RESUMEN
OBJECTIVE: To observe the therapeutic effects and underlying mechanism of baicalin against colon cancer. METHODS: The effects of baicalin on the proliferation and growth of colon cancer cells MC38 and CT26. WT were observed and predicted potential molecular targets of baicalin for colon cancer therapy were studied by network pharmacology. Furthermore, molecular docking and drug affinity responsive target stability (DARTS) analysis were performed to confirm the interaction between potential targets and baicalin. Finally, the mechanisms predicted by in silico analyses were experimentally verified in-vitro and in-vivo. RESULTS: Baicalin significantly inhibited proliferation, invasion, migration, and induced apoptosis in MC38 and CT26 cells (all P<0.01). Additionally, baicalin caused cell cycle arrest at the S phase, while the G0/G1 phase was detected in the tiny portion of the cells. Subsequent network pharmacology analysis identified 6 therapeutic targets associated with baicalin, which potentially affect various pathways including 39 biological processes and 99 signaling pathways. In addition, molecular docking and DARTS predicted the potential binding of baicalin with cyclin dependent kinase inhibitor 2A (CDKN2A), protein kinase B (AKT), caspase 3, and mitogen-activated protein kinase (MAPK). In vitro, the expressions of CDKN2A, MAPK, and p-AKT were suppressed by baicalin in MC38 and CT26 cells. In vivo, baicalin significantly reduced the tumor size and weight (all P<0.01) in the colon cancer mouse model via inactivating p-AKT, CDKN2A, cyclin dependent kinase 4, cyclin dependent kinase 2, interleukin-1, tumor necrosis factor α, and activating caspase 3 and mouse double minute 2 homolog signaling (all P<0.05). CONCLUSION: Baicalin suppressed the CDKN2A protein level to prevent colon cancer and could be used as a therapeutic target for colon cancer.
RESUMEN
As promising luminescence nanoparticles, near-infrared (NIR) persistent luminescence nanoparticles (PLNPs) have received extensive attention in the field of high-sensitivity bioimaging in recent years. However, NIR PLNPs face problems such as short excitation wavelengths and single imaging modes, which limit their applications in in vivo reactivated imaging and multimodal imaging. Here, we report for the first time novel Gd2GaTaO7:Cr3+,Yb3+ (GGTO) NIR PLNPs that integrate X-ray activated NIR persistent luminescence (PersL), high X-ray attenuation and excellent magnetic properties into a single nanoparticle (NP). In this case, Cr3+ is used as the luminescence center. The co-doped Yb3+ and coating effectively enhance the X-ray activated NIR PersL. At the same time, the presence of the high-Z element Ta also makes the GGTO NPs exhibit high X-ray attenuation performance, which can be used as a CT contrast agent to achieve in vivo CT imaging. In addition, since the matrix contains a large amount of Gd, the GGTO NPs show remarkable magnetic properties, which can realize in vivo MR imaging. GGTO NPs combine the trimodal benefits of X-ray reactivated PersL, CT and MR imaging and are suitable for single or combined applications that require high sensitivity and spatial resolution imaging.
Asunto(s)
Imagen por Resonancia Magnética , Nanopartículas , Animales , Nanopartículas/química , Ratones , Rayos X , Luminiscencia , Rayos Infrarrojos , Gadolinio/química , Tomografía Computarizada por Rayos X , Medios de Contraste/química , Iterbio/química , Humanos , Imagen MultimodalRESUMEN
Parkinson's disease (PD) represents the second most widespread neurodegenerative disease, and early monitoring and diagnosis are urgent at present. Tyrosine hydroxylase (TH) is a key enzyme for producing dopamine, the levels of which can serve as an indicator for assessing the severity and progression of PD. This renders the specific detection and visualization of TH a strategically vital way to meet the above demands. However, a fluorescent probe for TH monitoring is still missing. Herein, three rationally designed wash-free ratiometric fluorescent probes were proposed. Among them, TH-1 exhibited ideal photophysical properties and specific dual-channel bioimaging of TH activity in SH-SY5Y nerve cells. Moreover, the probe allowed for in vivo imaging of TH activity in zebrafish brain and living striatal slices of mice. Overall, the ratiometric fluorescent probe TH-1 could serve as a potential tool for real-time monitoring of PD in complex biosystems.
Asunto(s)
Colorantes Fluorescentes , Tirosina 3-Monooxigenasa , Pez Cebra , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Tirosina 3-Monooxigenasa/metabolismo , Tirosina 3-Monooxigenasa/análisis , Animales , Ratones , Humanos , Imagen Óptica , Línea Celular Tumoral , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismoRESUMEN
Intravenous immunoglobulin (IVIG) is a first-line drug prepared from human plasma for the treatment of autoimmune diseases (AIDs), especially immune thrombocytopenia (ITP). Significant differences exist in protein types and expression levels between male and female plasma, and the prevalence of autoimmune diseases varies between sexes. The present study seeks to explore potential variations in IVIG sourced from distinct sex-specific plasma (DSP-IVIG), including IVIG sourced from female plasma (F-IVIG), IVIG sourced from male plasma (M-IVIG), and IVIG sourced from a blend of male and female plasma (Mix-IVIG). To address this question, we used an ITP mouse model and a monocyte-macrophage inflammation model treated with DSP IVIG. The analysis of proteomics in mice suggested that the pathogenesis and treatment of ITP may involve FcγRs mediated phagocytosis, apoptosis, Th17, cytokines, chemokines, and more. Key indicators, including the mouse spleen index, CD16+ macrophages, M1, M2, IL-6, IL-27, and IL-13, all indicated that the efficacy in improving ITP was highest for M-IVIG. Subsequent cell experiments revealed that M-IVIG exhibited a more potent ability to inhibit monocyte phagocytosis. It induced more necrotic M2 cells and fewer viable M2, resulting in weaker M2 phagocytosis. M-IVIG also demonstrated superiority in the downregulation of surface makers CD36, CD68, and CD16 on M1 macrophages, a weaker capacity to activate complement, and a stronger binding ability to FcγRs on the THP-1 surface. In summary, DSP-IVIG effectively mitigated inflammation in ITP mice and monocytes and macrophages. However, M-IVIG exhibited advantages in improving the spleen index, regulating the number and typing of M1 and M2 macrophages, and inhibiting macrophage-mediated inflammation compared to F-IVIG and Mix-IVIG.
Asunto(s)
Púrpura Trombocitopénica Idiopática , Trombocitopenia , Masculino , Femenino , Humanos , Animales , Ratones , Inmunoglobulinas Intravenosas/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Trombocitopenia/tratamiento farmacológico , Citocinas , Inflamación/tratamiento farmacológicoRESUMEN
Mitochondrial dynamics regulate the quality and morphology of mitochondria. Calcium (Ca2+) plays an important role in regulating mitochondrial function. Here, we investigated the effects of optogenetically engineered Ca2+ signaling on mitochondrial dynamics. More specifically, customized illumination conditions could trigger unique Ca2+ oscillation waves to trigger specific signaling pathways. In this study, we found that modulating Ca2+ oscillations by increasing the light frequency, intensity and exposure time could drive mitochondria toward the fission state, mitochondrial dysfunction, autophagy and cell death. Moreover, illumination triggered phosphorylation at the Ser616 residue but not the Ser637 residue of the mitochondrial fission protein, dynamin-related protein 1 (DRP1, encoded by DNM1L), via the activation of Ca2+-dependent kinases CaMKII, ERK and CDK1. However, optogenetically engineered Ca2+ signaling did not activate calcineurin phosphatase to dephosphorylate DRP1 at Ser637. In addition, light illumination had no effect on the expression levels of the mitochondrial fusion proteins mitofusin 1 (MFN1) and 2 (MFN2). Overall, this study provides an effective and innovative approach to altering Ca2+ signaling for controlling mitochondrial fission with a more precise resolution than pharmacological approaches in the temporal dimension.
Asunto(s)
Calcio , Dinámicas Mitocondriales , Dinámicas Mitocondriales/fisiología , Calcio/metabolismo , Dinaminas/genética , Dinaminas/metabolismo , Mitocondrias/metabolismo , Fosforilación , Muerte Celular , Proteínas Mitocondriales/metabolismoRESUMEN
Osteoporosis is mainly a geriatric disease with a high incidence, and the resulting spinal fractures and hip fractures cause great harm to patients. Anti-osteoporosis drugs are the main treatment for osteoporosis currently, but these drugs have potential clinical limitations and side effects, so the development of new therapies is of great significance to patients with osteoporosis. Electrical stimulation therapy mainly includes pulsed electromagnetic fields (PEMF), direct current (DC), and capacitive coupling (CC). Meanwhile, electrical stimulation therapy is clinically convenient without side effects. In recent years, many researchers have explored the use of electrical stimulation therapy for osteoporosis. Based on this, the role of electrical stimulation therapy in osteoporosis was summarized. In the future, electrical stimulation might become a new treatment for osteoporosis.
Asunto(s)
Terapia por Estimulación Eléctrica , Magnetoterapia , Osteoporosis , Humanos , Anciano , Osteoporosis/terapia , Osteoporosis/etiología , Terapia por Estimulación Eléctrica/efectos adversos , Terapia por Estimulación Eléctrica/métodos , Magnetoterapia/métodos , Estimulación Eléctrica/efectos adversosRESUMEN
The heartwood of Syringa oblata Lindl. (SO) is one of Mongolian folk medicines to treat insomnia and pain, while its pharmacological evaluation and underlying mechanism remain unclear. In this study, the sedative effect of ethanol extract of SO (ESO) was evaluated with the locomotor activity test and the threshold dose of pentobarbital sodium-induced sleep test in mice, and the hot plate test, acetic acid-induced writhing test, and formalin test in mice were used to evaluate its analgesic effect. The underlying mechanism of ESO analgesia was explored by RT-PCR and western blot analysis, which is associated with the regulation of the NF-κB signaling pathway. Besides, the main constituents of ESO were characterized by LC/MS data analysis and comparison with isolated pure compounds. The current findings brought evidence for clinical application and further pharmacological and phytochemical studies on SO.
Asunto(s)
Lignanos , Syringa , Ratones , Animales , Etanol , Hipnóticos y Sedantes/efectos adversos , Syringa/química , Lignanos/farmacología , Medicina Tradicional Mongoliana , Analgésicos/farmacología , Analgésicos/uso terapéutico , Dolor/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
Manipulation of autophagic processes has emerged as a promising strategy for synergizing nanoagent-mediated photothermal therapy (PTT). Most of the current studies focus on improving PTT efficacy by inhibiting pro-survival autophagy induced by the heat generated from the photothermal process. However, autophagy induced by the nanoagents is usually ignored, which may weaken the effect of autophagy-mediated efficacy improvement in PTT if induced autophagy is pro-death. Therefore, this work aims at developing a nanoagent that is able to induce heat-synergetic pro-survival autophagy to optimize the efficacy of PTT. An approach is developed to coat carbon layer, polyethylenimine (PEI), and folic acid (FA) on NaYF4 :Er,Yb,Nd@NaNdF4 (DCNPs@C@PEI@FA, DCPF) nanoparticles successively, giving access to the nanoagent to induce pro-survival autophagy. The synthetic imaging-guided photothermal nanoagent displays outstanding targeting ability and biocompatibility based on the surface modification of PEI and FA. By using an autophagy inhibitor chloroquine, a conspicuously synergistic effect on DCPF-mediated PTT in vitro and in vivo tumor models (HeLa) is achieved. A promising strategy is presented here to enhance the efficacy of imaging-guided PTT by modulating the autophagy induced by the nanoagent.
Asunto(s)
Hipertermia Inducida , Nanocompuestos , Nanopartículas , Neoplasias , Humanos , Fototerapia , Terapia Fototérmica , Neoplasias/terapia , Células HeLa , Nanocompuestos/uso terapéutico , AutofagiaRESUMEN
The phytochemical investigation on the leaves of Psidium guajava Linn. led to the isolation and identification of 18 compounds, including six guavinoside (1-6), four flavonoids (7-10), eight triterpenoids (11-17) and one lignans (18). All chemical structures were elucidated via NMR spectroscopic methods, and further supported by comparison with literature data. Compounds 12, 14, 16 and 18 was isolated from the Myrtaceae family for the first time. The chemotaxonomic significance of these compounds was also discussed based on their structure types, as well as compounds-genus/family network analysis. The results showed that there were close chemotaxonomic relationships among the Myrtaceae, Asteraceae, and Lamiaceae families. Guavinosides A-F could be considered as valuable chemotaxonomic markers of Myrtaceae family, while guavinosides C-F might serve as chemotaxonomic markers for distinguishing the P. guajava.
Asunto(s)
Myrtaceae , Psidium , Humanos , Psidium/química , Hojas de la Planta/química , Extractos Vegetales/química , Flavonoides/químicaRESUMEN
The husks of Xanthoceras sorbifolia Bunge were explored resulting in the isolation of nine undescribed compounds and seven known compounds. Their structures were defined by NMR spectroscopic techniques, HRESIMS analyses and DP4+ possibility analysis. Three of them showed evident inhibition on NO productions in LPS-induced BV-2 cells by controlling the expression of the nuclear factor-kappa-B (NF-κB) signaling pathway. Furthermore, they also markedly decreased the expression of the proteins COX-2 and iNOS. In addition, most compounds showed no cytotoxicity against Hep 3B, A549, HCT 116, AGS, MCF-7 cell lines. These findings showed that the husks of X. sorbifolia might have considerable potential for the prevention of inflammation-related neurodegenerative disorders.
RESUMEN
A new amide (1), two new phenylpropanoid derivatives (2, 3), along with three new natural products, including three nitrogen chirality compounds, N-(3-methoxy-1,3-dioxopropyl)-D-phenylalanine methyl ester (4), N-(3-methoxy-1,3-dioxopropyl)-L-phenylalanine methyl ester (5), and N-acetyl-L-phenylalanine methyl ester (6), as well as dimethyl (2R,3R)-2-hydroxy-3-(((E)-3-(4-hydroxyphenyl)acryloyl)oxy)succinate (7) and dimethyl (S,E)-2-((3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)succinate (8) were isolated from Delphinium kamaonense Hunth. Their structures were elucidated by extensive analysis of 1D and 2D NMR, and HR-ESI-MS experiments, and the absolute configurations were determined by comparative analysis of specific optical rotation. Compound 1 exhibited a moderate cytotoxicity effect against Hep-3B cancer cell lines (IC50 41.39±0.13â µM) and an excellent antioxidant activity (IC50 0.527±0.06â µM in ABTS assay, and 1.235±0.09â µM in DPPH assay, respectively), which was superior to vitaminâ C in ABTS (IC50 1.670±0.07â µM) and DPPH (IC50 19.10±0.40â µM) methods.
Asunto(s)
Antineoplásicos , Delphinium , Antineoplásicos/farmacología , Antioxidantes/farmacología , Delphinium/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , SuccinatosRESUMEN
Two previously undescribed diterpenes (1 and 2), as well as one curious triterpenoid were isolated from Clinopodium polycephalum, a medicinal plant distributed in southwestern and eastern China. Their structures were elucidated using MS analyses, UV spectrum, and extensive 2D-homo and heteronuclear NMR data interpretations. Among them, 1 had an unusual skeletal characteristic produced by a rare methyl migration pathway. All monomer compounds exhibited inhibitory effects on NO production in LPS-induced RAW 264.7 cells without affecting cell viabilities, which were comparable to that of positive control.
Asunto(s)
Diterpenos , Lamiaceae , Triterpenos , Abietanos/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Diterpenos/química , Diterpenos/farmacología , Estructura Molecular , Triterpenos/farmacologíaRESUMEN
As a part of systematic studies on Syringa pinnatifolia, a continued phytochemical investigation guided by 1 H-NMR and LC/MS data on the ethanol extract afforded five new dimeric eremophilane sesquiterpenoids, namely syringenes M-Q (1-5). These structures were elucidated by extensive analysis of spectroscopic data, including infrared (IR), high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), nuclear magnetic resonance (NMR), quantum-mechanics-based computational analysis of NMR chemical shifts, and single-crystal X-ray diffraction. Compounds 4 and 5 showed inhibitory activities against NO production induced by lipopolysaccharide in RAW264.7 macrophage cells, with IC50 values of 5.1 and 9.3â µM, compared to positive control indomethacin (IC50 33.6â µM). These dimeric eremophilane sesquiterpenoids may be potential markers for discriminating this species from the genus Syringa and the Oleaceae family.
Asunto(s)
Sesquiterpenos , Syringa , Estructura Molecular , Sesquiterpenos Policíclicos , Sesquiterpenos/química , Sesquiterpenos/farmacología , Espectrometría de Masa por Ionización de Electrospray , Syringa/químicaRESUMEN
A phytochemical investigation guided by 1H NMR and LC-MS data on the ethanol extract of Syringa pinnatifolia stems led to the isolation of 11 new dimeric eremophilane sesquiterpenoids, namely, syringenes A-K (1-11) and one known analog (12, syringene L). These structures were elucidated by extensive analysis of spectroscopic data, single-crystal X-ray diffraction, and computational methods. Biological assays revealed that 1-12 exhibited different degrees of anti-inflammatory effects, and 5 and 6 showed significant cytotoxicity against human hepatoma HepG2 cells with IC50 values of 12.3 and 12.9 µM, respectively. Furthermore, flow cytometry assays and western blot analysis revealed that 5 and 6 promoted the apoptosis of HepG2 cells by activating ERK. Finally, the molecular docking analysis implied that the carbonyl and hydroxy groups at the C-11/C-6' of 5 and 6 had a good binding affinity with ERK.
Asunto(s)
Sesquiterpenos , Syringa , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Sesquiterpenos Policíclicos , Sesquiterpenos/química , Syringa/químicaRESUMEN
A pair of enantiomers with a rearranged dimeric phenylethanol skeleton, namely (±)-disyringol A (1a and 1b), were isolated from the stem barks of Syringa pinnatifolia. The structures were established using IR, UV, MS, and NMR data, and their absolute configurations were resolved by experimental and calculated ECD data analysis. Their biosynthetic pathway was speculated on the basis of a phenylethanoid precursor and was proved by a total synthesis. Compounds 1a and 1b showed the inhibition against NO production in LPS-induced RAW264.7 cells with their IC50 values of 27.28 and 24.64 µM, respectively, however no protective effect was observed against the hypoxia-induced injuries to H9c2 cells.
Asunto(s)
Syringa , Animales , Ratones , Estructura Molecular , Células RAW 264.7 , Esqueleto , Estereoisomerismo , Syringa/químicaRESUMEN
Five new sesquiterpenoids, alashanoids O-S (1-5), along with three known analogs (6-8) were isolated from the peeled stems of Syringa pinnatifolia. Their structures were elucidated by analysis of extensive spectroscopic data including ESI-MS, 1D, 2D NMR. The absolute configurations were determined by comparing its experimental and calculated electronic circular dichroism, calculated OR, calculated NMR, and single crystal X-ray diffraction data analysis. Compounds 1 and 2 belong to the seco-humulane type and possess a rare 13-membered oxygen heterocycle framework, and 3-5 belong to eremophilane-type. Compounds 1, 2, and 5 showed inhibitory effects against NO production in LPS-induced RAW264.7 macrophage cells with its IC50 values of 11.86±2.34, 72.08±7.72, and 69.22±15.29â µM, respectively, compared with the positive control indomethacin (IC50 =31.52â µM).
Asunto(s)
Sesquiterpenos , Syringa , Espectroscopía de Resonancia Magnética , Estructura Molecular , Sesquiterpenos Policíclicos , Sesquiterpenos/química , Sesquiterpenos/farmacología , Syringa/químicaRESUMEN
Osteoporosis, a systemic bone disease, is characterized by decreased bone density due to various reasons, destructed bone microstructure, and increased bone fragility. The incidence of osteoporosis is very high among the elderly, and patients with osteoporosis are prone to suffer from spine fractures and hip fractures, which cause great harm to patients. Meanwhile, osteoporosis is mainly treated with anti-osteoporosis drugs that have side effects. Therefore, the development of new treatment modalities has a significant clinical impact. Sympathetic nerves play an important role in various physiological activities and the regulation of osteoporosis as well. Therefore, the role of sympathetic nerves in osteoporosis was reviewed, aiming to provide information for future targeting of sympathetic nerves in osteoporosis.
RESUMEN
Small interfering RNA (siRNA)-based gene therapy has been widely studied as a promising treatment for malignant triple-negative breast cancer (TNBC), but efficient delivery of siRNA still remains a challenge. In this study, a smart manganese dioxide (MnO2)-based lanthanide nanoprobe therapeutic nanoplatform (ErNPs@MnO2-siS100A4-RGD) was developed for tumor imaging and precise stimuli-responsive S100A4 siRNA (siS100A4)-mediated gene therapy in synergism with chemodynamic therapy (CDT) of TNBC. ErNPs@MnO2-siS100A4-RGD has a tumor microenvironment-responsive capability attributed to the presence of MnO2, which can be degraded by glutathione (GSH) in the tumor region while releasing siRNA and generating Mn2+ to achieve precise gene therapy and a Fenton-like reaction-mediated CDT effect on TNBC. Subsequently, the lanthanide nanoprobes (ErNPs) are exposed to the second near-infrared region (NIR-II) fluorescence emission to realize the precise tumor location. Both the in vitro and in vivo results demonstrated that the smart nanoplatform possessed high siRNA delivery efficiency and GSH-responsive precise siRNA releasing ability, and compared with individual gene therapy, the GSH-depletion-enhanced CDT effect further reinforced TNBC inhibition, demonstrating excellent GSH-responsive-enhanced NIR-II precise tumor imaging therapy. These results indicate that the nanoplatform provides a crucial foundation for further research on theranostic systems of TNBC.
Asunto(s)
Antineoplásicos/uso terapéutico , Portadores de Fármacos/química , Nanopartículas del Metal/química , ARN Interferente Pequeño/uso terapéutico , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Neoplasias de la Mama Triple Negativas/terapia , Animales , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Quimioterapia , Erbio/química , Terapia Genética , Glutatión/metabolismo , Humanos , Compuestos de Manganeso/química , Compuestos de Manganeso/metabolismo , Ratones Desnudos , Óxidos/química , Óxidos/metabolismo , Proteína de Unión al Calcio S100A4/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The ability of a single Ca2+ ion to play an important role in cell biology is highlighted by the need for cells to form Ca2+ signals in the dimensions of space, time, and amplitude. Thus, spatial and temporal changes in intracellular Ca2+ concentration are important for determining cell fate. Optogenetic technology has been developed to provide more precise and targeted stimulation of cells. Here, U2OS cells overexpressing Ca2+ translocating channelrhodopsin (CatCh) were used to mediate Ca2+ influx through blue light illumination with various parameters, such as intensity, frequency, duty cycle, and duration. We identified that several Ca2+ -dependent transcription factors and certain kinases can be activated by specific Ca2+ waves. Using a wound-healing assay, we found that low-frequency Ca2+ oscillations increased cell migration through the activation of NF-κB. This study explores the regulation of cell migration by Ca2+ signals. Thus, we can choose optical parameters to modulate Ca2+ waves and achieve activation of specific signaling pathways. This novel methodology can be applied to clarify related cell-signaling mechanisms in the future.