RESUMEN
Deep-tissue optical imaging and photodynamic therapy (PDT) remain a big challenge for the diagnosis and treatment of cancer. Chemiluminescence (CL) has emerged as a promising tool for biological imaging and in vivo therapy. The development of covalent-binding chemiluminescence agents with high stability and high chemiluminescence resonance energy transfer (CRET) efficiency is urgent. Herein, we design and synthesize an unprecedented chemiluminescent conjugated polymer PFV-Luminol, which consists of conjugated polyfluorene vinylene (PFV) main chains and isoluminol-modified side chains. Notably, isoluminol groups with chemiluminescent ability are covalently linked to main chains by amide bonds, which dramatically narrow their distance, greatly improving the CRET efficiency. In the presence of pathologically high levels of various reactive oxygen species (ROS), especially singlet oxygen (1O2), PFV-Luminol emits strong fluorescence and produces more ROS. Furthermore, we construct the PFV-L@PEG-NPs and PFV-L@PEG-FA-NPs nanoparticles by self-assembly of PFV-Luminol and amphiphilic copolymer DSPE-PEG/DSPE-PEG-FA. The chemiluminescent PFV-L@PEG-NPs nanoparticles exhibit excellent capabilities for in vivo imaging in different inflammatory animal models with great tissue penetration and resolution. In addition, PFV-L@PEG-FA-NPs nanoparticles show both sensitive in vivo chemiluminescence imaging and efficient chemiluminescence-mediated PDT for antitumors. This study paves the way for the design of chemiluminescent probes and their applications in the diagnosis and therapy of diseases.
Asunto(s)
Nanopartículas , Neoplasias , Fotoquimioterapia , Animales , Especies Reactivas de Oxígeno , Polímeros/química , Luminol , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Nanopartículas/química , Inflamación/diagnóstico por imagen , Inflamación/tratamiento farmacológico , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/químicaRESUMEN
Asparagine, an important amino acid in mammals, is produced in several organs and is widely used for the production of other nutrients such as glucose, proteins, lipids, and nucleotides. Asparagine has also been reported to play a vital role in the development of cancer cells. Although several types of cancer cells can synthesise asparagine alone, their synthesis levels are insufficient to meet their requirements. These cells must rely on the supply of exogenous asparagine, which is why asparagine is considered a semi-essential amino acid. Therefore, nutritional inhibition by targeting asparagine is often considered as an anti-cancer strategy and has shown success in the treatment of leukaemia. However, asparagine limitation alone does not achieve an ideal therapeutic effect because of stress responses that upregulate asparagine synthase (ASNS) to meet the requirements for asparagine in cancer cells. Various cancer cells initiate different reprogramming processes in response to the deficiency of asparagine. Therefore, it is necessary to comprehensively understand the asparagine metabolism in cancers. This review primarily discusses the physiological role of asparagine and the current progress in the field of cancer research.
Asunto(s)
Leucemia , Neoplasias , Animales , Asparagina , Aminoácidos , Glucosa , MamíferosRESUMEN
INTENTION: Immunosuppressive therapy is the major treatment approach for patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Due to impaired cellular immunological function and the use of glucocorticoids and immunosuppressants, AAV patients are predisposed to opportunistic infections, including tuberculosis (TB). This retrospective study aims to analyze the clinical characteristics of patients with AAV and TB and explore suitable glucocorticoid regimens for them. So as to provide a basis for future clinical guidelines and have important value for guiding clinical treatment. METHODS: This study retrospectively reviewed 58 AAV patients (18-80 years old) with TB admitted to Changsha Central Hospital Affiliated with the University of South China from 2016.1 to 2023.4 Patients were divided into standard-dose and reduced-dose glucocorticoid groups before retrospectively analyzing their medical records. RESULTS: A total of 58 AAV patients with TB were enrolled, with 15 dying throughout the monitoring period. Through analysis data, compared with the standard-dose group, the reduced group had less proteinuria and hematuria. In survival analysis, the reduced-dose glucocorticoid group had lower mortality than the standard-dose group (P = 0.03); however, no significant difference was noted in the use of immunoglobulin (P = 0.39), tuberculosis activity (P = 0.64), and age stratification (P = 0.40). The BVAS score before treatment and 6 months post-treatment suggest that the two regimens cause the same risk of ESKD (P > 0.05). CONCLUSION: In conclusion, the reduced glucocorticoid dose group can achieve the same curative effect as the standard dose group and has less damage to the kidney in hematuria and proteinuria. Therefore, the reduced glucocorticoid dose treatment regimen may be more suitable for AAV patients with TB.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Glucocorticoides , Tuberculosis , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Masculino , Femenino , Anciano , Adulto , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Adulto Joven , Anciano de 80 o más Años , Adolescente , Tuberculosis/tratamiento farmacológico , Tuberculosis/complicaciones , China , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéuticoRESUMEN
PURPOSE: The purpose of this study was to understand and analyze the risk factors of peripherally inserted central catheter (PICC)-related venous thrombosis in adult patients with cancer. METHODS: This observational cohort study included adult patients with cancer who underwent color Doppler ultrasound at the Xiangya Hospital of Central South University, Hunan Provincial Maternal and Child Healthcare Hospital, and Xiangya Changde Hospital, Hunan Province, from January 1, 2017 to December 31, 2021. Univariate and multivariate logistic regression analyses were performed to determine the risk factors of PICC-related venous thrombosis. RESULTS: After risk adjustment, multivariate logistic regression analysis revealed statistically significant associations between PICC-related venous thrombosis and age > 65 years old (OR: 1.791, CI: 1.343-2.389), male sex (OR: 1.398, CI: 1.057-1.849), white blood cell count > 9.5 × 109 /L (OR: 1.422, CI: 1.041-1.942), APTT < 25 s (OR: 2.006, CI: 1.431-2.811), gastrointestinal tumor (OR: 2.191, CI: 1.406-3.414), infection (OR:7.619, CI: 5.783-10.037), the use of cisplatin (OR: 2.374, CI: 1.714-3.214), vincristine (OR: 2.329, CI: 1.447-3.749), the use of polyurethane (OR: 2.449, CI: 1.863-3.219) and open-ended catheters (OR:1.660, CI: 1.131-2.439), keeping time of the catheter (days) (OR: 1.003, CI: 1.001-1.005) were associated with PICC-related venous thrombosis. CONCLUSION: We identified that the presence of age > 65 years old, male sex, white blood cell count > 9.5 × 109 /L, APTT < 25 s, gastrointestinal tumor, infection, the use of cisplatin and vincristine, the use of polyurethane, open-ended catheters and keeping time of the catheter (days), were associated with PICC-related venous thrombosis.
RESUMEN
Anxiety disorders are the most common psychiatric condition, but the etiology of anxiety disorders remains largely unclear. Our previous studies have shown that neuroplastin 65 deficiency (NP65-/-) mice exhibit abnormal social and mental behaviors and decreased expression of tryptophan hydroxylase 2 (TPH2) protein. However, whether a causal relationship between TPH2 reduction and anxiety disorders exists needs to be determined. In present study, we found that replenishment of TPH2 in dorsal raphe nucleus (DRN) enhanced 5-HT level in the hippocampus and alleviated anxiety-like behaviors. In addition, injection of AAV-NP65 in DRN significantly increased TPH2 expression in DRN and hippocampus, and reduced anxiety-like behaviors. Acute administration of exogenous 5-HT or HTR3 agonist SR57227A in hippocampus mitigated anxiety-like behaviors in NP65-/- mice. Moreover, replenishment of TPH2 in DRN partly repaired the impairment of long-term potentiation (LTP) maintenance in hippocampus of NP65-/- mice. Finally, we found that loss of NP65 lowered transcription factors Lmx1b expression in postnatal stage and replenishment of NP65 in DRN reversed the decrease in Lmx1b expression of NP65-/- mice. Together, our findings reveal that NP65 deficiency induces anxiety phenotype by downregulating DRN-hippocampus serotonergic-HTR3 transmission. These studies provide a novel and insightful view about NP65 function, suggesting an attractive potential target for treatment of anxiety disorders.
Asunto(s)
Ansiedad , Núcleo Dorsal del Rafe , Hipocampo , Ratones Noqueados , Receptores de Serotonina 5-HT3 , Serotonina , Triptófano Hidroxilasa , Animales , Núcleo Dorsal del Rafe/metabolismo , Hipocampo/metabolismo , Ansiedad/metabolismo , Serotonina/metabolismo , Ratones , Masculino , Triptófano Hidroxilasa/genética , Triptófano Hidroxilasa/metabolismo , Triptófano Hidroxilasa/deficiencia , Receptores de Serotonina 5-HT3/metabolismo , Receptores de Serotonina 5-HT3/genética , Ratones Endogámicos C57BL , Fenotipo , Potenciación a Largo PlazoRESUMEN
This study examines the dynamic relationship between global value chain integration, and carbon emissions, in 57 developing economies from 2000 to 2018. Our results show a multipart link between GVC involvement and carbon emissions. Specifically, forward participation, which involves domestic content in foreign exports, offers the potential to reduce emissions, whereas backward participation, defined by foreign content in domestic exports, typically increases emissions. This imbalance draws attention to the dual nature of using mineral resources, which can contribute to and mitigate environmental damage depending on the extent of GVC engagement. The NARDL model employed in the study also reveals the dynamic and nonlinear responses of carbon emissions to variations in the utilization of mineral resources within GVCs. Our findings show that positive shocks to mineral resources use within GVCs negatively influence carbon emissions, while adverse shocks have less impact. The results have significant policy implications, indicating that developing nations should prioritize environmental sustainability while planning their GVC participation. This entails promoting value-added mining resource use initiatives and pushing for strict environmental regulations in GVCs. Our results also highlight the significance of implementing customized measures to mitigate economic activity's asymmetric and nonlinear impacts on environmental quality. It enlightens policymakers in developing nations on balancing environmental conservation and economic growth in a global economy that is becoming more interconnected.
Asunto(s)
Conservación de los Recursos Naturales , Carbono/análisisRESUMEN
Natural resources have a significant impact on economic and political landscapes of developing countries which determines environmental sustainability. This study explores the convoluted connection between governance and natural resources, examining how resource abundance might influence governance quality. The main components of this dynamic that the theoretical framework considers are the Rentier effects, the repression effects, and the obstruction of modernization. This study creates a governance index applying principal component analysis (PCA) on several governance characteristics, such as political stability, rule of law, government efficacy, regulation and control of corruption, to measure governance comprehensively. Natural resource exports, rents, and the differentiation between renewable and non-renewable natural resources are the three proxies used to quantify natural resources, providing a more nuanced view. To calculate the effect of renewable and non-renewable natural resources on governance in developing nations, the econometric methodology uses a dynamic panel model and system GMM. This analysis reveals that the ability of renewable resources to promote inclusive development has a favourable impact on governance. On the other hand, non-renewable resources show a negative correlation, mainly because of their vulnerability to swings in the world price and their propensity to consolidate power and promote corruption. The significance of differentiating between natural resource types is highlighted in this study, along with the possible advantages of renewable resources for governance and the disadvantages of an over-reliance on non-renewable resources. Policymakers, researchers, and practitioners interested in the development and governance difficulties encountered by resource-rich developing nations can benefit greatly from this research's larger and more complex understanding of the link between natural resources and governance.
Asunto(s)
Conservación de los Recursos Naturales , Recursos Naturales , Países en DesarrolloRESUMEN
The growing presence of yttrium (Y) in the environment raises concern regarding its safety and toxicity. However, limited toxicological data are available to determine cardiotoxicity of Y and its underlying mechanisms. In the present study, yttrium chloride (YCl3) intervention with different doses was performed in male Kunming mice for the toxicological evaluation of Y in the heart. After 28 days of intragastric administration, 500 mg/kg·bw YCl3 induces iron accumulation in cardiomyocytes, and triggers ferroptosis through the glutathione peroxidase 4 (GPX4)/glutathione (GSH)/system Xc- axis via the inhibition of Nrf2 signaling pathway. This process led to cardiac lipid peroxidation and inflammatory response. Further RNA sequencing transcriptome analysis found that many genes involved in ferroptosis and lipid metabolism-related pathways were enriched. The ferroptosis induced by YCl3 in cardiomyocytes ultimately caused cardiac injury and dysfunction in mice. Our findings assist in the elucidation of the potential subacute cardiotoxicity of Y3+ and its underlying mechanisms.
Asunto(s)
Ferroptosis , Miocitos Cardíacos , Masculino , Ratones , Animales , Peroxidación de Lípido , Cardiotoxicidad , Itrio , Inflamación , HierroRESUMEN
Covalent organic framework materials (COFs), as a new type of organic porous material, not only have the characteristics of flexible structure, abundant resources, environmental friendliness, etc., but also have the characteristics of a regular structure and uniform pore channels, so they have broad application prospects in secondary batteries. Their functional group structure, type, and number of active sites play a crucial role in the performance of different kinds of batteries. Therefore, this article starts from these aspects, summarizes the application and research progress of the COF anode materials used in lithium-ion batteries, sodium-ion batteries, and potassium-ion batteries in recent years, discusses the energy storage mechanism of COF materials, and expounds the application prospects of COF electrodes in the field of energy storage.
RESUMEN
Stimuli-responsive drug release and photodynamic therapy (PDT) have aroused extensive attention for their enormous potential in antitumor treatment. pH-responsive drug delivery systems (PFE-DOX-1 and PFE-DOX-2) based on water-soluble conjugated polymers were constructed in this work for high-performance synergistic chemo-/PDT therapy, in which the anticancer drug doxorubicin (DOX) is covalently attached to the side chains of the conjugated polymers via acid-labile imine and acylhydrazone bonds. Concurrently, the intense fluorescence of poly(fluorene-co-ethynylene) (PFE) is effectively quenched due to the energy/electron transfer (ET) between the PFE-conjugated backbone and DOX. Effective pH-responsive drug release from PFE-DOX-2 is achieved by the cleavage of acylhydrazone linkages in the acidic tumor intracellular microenvironment. Additionally, the drug release process can be monitored by the recovered fluorescence of conjugated polymers. Furthermore, the conjugated polymers can produce reactive oxygen species (ROS) under light irradiation after drug release in an acidic environment, which prevents possible phototoxicity to normal tissues. It is noted that PFE-DOX-2 demonstrates remarkable antitumor cell performance, which is attributed to its efficient cell uptake and powerful synergistic chemo-/PDT therapeutic effectiveness. This report thus provides a promising strategy for in vivo anticancer treatment with the construction of a stimuli-responsive multifunctional drug delivery system.
Asunto(s)
Antineoplásicos , Nanopartículas , Fotoquimioterapia , Polímeros , Sistemas de Liberación de Medicamentos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Doxorrubicina/química , Concentración de Iones de Hidrógeno , Liberación de Fármacos , Nanopartículas/química , Línea Celular TumoralRESUMEN
The Space-Air-Ground Integrated Network (SAGIN) expands cyberspace greatly. Dynamic network architecture, complex communication links, limited resources, and diverse environments make SAGIN's authentication and key distribution much more difficult. Public key cryptography is a better choice for terminals to access SAGIN dynamically, but it is time-consuming. The semiconductor superlattice (SSL) is a strong Physical Unclonable Function (PUF) to be the hardware root of security, and the matched SSL pairs can achieve full entropy key distribution through an insecure public channel. Thus, an access authentication and key distribution scheme is proposed. The inherent security of SSL makes the authentication and key distribution spontaneously achieved without a key management burden and solves the assumption that excellent performance is based on pre-shared symmetric keys. The proposed scheme achieves the intended authentication, confidentiality, integrity, and forward security, which can defend against masquerade attacks, replay attacks, and man-in-the-middle attacks. The formal security analysis substantiates the security goal. The performance evaluation results confirm that the proposed protocols have an obvious advantage over the elliptic curve or bilinear pairings-based protocols. Compared with the protocols based on the pre-distributed symmetric key, our scheme shows unconditional security and dynamic key management with the same level performance.
RESUMEN
As the incidence of diabetes mellitus is rapidly increasing worldwide,that of related complications,such as diabetic kidney disease(DKD),also increases,conferring a heavy economic burden on the patients,families,society,and government.Diabetes mellitus complicated with chronic kidney disease(CKD)includes DKD and the CKD caused by other reasons.Because of the insufficient knowledge about CKD,the assessment of diabetes mellitus complicated with CKD remains to be improved.The therapies for diabetes mellitus complicated with CKD focus on reducing the risk factors.In clinical practice,DKD may not be the CKD caused by diabetes.According to clinical criteria,some non-diabetic kidney disease may be misdiagnosed as DKD and not be treated accurately.This review summarizes the status quo and research progress in the assessment,diagnosis,and treatment of diabetes mellitus complicated with CKD and predicts the directions of future research in this field.
Asunto(s)
Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Nefropatías Diabéticas , Insuficiencia Renal Crónica , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/terapia , Nefropatías Diabéticas/etiología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/terapia , Factores de Riesgo , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/terapiaRESUMEN
BACKGROUND: The systemic immune-inflammation index (SII) has been reported to have prognostic ability in various cardiovascular diseases; however, it has not been studied in type-B aortic dissection (TBAD). We aimed to explore the relation of SII with short-term and long-term outcomes in TBAD patients undergoing thoracic endovascular repair (TEVAR). METHODS: We performed a retrospective analysis of a prospectively maintained database from 2010 to 2017. The patients were divided into two groups (high SII and low SII) as per the optimal cut-off value determined using the receiver operating characteristic curve. Multivariate logistic and Cox regression analyses were performed to analyse the relationship between the SII and the short-term and long-term outcomes. RESULTS: A total of 805 TBAD patients who underwent TEVAR were enrolled. Twenty-six (3.2%) patients died during hospitalisation. At the end of a median follow-up duration of 48.80 mon, 70 (9.8%) patients had died. The patients were divided into the high-SII group [n = 333 (41.4%%)] and the low-SII group [n = 472 (58.6%)] as per the optimal cut-off value of 1,062. Multivariable logistic analyses showed that a high-SII score was independently associated with major adverse cardiovascular events (MACEs) in-hospital (odd ratio [OR], 1.67; 95% confidence interval [CI], 1.13-2.47; p = .01). In addition, multivariable Cox analyses showed that a high-SII score could be an independent indicator for follow-up adverse events (hazard ratio [HR], 1.70; 95% CI, 1.14-2.56, p = .01). CONCLUSIONS: Systemic immune-inflammation index is associated with both in-hospital and long-term outcomes in patients with TBAD undergoing TEVAR. Therefore, SII may serve as valuable tool for risk stratification before intervention.
Asunto(s)
Aneurisma de la Aorta Torácica/cirugía , Disección Aórtica/cirugía , Procedimientos Endovasculares , Inflamación/inmunología , Adulto , Disección Aórtica/complicaciones , Aneurisma de la Aorta Torácica/complicaciones , Femenino , Humanos , Inflamación/complicaciones , Inflamación/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de TiempoRESUMEN
Increasing exploration of rare-earth elements (REEs) has resulted in a high REEs' exposure risk. Owing to their persistence and accumulation of REEs in the environment, their adverse effects have caused widespread concern. However, limited toxicological data are available for the adverse effects of yttrium (Y) and its underlying mechanisms of action. In the present study, H9c2 cardiomyocytes were used in vitro model to investigate the cardiotoxicity of yttrium chloride (YCl3). Results show that YCl3 treatment resulted in reactive oxygen species (ROS) overproduction, decrease in ∆Ψm, and DNA damage. Mechanistically, we detected expression levels of protein in response to cellular DNA damage and antioxidative defense. Results indicated that the phosphorylation of histone H2AX remarkably increased in a dose-dependent manner. At a high YCl3-exposure concentration (120 µM), specific DNA damage sensors ATM/ATR-Chk1/Chk2 were significantly decreased. The protein levels of key antioxidant genes Nrf2/PPARγ/HO-1 were also remarkably inhabited. Additionally, the antioxidant N-acetyl-L-cysteine (NAC) pretreatment promoted the activation of antioxidative defense Nrf2/PPARγ signaling pathways, and prevented the production of cellular ROS, thus protecting the DNA from cleavage. Altogether, our findings suggest that YCl3 can induce DNA damage through causing intracellular ROS overproduction and inhibition of antioxidative defense, leading to cytotoxicity in H9c2 cardiomyocytes.
Asunto(s)
Daño del ADN/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Itrio/toxicidad , Animales , Antioxidantes/metabolismo , Cardiotoxicidad/etiología , Línea Celular , Miocitos Cardíacos/patología , Factor 2 Relacionado con NF-E2/metabolismo , PPAR gamma/metabolismo , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
The sensitive recognition and effective inhibition of toxic amyloid ß protein (Aß) aggregates play a critical role in early diagnosis and treatment of neurodegenerative diseases. In this work, a new conjugated oligo(fluorene-co-phenylene) (OFP) modified with 1,8-naphthalimide (NA) derivative OFP-NA-NO2 is designed and synthesized as a ratiometric fluorescence probe for sensing Aß, inhibiting the assembly of Aß, and detoxicating the cytotoxicity of Aß aggregates. In the presence of Aß, the active ester group on the side chain of OFP-NA-NO2 can covalently react with the amino group on Aß, effectively inhibiting the formation of Aß aggregates and degrading the preformed fibrils. In this case, the fluorescence intensity ratio of NA to OFP (INA /IOFP ) increases greatly. The detection limit is calculated to be 89.9 nM, presenting the most sensitive ratiometric recognition of Aß. Interestingly, OFP-NA-NO2 can dramatically recover the cell viability of PC-12 and restore the Aß-clearing ability of microglia. Therefore, this ratiometric probe exhibits the targeted recognition of Aß, effective inhibition of Aß aggregates, and detox effect, which is potential for early diagnosis and treatment of neurodegenerative diseases.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Amiloide , Animales , Colorantes Fluorescentes , Microglía , Células PC12 , RatasRESUMEN
Although adequate periconceptional folic acid (FA) supplementation has reduced the occurrence of pregnancies affected by neural tube defects (NTDs), the mechanisms underlying FA-resistant NTDs are poorly understood, and thus NTDs still remain a global public health concern. A high level of Krüppel-like factor 12 (KLF12) exerts deleterious effects on heath in most cases, but evidence for its roles in development has not been published. We observed KLF12-overexpressing mice showed disturbed neural tube development. KLF12-overexpressing fetuses died in utero at approximately 10.5 days post-coitus, with 100% presenting cranial NTDs. Neither FA nor formate promoted normal neural tube closure in mutant fetuses. The RNA-seq results showed that a high level of KLF12 caused NTDs in mice via overactivating the sonic hedgehog (Shh) signaling pathway, leading to the upregulation of patched 1, GLI-Krüppel family member GLI1, hedgehog-interacting protein, etc., whereas FA metabolism-related enzymes did not express differently. PF-5274857, an antagonist of the Shh signaling pathway, significantly promoted dorsolateral hinge point formation and partially rescued the NTDs. The regulatory hierarchy between a high level of KLF12 and FA-resistant NTDs might provide new insights into the diagnosis and treatment of unexplained NTDs in the future.
Asunto(s)
Ácido Fólico/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Defectos del Tubo Neural/genética , Transducción de Señal/genética , Animales , Femenino , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , RatonesRESUMEN
Single-molecule magnets (SMMs) are expected to be promising candidates for the applications of high-density information storage materials and quantum information processing. Lanthanide SMMs have attracted considerable interest in recent years due to their excellent performance. It has always been interesting but not straightforward to study the relaxation and blocking mechanisms by embedding 3d ions into 4f SMMs. Here we report a family of air-stable 3d-4f ion-pair compounds, YFe (1), DyCr (2), DyFe (3), DyCo (4), and Dy0.04Y0.96Fe (5), composed of pentagonal bipyramidal (D5h) LnIII cations and transition metallocyanate anions. The ion-pair nature makes the dipole-dipole interactions almost the only component of the magnetic interactions that can be clarified and analytically resolved under proper approximation. Therefore, this family provides an intuitive opportunity to investigate the effects of 3d-4f and 4f-4f magnetic interactions on the behavior of site-resolved 4f SMMs. Dynamic magnetic measurements of 1 under a 4 kOe external field reveal slow magnetic relaxation originating from the isolated [FeIII]LS (S = 1/2) ions. Under zero dc field, compounds 2-5 show similar magnetic relaxation processes coming from the separated pentagonal bipyramidal (D5h) DyIII ions with high Orbach barriers of 592(5), 596(4), 595(3), and 606(4) K, respectively. Comparatively, both compounds 3 and 5 exhibit two distinct relaxation processes, respectively from the [FeIII]LS and DyIII [Ueff = 596(4) K for 3 and 610(7) K for 5] ions, under a 4 kOe dc field. The dipolar interactions between the neighboring TMIII (TM = transition metal, CrIII or [FeIII]LS) and DyIII ions were revealed to have little effect on the thermal relaxation in compounds 2, 3, and 5, or the coexistence of the two separate relaxation processes in compounds 3 and 5 under a 4 kOe dc field, but they significantly affect the quantum tunneling of magnetization and the magnetic hysteresis behavior of 2 and 3 at low temperatures compared to those of 4.
RESUMEN
Natural products were extracted from traditional Chinese herbal emerging as potential therapeutic drugs for treating cardiovascular diseases. This study examines the role and underlying mechanism of dihydromyricetin (DMY), a natural compound extracted from Ampelopsis grossedentata, in atherosclerosis. DMY treatment significantly inhibits atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4-positive T cells in the vessel wall and hepatic inflammation, whereas increases nitric oxide (NO) production and improves lipid metabolism in apolipoprotein E-deficient (Apoe-/- ) mice. Yet, those protective effects are abrogated by using NOS inhibitor L-NAME in Apoe-/- mice received DMY. Mechanistically, DMY decreases microRNA-21 (miR-21) and increases its target gene dimethylarginine dimethylaminohydrolase-1 (DDAH1) expression, an effect that reduces asymmetric aimethlarginine (ADMA) levels, and increases endothelial NO synthase (eNOS) phosphorylation and NO production in cultured HUVECs, vascular endothelium of atherosclerotic lesions and liver. In contrast, systemic delivery of miR-21 in Apoe-/- mice or miR-21 overexpression in cultured HUVECs abrogates those DMY-mediated protective effects. These data demonstrate that endothelial miR-21-inhibited DDAH1-ADMA-eNOS-NO pathway promotes the pathogenesis of atherosclerosis which can be rescued by DMY. Thus, DMY may represent a potential therapeutic adjuvant in atherosclerosis management.
Asunto(s)
Apolipoproteínas E/deficiencia , Aterosclerosis/tratamiento farmacológico , Flavonoles/farmacología , Flavonoles/uso terapéutico , Células Endoteliales de la Vena Umbilical Humana/metabolismo , MicroARNs/metabolismo , Óxido Nítrico/biosíntesis , Amidohidrolasas/metabolismo , Animales , Arginina/análogos & derivados , Arginina/metabolismo , Aterosclerosis/sangre , Activación Enzimática/efectos de los fármacos , Humanos , Inflamación/patología , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Hígado/patología , Masculino , Ratones Endogámicos C57BL , MicroARNs/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Herein, we describe a method for the synthesis of aryl-(het)aryl ketones by Rh(III)-catalyzed direct coupling between quinoline-8-carbaldehydes and (het)arylboronic acids. The method has a broad substrate scope, a high functional group tolerance, and uses commercially available starting materials. Scale-up of the reaction and subsequent synthesis of tubulin polymerization inhibitor demonstrated its utilities. A plausible mechanism was proposed on the basis of the fact that a stable cycloacylrhodium intermediate complex could be used as catalyst, and the complex reacted stoichiometrically with (het)arylboronic acids.
Asunto(s)
Quinolinas , Rodio , Ácidos Borónicos , Catálisis , CetonasRESUMEN
A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 µM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 µM) which was stronger than neostigmine (12.01 ± 0.45 µM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer's disease.