ID 6LTI) was successfully determined by X-ray diffraction. Meanwhile, there was a strong binding capability between NVP-AUY922 and its target Hsp90N verified by TSA (ΔTm, -15.56 ± 1.78°C) and ITC (K d, 5.10 ± 2.10 nM). Results by the complex crystal structure, TSA and ITC verified that NVP-AUY922 well accommodated in the ATP-binding pocket of Hsp90N to disable the molecular chaperone activity of Hsp90. Therefore, NVP-AUY922 exhibited approving inhibitory activity on NSCLC cell line H1299 (IC50, 2.85 ± 0.06 µM) by inhibiting cell proliferation, inducing cell cycle arrest and promoting cell apoptosis. At the basis of the complex crystal structure and molecular interaction analysis, thirty-two new NVP-AUY922 derivatives were further designed, and among which twenty-eight new ones display enhanced binding force with Hsp90N by molecular docking evaluation. The results would promote anti-NSCLC new drug development to overcome drug resistance based on the lead compound NVP-AUY922.
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Matrine is an alkaloid extracted from traditional Chinese herbs including Sophora flavescentis, Sophora alopecuroides, Sophora root, etc. It has the dual advantages of traditional Chinese herbs and chemotherapy drugs. It exhibits distinct benefits in preventing and improving chronic diseases such as cardiovascular disease and tumors. The review introduced recent research progresses on extraction, synthesis and derivatization of Matrine. The summary focused on the latest research advances of Matrine on anti-atherosclerosis, anti-hypertension, anti-ischemia reperfusion injury, anti-arrhythmia, anti-diabetic cardiovascular complications, anti-tumor, anti-inflammatory, anti-bacterium, anti-virus, which would provide new core structures and new insights for new drug development in related fields.
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Malignant tumors seriously threaten people's health and life worldwide. Natural products, with definite pharmacological effects and known chemical structures, present dual advantages of Chinese herbs and chemotherapeutic drug. Some of them exhibit favorable anti-cancer activity. Natural products were categorized into eight classes according to their chemical structures, including alkaloids, terpenoids and volatile oils, inorganic salts, phenylpropanoids, flavonoids and isoflavones, quinone, saponins and polysaccharides. The review focused on the latest advances in anti-cancer activity of representative natural products for every class. Additionally, anti-cancer molecular mechanism and derivatization of natural products were summarized in detail, which would provide new core structures and new insights for anti-cancer new drug development.
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Hypertension is a major risk factor for cardiovascular disease and Chinese herb monomers could provide new structural skeletons for anti-hypertension new drug development. Paeonol is a Chinese herbal monomer extracted from Cortex moutan, exhibited some anti-hypertensive activity. The study focused on the structural optimization of paeonol to provide promising lead compounds for anti-hypertension new drug development. Herein, twelve new paeonol derivatives (PD) were designed and synthesized and their vasodilation activity was evaluated by in vitro vasodilation drug screening platform based on Myograph. Its anti-hypertension activity, PD-C302 (2-hydroxy-4-methoxyvalerophenone) as a representative with the optimal vasodilation activity, was determined by its response to blood pressure in spontaneously hypertensive rats (SHR) in vivo. Moreover, its molecular mechanism was probed by the vasodilation activity of rat superior mesenteric artery rings with or without endothelium pre-contracted by potassium chloride (KCl) or phenylephrine hydrochloride (PE). It was indicated that PD-C302 significantly reduced the blood pressure in SHR, which would involve in PD-C302-induced vasodilation. Furthermore, endothelium-dependent pathways and endothelium-independent pathways both contributed importantly to PD-C302-induced vasodilation at low concentration of PD-C302. Endothelium-independent pathways (vascular smooth muscle cell-mediated vasodilation), were mainly responsible for the PD-C302-induced vasodilation at high concentration of PD-C302, which involved in opening multiple K+ channels to restrain Ca2+ channels, and then triggered vasodilation to reduce blood pressure. PD-C302 has a simple structure and favorable anti-hypertensive activity in vivo, which could be a promising lead compound for anti-hypertension new drug development.
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Hipertensión , Vasodilatación , Acetofenonas , Animales , Antihipertensivos/metabolismo , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Endotelio Vascular , Cloruro de Potasio/farmacología , Ratas , Ratas Endogámicas SHRRESUMEN
Bladder cancer (BC) is the most common malignant tumor in the urinary system, and its early diagnosis is conducive to improving clinical prognosis and prolonging overall survival time. However, few biomarkers with high sensitivity and specificity are used as diagnostic markers for BC. Multiple long non-coding RNAs (lncRNAs) are abnormally expressed in BC, and play key roles in tumorigenesis, progression and prognosis of BC. In this review, we summarize the expression, function, molecular mechanisms and the clinical significance of lncRNAs on bladder cancer. There are more than 100 dysregulated lncRNAs in BC, which are involved in the regulation of proliferation, cell cycle, apoptosis, migration, invasion, metabolism and drug resistance of BC. Meanwhile, the molecular mechanisms of lncRNAs in BC was explored, including lncRNAs interacting with DNA, RNA and proteins. Additionally, the abnormal expression of thirty-six lncRNAs is closely associated with multiple clinical characteristics of BC, including tumor size, metastasis, invasion, and drug sensitivity or resistance of BC. Furthermore, we summarize some potential diagnostic and prognostic biomarkers of lncRNA for BC. This review provides promising novel biomarkers in early diagnosis, prognosis and monitoring of BC based on lncRNAs.
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BACKGROUND: Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns. METHODS: In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification. RESULTS: Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, ß-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/ß-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNAPKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34-beclin-1-related bone mineralization via vascular calcification. CONCLUSION: The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.