RESUMEN

OBJECTIVE: Previous results about prognostic value of CD4+ T cells in follicular lymphoma (FL) remain controversial. METHODS: Immunohistochemistry was used to examine expression of positive CD4 cells in 103 patients with FL 1-3A. Early failure was described as failing to achieve event-free survival (EFS) at 12 or 24 months. RESULTS: There were 49 (47.6%) male and 54 (52.4%) females, with a median age of 54 years. Compared to patients with <20% of positive CD4 cells, patients with ≥20% of positive CD4 cells exhibited a significant lower risk of early failure (2-year EFS rate: 56.7% vs 73.5%, p = 0.047). When patients were stratified based on positive CD4 cell combined with FLIPI, the median EFS (p = 0.002) and median OS (p = 0.007) were significantly different. CONCLUSIONS: This study demonstrated that higher expression of positive CD4 cells predicts lower risk of early failure in follicular lymphoma, and combination analysis of CD4 and FLIPI could better predict disease relapse and survival outcome.

Asunto(s)

Linfocitos T CD4-Positivos , Linfoma Folicular , Humanos , Linfoma Folicular/mortalidad , Linfoma Folicular/patología , Linfoma Folicular/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Anciano , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Pronóstico , Anciano de 80 o más Años , Supervivencia sin Progresión

RESUMEN

HIV associated neuropathic pain (HANP) is a common complication of AIDS. Intrathecal injection of recombinant HIV-1 gp120 in mice is a well-known model. Previous RNA sequencing revealed spinal TLR2 acts as a differentially expressed gene in HANP mice. The spinal TLR2 is involved in HANP, but its role and underlying mechanism remains unclear. In this study the transcription, expression and distribution characteristics of TLR2 in the spinal cord of HANP male mice have been analyzed by qRT-PCR, Western blotting, and immunofluorescent staining. We found that TLR2 expression was upregulated in the spinal dorsal horn and mainly distributed in microglial cells, and blocking TLR2 relieved pain of HANP mice. Following stimulation by gp120 microglial cells upregulate TLR2 expression and become activated. The activation stimulates their differentiation into the M1 type, increasing IL-1ß and TNF-α expression while inhibiting IL-10 expression. Silencing the Tlr2 gene slows down the activation, polarization, and secretion of pro-inflammatory factors in microglial cells induced by gp120, and enhances the expression of anti-inflammatory factors. Further analysis of the impact of gp120 on downstream signaling pathways of TLR2 in microglial cells, including NF-κB, MAPK (p38MAPK, ERK, and JNK) and PI3K/AKT, revealed that TLR2-NF-κB signaling plays a crucial role in the activation and polarization of microglial cells by gp120. Activation of NF-κB signaling aggravates pain in HANP mice, while blocking it lightens pain. This data indicates that gp120, through the TLR2-NF-κB signaling, activates spinal microglial cells, promotes the secretion of inflammatory cytokines, leading to HANP. This provides new targets to develop drugs for HANP.

Asunto(s)

Citocinas , Proteína gp120 de Envoltorio del VIH , Microglía , FN-kappa B , Neuralgia , Transducción de Señal , Receptor Toll-Like 2 , Regulación hacia Arriba , Animales , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/genética , Proteína gp120 de Envoltorio del VIH/toxicidad , Microglía/metabolismo , Microglía/efectos de los fármacos , Neuralgia/metabolismo , Ratones , FN-kappa B/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Citocinas/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Ratones Endogámicos C57BL , Médula Espinal/metabolismo , Médula Espinal/efectos de los fármacos

RESUMEN

Superficial cartilage defects represent the most prevalent type of cartilage injury encountered in clinical settings, posing significant treatment challenges. Here, we fabricated a cartilage extracellular matrix mimic hydrogel (GHC, consisting of Gelatin, Hyaluronic acid, and Chondroitin sulfate) to avoid the exacerbation of cartilage deterioration, which is often driven by the accumulation of reactive oxygen species (ROS) and a pro-inflammatory microenvironment. The GHC hydrogel exhibited multifunctional properties, including in situ formation, tissue adhesiveness, anti-ROS capabilities, and the promotion of chondrogenesis. The enhancement of tissue adhesion was achieved by chemically modifying hyaluronic acid and chondroitin sulfate with o-nitrobenzene, enabling a covalent connection to the cartilage surface upon light irradiation. In vitro characterization revealed that GHC hydrogel facilitated chondrocyte adhesion, migration, and differentiation into cartilage. Additionally, GHC hydrogels demonstrated the ability to scavenge ROS in vitro and inhibit the production of inflammatory factors by chondrocytes. In the animal model of superficial cartilage injury, the hydrogel effectively promoted cartilage ECM regeneration and facilitated the interface integration between the host tissue and the material. These findings suggest that the multifunctional GHC hydrogels hold considerable promise as a strategy for cartilage defect repair. STATEMENT OF SIGNIFICANCE: Superficial cartilage defects represent the most prevalent type of cartilage injury encountered in the clinic. Previous cartilage tissue engineering materials are only suitable for full-thickness cartilage defects or osteochondral defects. Here, we developed a multifunctional GHC hydrogel composed of gelatin, hyaluronic acid, and chondroitin sulfate, which are natural cartilage extracellular matrix components. The drug-free and cell-free hydrogel not only avoids immune rejection and drug toxicity, but also shows good mechanical properties and biocompatibility. More importantly, the GHC hydrogel could adhere tightly to the superficial cartilage defects and promote cartilage regeneration while protecting against oxidation. This natural ingredients and multifunctional hydrogel is a potential material for repairing superficial cartilage defects.

RESUMEN

Herein, the intermolecular, photoaerobic aza-Wacker coupling of azoles with alkenes by means of dual and ternary selenium-π-acid multicatalysis is presented. The title method permits an expedited avenue toward a broad scope of N-allylated azoles and representative azinones under mild conditions with broad functional group tolerance, as is showcased in more than 60 examples including late-stage drug derivatizations. From a regiochemical perspective, the protocol is complementary to cognate photoredox catalytic olefin aminations, as they typically proceed through either allylic hydrogen atom abstraction or single electron oxidation of the alkene substrate. These methods predominantly result in C-N bond formations at the allylic periphery of the alkene or the less substituted position of the former π-bond (i.e., anti-Markovnikov selectivity). The current process, however, operates through a radical-polar crossover mechanism, which solely affects the selenium catalyst, thus allowing the alkene to be converted strictly through an ionic two-electron transfer regime under Markovnikov control. In addition, it is shown that the corresponding N-vinyl azoles can also be accessed by sequential or one-pot treatment of the allylic azoles with base, thus emphasizing the exquisite utility of this method.

RESUMEN

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) display high molecular heterogeneity, but the International Prognostic Index (IPI) considers only clinical indicators and has not been updated to include molecular data. Therefore, we developed a widely applicable novel scoring system with molecular indicators screened by artificial intelligence (AI) that achieves accurate prognostic stratification and promotes individualized treatments. METHODS: We retrospectively enrolled a cohort of 401 patients with DLBCL from our hospital, covering the period from January 2015 to January 2019. We included 22 variables in our analysis and assigned them weights using the random survival forest method to establish a new predictive model combining bidirectional long-short term memory (Bi-LSTM) and logistic hazard techniques. We compared the predictive performance of our "molecular-contained prognostic model" (McPM) and the IPI. In addition, we developed a simplified version of the McPM (sMcPM) to enhance its practical applicability in clinical settings. We also demonstrated the improved risk stratification capabilities of the sMcPM. RESULTS: Our McPM showed superior predictive accuracy, as indicated by its high C-index and low integrated Brier score (IBS), for both overall survival (OS) and progression-free survival (PFS). The overall performance of the McPM was also better than that of the IPI based on receiver operating characteristic (ROC) curve fitting. We selected five key indicators, including extranodal involvement sites, lactate dehydrogenase (LDH), MYC gene status, absolute monocyte count (AMC), and platelet count (PLT) to establish the sMcPM, which is more suitable for clinical applications. The sMcPM showed similar OS results (P < 0.0001 for both) to the IPI and significantly better PFS stratification results (P < 0.0001 for sMcPM vs. P = 0.44 for IPI). CONCLUSIONS: Our new McPM, including both clinical and molecular variables, showed superior overall stratification performance to the IPI, rendering it more suitable for the molecular era. Moreover, our sMcPM may become a widely used and effective stratification tool to guide individual precision treatments and drive new drug development.

Asunto(s)

Inteligencia Artificial , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , China/epidemiología , Anciano , Adulto , Anciano de 80 o más Años , Adulto Joven , Adolescente

RESUMEN

Viral infection can regulate the cell cycle, thereby promoting viral replication. Hijacking and altering the cell cycle are important for the virus to establish and maintain a latent infection. Previously, Spodoptera exigua multiple nucleopolyhedrovirus (SeMNPV)-latently infected P8-Se301-C1 cells, which grew more slowly than Se301 cells and interfered with homologous SeMNNPV superinfection, were established. However, the effects of latent and superinfection with baculoviruses on cell cycle progression remain unknown. In this study, the cell cycle profiles of P8-Se301-C1 cells and SeMNPV or Autographa californica multiple nucleopolyhedrovirus (AcMNPV)-infected P8-Se301-C1 cells were characterized by flow cytometry. The results showed that replication-related genes MCM4, PCNA, and BAF were down-regulated (p < 0.05) in P8-Se301-C1 cells, and the S phase of P8-Se301-C1 cells was longer than that of Se301 cells. P8-Se301-C1 cells infected with SeMNPV did not arrest in the G2/M phase or affect the expression of Cyclin B and cyclin-dependent kinase 1 (CDK1). Furthermore, when P8-Se301-C1 cells were infected with SeMNPV after synchronized treatment with hydroxyurea and nocodazole, light microscopy and qRT-PCR analysis showed that, compared with unsynchronized cells and S and G2/M phase cells, SeMNPV-infected P8-Se301-C1 cells in G1 phase induced G2/M phase arrest, and the amount of virus adsorption and intracellular viral DNA replication were significantly increased (p < 0.05). In addition, budded virus (BV) production and occlusion body (OB)-containing cells were both increased at 120 h post-infection (p < 0.05). The expression of Cyclin B and CDK1 was significantly down-regulated at 48 h post-infection (p < 0.05). Finally, the arrest of SeMNPV-infected G1 phase cells in the G2/M phase increased BV production (p < 0.05) and the number of OB-containing cells. In conclusion, G1 phase infection and G2/M arrest are favorable to SeMNPV proliferation in P8-Se301-C1 cells, thereby alleviating the homologous superinfection exclusion. The results contribute to a better understanding of the relationship between baculoviruses and insect cell cycle progression and regulation.

Asunto(s)

Puntos de Control de la Fase G2 del Ciclo Celular , Nucleopoliedrovirus , Spodoptera , Sobreinfección , Replicación Viral , Animales , Nucleopoliedrovirus/fisiología , Línea Celular , Spodoptera/virología , Sobreinfección/virología , Fase G1

RESUMEN

Methods for regioselective N-trideuteromethylation of tautomeric polyaza heterocycles are highly sought-after. Disclosed herein is an N-trideuterated methylation reaction of imidazoles and pyrazoles with high regioselectivity and deuterium purity using easily available CF3SO3CD3 as the -CD3 source. This method enables the easy synthesis of important deuterium-labeled azoles, including dimetridazole-d3, ipronidazole-d3, hydroxy dimetridazole-d3, and ronidazole-d3.

RESUMEN

Since oxidative stress is often associated with neurodegenerative diseases, antioxidants are likely to confer protection against neurodegeneration. Despite an increasing number of food-derived peptides being identified as antioxidants, their antineurodegenerative potentials remain largely unexplored. Here, a sea cucumber peptide preparation - the peptide-rich fraction of <3 kDa (UF<3K) obtained by ultrafiltration from Apostichopus japonicus protein hydrolyzate - was found to protect PC12 cells and Caenorhabditis elegans from neurodegeneration by reducing oxidative stress and apoptosis, demonstrating its in vitro and in vivo neuroprotective effects. As many food-originated peptides are cryptides (cryptic peptides - short amino acid sequences encrypted in parent proteins) released in quantities by protein hydrolysis, UF<3K was subjected to sequencing analysis. As expected, a large repertoire of peptides were identified in UF<3K, establishing a sea cucumber cryptome (1238 peptides in total). Then 134 peptides were randomly selected from the cryptome (>10%) and analyzed for their antioxidant activities using a number of in silico bioinformatic programs as well as in vivo experimental assays in C. elegans. From these results, a novel antioxidant peptide - HoloPep#362 (FETLMPLWGNK) - was shown to not only inhibit aggregation of neurodegeneration-associated polygluatmine proteins but also ameliorate behavioral deficits in proteotoxicity nematodes. Proteomic analysis revealed an increased expression of several lysosomal proteases by HoloPep#362, suggesting proteostasis maintenance as a mechanism for its antineurodegenerative action. These findings provide an insight into the health-promoting potential of sea cucumber peptides as neuroprotective nutraceuticals and also into the importance of training in silico peptide bioactivity prediction programs with in vivo experimental data.

Asunto(s)

Antioxidantes , Caenorhabditis elegans , Fármacos Neuroprotectores , Estrés Oxidativo , Péptidos , Pepinos de Mar , Animales , Caenorhabditis elegans/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/química , Péptidos/farmacología , Péptidos/química , Pepinos de Mar/química , Estrés Oxidativo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Células PC12 , Ratas , Enfermedades Neurodegenerativas/tratamiento farmacológico , Simulación por Computador

Asunto(s)

Núcleos Cerebelosos , Selenio , Humanos , Núcleos Cerebelosos/diagnóstico por imagen

RESUMEN

Ferroptosis, an iron-dependent regulated cell death caused by excessive lipid peroxide accumulation, has emerged as a promising therapeutic target in various cancers, including non-small cell lung cancer (NSCLC). In this study, we identified the long non-coding RNA RGMB-AS1 as a key regulator of ferroptosis in NSCLC. Mechanistically, RGMB-AS1 interacted with heme oxygenase 1 (HMOX1) and prevented its ubiquitination by the E3 ligase TRC8, leading to increased HMOX1 stability and enhanced ferroptosis. Additionally, RGMB-AS1 bound to the 82-87 amino acid region of N-alpha-acetyltransferase 10 (NAA10), stimulating its acetyltransferase activity and promoting the conversion of acetyl-CoA to HMG-CoA, further contributing to ferroptosis. The RGMB-AS1-HMOX1 and RGMB-AS1-NAA10 axes synergistically inhibited NSCLC growth both in vitro and in vivo. Clinically, low RGMB-AS1 expression was associated with advanced tumor stage and poor overall survival in NSCLC patients. Furthermore, adeno-associated virus-mediated RGMB-AS1 overexpression significantly suppressed tumor growth in mouse xenograft models. Our findings uncover a novel lncRNA-mediated regulatory mechanism of ferroptosis and highlight the potential of RGMB-AS1 as a prognostic biomarker and therapeutic target in NSCLC.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Ferroptosis , Hemo-Oxigenasa 1 , Neoplasias Pulmonares , ARN Largo no Codificante , Ubiquitinación , Ferroptosis/genética , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Animales , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Ratones , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Femenino , Masculino , Ratones Desnudos , Células A549 , Ensayos Antitumor por Modelo de Xenoinjerto , Proliferación Celular

RESUMEN

The floatable photocatalyst at N2-water interface allows the adequate supply of N2 reactant and the utilization of photothermal energy for photocatalytic N2 fixation, however, the presence of non-volatile NO3- product poses a challenge to the stability as it easily covers the catalytic active sites. Herein, a floatable TiO2/Bi/CC (Carbon cloth) photocatalyst was designed, in which the non-volatile NO3- can be transformed to the volatile NH3 via the newly synergistic relay photocatalysis pathway (N2 â†’ NO3- â†’ NH3) between TiO2 (N2 â†’ NO3-) and Bi (NO3- â†’ NH3). Attractively, the spontaneous NO3- â†’ NO2- step occurs on Bi component to promote the relay pathway performing. Therefore, TiO2/Bi/CC system displays better long-term stability than TiO2/CC, and moreover, it achieves a higher NH3 yield of 8.28 mmol L-1 h-1 g-1 (i.e. 4.14 mmol h-1 m-2) than that 1.46 mmol L-1 h-1 g-1 for TiO2/Bi powder. Importantly, the N2 fixation products by TiO2/Bi/CC effectively promote lettuce growth and enhance lettuce nutrient contents, which further validates the feasibility of this system in large-scale application of crop cultivation.

RESUMEN

Stormwater harvesting (SWH) addresses the UN's Sustainable Development Goals (SDGs). Conventional stormwater control measures (SCMs) effectively remove particulate and colloidal contaminants from urban runoff; however, they fail to retain dissolved contaminants, particularly substances of concern like polycyclic aromatic hydrocarbons (PAHs) and heavy metals (HMs), thereby hindering the SWH applicability. Here, inspired by protein folding in nature, we reported a novel biomimetic SCM for the efficient removal of dissolved PAHs and HMs from urban runoff. Lab-scale tests were conducted together with a more mechanistic investigation on how the contaminants were removed. By integrating hydrophobic organic chains with low-cost hydrophilic flocculant matrixes, our biomimetic flocculants achieved a 1.4-9.5 times removal of all detected dissolved PAHs and HMs, while enhancing the removal of a wide-spectrum of particulate and colloidal contaminants, compared to existing SCMs. Ecotoxicity, as indicated by newborn Daphnia magna as experimental organisms, was reduced from "acute toxicity" of the original runoff sample (toxic unit of ∼2.6) to "non-toxicity" (toxic unit < 0.4) of the treated water. The improved performance is attributed to the protein-folding-like features of the bioinspired flocculants providing: (i) stronger binding to PAHs (via hydrophobic association) and HMs (via coordination), and (ii) the ability of spontaneous aggregation. The bio-inspired approach in this work holds strong promise as an alternative or supplementary component in SCM systems, and is expected to contribute to sustainable water management practices in relation to SDGs.

Asunto(s)

Metales Pesados , Hidrocarburos Policíclicos Aromáticos , Contaminantes Químicos del Agua , Hidrocarburos Policíclicos Aromáticos/análisis , Contaminantes Químicos del Agua/química , Monitoreo del Ambiente , Metales Pesados/análisis

RESUMEN

Diabetic wound infection brings chronic pain to patients and the therapy remains a crucial challenge owing to the disruption of the internal microenvironment. Herein, we report a nano-composite hydrogel (ZnO@HN) based on ZnO nanoparticles and a photo-trigging hyaluronic acid which is modified by o-nitrobenzene (NB), to accelerate infected diabetic wound healing. The diameter of the prepared ZnO nanoparticle is about 50 nm. X-ray photoelectron spectroscopy (XPS) analysis reveals that the coordinate bond binds ZnO in the hydrogel, rather than simple physical restraint. ZnO@HN possesses efficient antioxidant capacity and it can scavenge DPPH about 40 % in 2 h and inhibit H2O2 >50 % in 8 h. The nano-composite hydrogel also exhibits satisfactory antibacterial capacity (58.35 % against E. coli and 64.03 % against S. aureus for 6 h). In vitro tests suggest that ZnO@HN is biocompatible and promotes cell proliferation. In vivo experiments reveal that the hydrogel can accelerate the formation of new blood vessels and hair follicles. Histological analysis exhibits decreased macrophages, increased myofibroblasts, downregulated TNF-α expression, and enhanced VEGFA expression during wound healing. In conclusion, ZnO@HN could be a promising candidate for treating intractable infected diabetic skin defection.

Asunto(s)

Diabetes Mellitus , Óxido de Zinc , Humanos , Ácido Hialurónico , Especies Reactivas de Oxígeno , Escherichia coli , Nanogeles , Óxido de Zinc/farmacología , Óxido de Zinc/uso terapéutico , Óxido de Zinc/química , Staphylococcus aureus , Peróxido de Hidrógeno , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/química , Cicatrización de Heridas , Diabetes Mellitus/tratamiento farmacológico , Hidrogeles/farmacología , Hidrogeles/química

RESUMEN

Background: Diabetic foot ulcers (DFUs) are a severe complication of diabetes. Persistent inflammation and impaired vascularization present considerable challenges in tissue wound healing. The aim of this study was to identify the crucial regulators of DFU wound healing and investigate their specific mechanisms in DFU. Methods: DFU RNA sequencing data were obtained to identify crucial feature genes. The expression levels of the feature genes and their corresponding microRNAs (miRNAs) were verified in clinical samples. Subsequently, the expression of CD68 was determined in DFU and non-diabetic foot skin samples. RAW 264.7 cells were treated with advanced glycation end products (AGEs) to determine their viability and apoptosis. Finally, the roles of the selected crucial genes and their corresponding miRNAs were investigated using in vitro experiments and a mouse model of diabetes. Results: Bioinformatic analysis showed that five crucial feature genes (CORO1A, CSF1R, CTSH, NFE2L3, and SLC16A10) were associated with DFU wound healing. The expression validation showed that miR-361-3p-CSF1R had a significant negative correlation and was thus selected for further experiments. AGEs significantly inhibited the viability of RAW 264.7 cells and enhanced their apoptosis; furthermore, the AGEs significantly downregulated CSF1R and increased miR-361-3p levels compared with the control cells. Additionally, inhibition of miR-361-3p decreased the cell apoptosis caused by AGEs and increased the levels of p-AKT/AKT and p-PI3K/PI3K, whereas CSF1R knockdown reversed the effects of miR-361-3p. In vivo experiments showed that miR-361-3p inhibition promoted wound healing in diabetic mice and regulated PI3K/AKT levels. Conclusions: AGEs may regulate macrophage apoptosis via the miR-361-3p/CSF1R axis and PI3K/AKT pathway, thereby influencing DFU wound healing.

RESUMEN

Diels-Alder cycloaddition of anthracene with olefin is achieved in a homogeneous solution via energy transfer under visible light. A series of substrates including electroneutral styrene derivatives can be successfully converted into the corresponding cycloadducts in a head-to-head orientation with high to excellent yields. The high ortho-regioselectivity, mild condition, and broad substrate scope enable promising advances in organic transformation.

RESUMEN

PIM2, part of the PIM kinase family along with PIM1 and PIM3, is often overexpressed in hematologic cancers, fueling tumor growth. Despite its significance, there are no approved drugs targeting it. In response to this challenge, we devised a thorough virtual screening workflow for discovering novel PIM2 inhibitors. Our process includes molecular docking and diverse scoring methods like molecular mechanics generalized born surface area, XGBOOST, and DeepDock to rank potential inhibitors by binding affinities and interaction potential. Ten compounds were selected and subjected to an adequate evaluation of their biological activity. Compound 2 emerged as the most potent inhibitor with an IC50 of approximately 135.7 nM. It also displayed significant activity against various hematological cancers, including acute myeloid leukemia, mantle cell lymphoma, and anaplastic large cell lymphoma (ALCL). Molecular dynamics simulations elucidated the binding mode of compound 2 with PIM2, offering insights for drug development. These results highlight the reliability and efficacy of our virtual screening workflow, promising new drugs for hematologic cancers, notably ALCL.

Asunto(s)

Neoplasias Hematológicas , Leucemia Mieloide Aguda , Humanos , Adulto , Simulación del Acoplamiento Molecular , Reproducibilidad de los Resultados , Relación Estructura-Actividad , Detección Precoz del Cáncer , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/patología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Serina-Treonina Quinasas

RESUMEN

OBJECTIVE: We investigated the correlation between serum C1q/TNF-related protein 4 (CTRP4) level and flow-mediated dilation (FMD) in patients with type 2 diabetes mellitus (T2DM), and evaluated the biological effects of CTRP4 on human umbilical vein endothelial cells (HUVECs). METHODS: A group of 165 patients diagnosed with T2DM were included in this study. Endothelial function was measured with the examination of brachial artery FMD. ELISA kit was used to measure the levels of CTRP4 in serum. HUVECs were stimulated with recombinant CTRP4 protein to assess its biological functions. RESULTS: The levels of CTRP4 showed a significant variation among three groups based on FMD tertiles (p = 0.001). What's more, FMD had a significant difference among three CTRP4 tertile groups (p < 0.05) and was negatively related to serum CTRP4 levels (r = -0.270, p < 0.001). In T2DM patients, logistic regression analysis demonstrated that CTRP4 was the primary influence factor of low FMD (p < 0.01). In receiver operating characteristic curve analysis, the area under the curve of CTRP4 for predicting low FMD was 0.66 (95%CI 0.58-0.75). When stimulated HUVECs with recombinant CTRP4 protein, we found that CTRP4 could concentration-dependently ameliorate proliferation and migration of HUVECs in wounding healing and transwell assay. This protein could also decrease the expression of IL-6 and TNF-α and promote the release of NO in HUVEC supernatants, with suppression of NF-κB and STAT3 phosphorylation. CONCLUSIONS: Serum CTRP4 concentrations were negatively associated with FMD. CTRP4 alleviated proliferation, migration and inflammation in HUVECs through the suppression of NF-κB and STAT3 signaling pathways.

Asunto(s)

Movimiento Celular , Proliferación Celular , Diabetes Mellitus Tipo 2 , Células Endoteliales de la Vena Umbilical Humana , Inflamación , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adipoquinas/sangre , Diabetes Mellitus Tipo 2/sangre , Endotelio Vascular/metabolismo , FN-kappa B/metabolismo

RESUMEN

A light-driven dual and ternary catalytic aza-Wacker protocol for the construction of 3-pyrrolines by partially disulfide-assisted selenium-π-acid multicatalysis is reported. A structurally diverse array of sulfonamides possessing homopolar mono-, di- and trisubstituted olefinic double bonds is selectively converted to the corresponding 3-pyrrolines in up to 95 % isolated yield and with good functional group tolerance. Advanced electrochemical mechanistic investigations of the protocol suggest a dual role of the disulfide co-catalyst. On the one hand, the disulfide serves as an electron hole shuttle between the excited photoredox catalyst and the selenium co-catalyst. On the other hand, the sulfur species engages in the final, product releasing step of the catalytic cycle by accelerating the ß-elimination of the selenium moiety, which was found in many cases to lead to considerably improved product yields.

RESUMEN

OBJECTIVE: To explore the effects of branched-chain amino acids (BCAAs) on nonalcoholic fatty pancreas disease (NAFPD) and its possible mechanism in high-fat diet (HFD) induced mice. MATERIALS AND METHODS: Pancreatic morphology and lipid infiltration was assessed by hematoxylin-eosin staining and immunohistochemistry, and lipid levels in the pancreas were determined using colorimetric enzymatic method. Relevant mechanism was investigated using western blotting and biochemical test. RESULTS: In HFD-fed mice, dietary BCAAs restriction could attenuate body weight increase, improve glucose metabolism, and reduce excessive lipid accumulation in the pancreas. Furthermore, expression of AMPKα and downstream uncoupling protein 1 were upregulated, while genes related to mammalian target of rapamycin complex 1 (mTORC1) signal pathway and lipid de novo synthesis were suppressed in HFD-BCAA restriction group compared with HFD and HFD-high BCAAs fed mice. In addition, BCAA restriction upregulated expression of BCAAs related metabolic enzymes including PPM1K and BCKDHA, and decreased the levels of BCAAs and branched chain keto acid in the pancreas. However, there was no difference in levels of lipid content in the pancreas and gene expression of AMPKα and mTORC1 between HFD and HFD-high BCAAs groups. CONCLUSIONS: Branched-chain amino acid restriction ameliorated HFD-induced NAFPD in mice by activation of AMPKα pathway and suppression of mTORC1 pathway.

Asunto(s)

Aminoácidos de Cadena Ramificada , Dieta Alta en Grasa , Ratones , Animales , Aminoácidos de Cadena Ramificada/metabolismo , Aminoácidos de Cadena Ramificada/farmacología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Páncreas/metabolismo , Lípidos , Ratones Endogámicos C57BL , Mamíferos/metabolismo