RESUMEN
Human limbs emerge during the fourth post-conception week as mesenchymal buds, which develop into fully formed limbs over the subsequent months1. This process is orchestrated by numerous temporally and spatially restricted gene expression programmes, making congenital alterations in phenotype common2. Decades of work with model organisms have defined the fundamental mechanisms underlying vertebrate limb development, but an in-depth characterization of this process in humans has yet to be performed. Here we detail human embryonic limb development across space and time using single-cell and spatial transcriptomics. We demonstrate extensive diversification of cells from a few multipotent progenitors to myriad differentiated cell states, including several novel cell populations. We uncover two waves of human muscle development, each characterized by different cell states regulated by separate gene expression programmes, and identify musculin (MSC) as a key transcriptional repressor maintaining muscle stem cell identity. Through assembly of multiple anatomically continuous spatial transcriptomic samples using VisiumStitcher, we map cells across a sagittal section of a whole fetal hindlimb. We reveal a clear anatomical segregation between genes linked to brachydactyly and polysyndactyly, and uncover transcriptionally and spatially distinct populations of the mesenchyme in the autopod. Finally, we perform single-cell RNA sequencing on mouse embryonic limbs to facilitate cross-species developmental comparison, finding substantial homology between the two species.
RESUMEN
We present a novel approach to induce charge density waves (CDWs) in metallic MA2Z4 materials, resembling the behavior observed in transition metal dichalcogenides (TMDCs). This method leverages the intercalating architecture to maintain the same crystal field and Fermi surface topologies. Our investigation reveals that CDW instability in these materials arises from electron-phonon coupling (EPC) between the d band and longitudinal acoustic (LA) phonons, mirroring TMDC's behavior. By combining α-MA2Z4 with 1H-MX2 materials in a predictive CDW phase diagram using critical EPC constants, we demonstrate the feasibility of extending CDW across material families with comparable crystal fields and reveal the crucial role in CDW instability of the competition between ionic charge transfer and electron correlation. We further uncover a strain-induced Mott transition in ß2-NbGe2N4 monolayer featuring star-of-David patterns. This work highlights the potential of intercalating architecture to engineer CDW materials, expanding our understanding of CDW instability and correlation physics.
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BACKGROUND: Muscle aging is associated with muscle stem cell (MuSC) senescence, a process of whose DNA damage accumulation is considered as one of the leading causes. BTG2 had been identified as a mediator of genotoxic and cellular stress signaling pathways, however, its role in senescence of stem cells, including MuSC, remains unknown. METHOD: We first compared MuSCs isolated from young and old mice to evaluate our in vitro model of natural senescence. CCK8 and EdU assays were utilized to assess the proliferation capacity of the MuSCs. Cellular senescence was further assessed at biochemical levels by SA-ß-Gal and γHA2.X staining, and at molecular levels by quantifying the expression of senescence-associated genes. Next, by performing genetic analysis, we identified Btg2 as a potential regulator of MuSC senescence, which was experimentally validated by Btg2 overexpression and knockdown in primary MuSCs. Lastly, we extended our research to humans by analyzing the potential links between BTG2 and muscle function decline in aging. RESULTS: BTG2 is highly expressed in MuSCs from elder mice showing senescent phenotypes. Overexpression and knockdown of Btg2 stimulates and prevents MuSCs senescence, respectively. In humans, high level of BTG2 is associated with low muscle mass in aging, and is a risk factor of aging-related diseases, such as diabetic retinopathy and HDL cholesterol. CONCLUSION: Our work demonstrates BTG2 as a regulator of MuSC senescence and may serve as an intervention target for muscle aging.
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Proteínas Inmediatas-Precoces , Enfermedades Musculares , Animales , Humanos , Ratones , Envejecimiento/fisiología , Senescencia Celular , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/metabolismo , Músculo Esquelético/fisiología , Músculos , Enfermedades Musculares/metabolismo , Células Madre/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Injury-induced fibroblast-to-myofibroblast differentiation is a key event of renal fibrosis. Yes-associated protein (YAP), a transcriptional coactivator, plays an important role in fibroblast activation and Smad transcriptional activity to promote transforming growth factor-ß (TGF-ß)-induced differentiation from fibroblasts to myofibrolasts. Macrophage stimulating 1/2 (MST1/2), a negative regulator of YAP, also increases in fibroblasts by TGF-ß stimulation. Here, we examined whether MST1/2, as a negative regulator, attenuated YAP and TGF-ß/Smad signaling in fibroblasts to reduce fibrosis. MST1/2 and YAP expression levels increased in platelet-derived growth factor receptor-α (PDGFRα)+ cells of obstructed kidneys following the increase of TGF-ß and renal fibrosis after unilateral ureteral obstruction. PDGFRα+ cell-specific knockout of Mst1/2 in mice increased unilateral ureteral obstruction-induced myofibroblast accumulation and fibrosis. In cultured fibroblasts, TGF-ß increased YAP and promoted its nucleus entry, but a high dose and prolonged treatment of TGF-ß increased the MST1/2 activation to prevent YAP from entering the nucleus. Our results indicate that MST1/2 is a negative feedback signal of TGF-ß-induced fibroblast differentiation.NEW & NOTEWORTHY Using a mouse model with macrophage stimulating 1/2 (Mst1/2) double knockout in PDGFRα+ cells and an MST1/2 inhibitor, we demonstrated that MST1/2 acted as a negative feedback signal of transforming growth factor-ß-induced fibroblast differentiation. Furthermore, we demonstrated that Hippo-MST as a negative feedback signal can decrease the renal fibrosis process. This finding contributes to our understanding of the mechanism of coregulated renal remodeling after injury.
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Péptidos y Proteínas de Señalización Intracelular , Riñón , Miofibroblastos , Proteínas Serina-Treonina Quinasas , Serina-Treonina Quinasa 3 , Fibroblastos/metabolismo , Fibrosis , Factor de Crecimiento de Hepatocito , Vía de Señalización Hippo , Humanos , Riñón/patología , Macrófagos/metabolismo , Miofibroblastos/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: The prognosis difference based on the depth of tumor muscularis propria invasion in gastric cancer (GC) was still debated, and therapy strategy for stage IB GC patient required further investigation. METHODS: A total of 380 patients with pT2 GC after radical surgery were retrospectively analyzed, including 185 in superficial muscularis propria (sMP) group and 195 in deep muscularis propria (dMP) group. RESULTS: The overall survival (OS) was significantly better for patients in sMP group than for patients in dMP group (P = 0.007). In multivariate analysis, depth of tumor invasion, pN stage, age, primary location, positive expression of p53, elevated maximal LDH, elevated initial CA19-9 and AFP level were independent prognostic factors for OS. The sMP group had a significantly better OS than dMP group (P = 0.014) in pN0 stage. After further stratification, the survival outcomes were not significantly different between deep muscularis propria tumor invasion without lymph node metastasis (dMPN0) group (stage IB) and superficial muscularis propria tumor invasion with stage 1-2 lymph node metastasis (sMPN1-2) group (stage II) (P = 0.100). Patients with adjuvant chemotherapy had a statistically better survival than those without in dMPN0 group (P = 0.045) and dMPN0 patients with adjuvant chemotherapy had better OS than sMPN1-2 patients (P = 0.015). In addition, greater postoperative survival could be observed in sMPN0 patients than dMPN0 patients in p53-positive group (P = 0.002), and similar OS could be seen between dMPN0 patients with p53-positive and T2N1-2 patients (P = 0.872). CONCLUSION: As a unique subclassification of stage IB GC, appropriate adjuvant chemotherapy should be considered for patients with dMPN0 stage. In addition, positive expression of p53, elevated LDH could be potential factors in identifying the different prognoses for stage IB GC patients.
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Neoplasias Gástricas , Humanos , Metástasis Linfática , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugíaRESUMEN
Although mitochondria are ubiquitous, each mitochondrial disease has surprisingly distinctly different pattern of tissue and organ involvement. Congruently, mutations in genes encoding for different mitochondrial tRNA synthetases result in the development of a very flamboyant group of diseases. Mutations in some of these genes, including aspartyl-tRNA synthetase (DARS2), lead to the onset of a white matter disease-leukoencephalopathy with brainstem and spinal cord involvement, and lactate elevation (LBSL) characterized by progressive spastic ataxia and characteristic leukoencephalopathy signature with multiple long-tract involvements. Puzzled by the white matter disease phenotypes caused by DARS2 deficiency when numerous other mutations in the genes encoding proteins involved in mitochondrial translation have a detrimental effect predominantly on neurons, we generated transgenic mice in which DARS2 was specifically depleted in forebrain-hippocampal neurons or myelin-producing cells. Our results now provide the first evidence that loss of DARS2 in adult neurons leads to strong mitochondrial dysfunction and progressive loss of cells. In contrast, myelin-producing cells seem to be resistant to cell death induced by DARS2 depletion despite robust respiratory chain deficiency arguing that LBSL might originate from the primary neuronal and axonal defect. Remarkably, our results also suggest a role for early neuroinflammation in the disease progression, highlighting the possibility for therapeutic interventions of this process.
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Aspartato-ARNt Ligasa/deficiencia , Vaina de Mielina/metabolismo , Neuronas/metabolismo , Animales , Apoptosis , Aspartato-ARNt Ligasa/genética , Aspartato-ARNt Ligasa/metabolismo , Tronco Encefálico/metabolismo , Modelos Animales de Enfermedad , Leucoencefalopatías/genética , Leucoencefalopatías/metabolismo , Ratones , Ratones Transgénicos , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Malformaciones del Sistema Nervioso/metabolismo , Médula Espinal/metabolismo , Degeneraciones Espinocerebelosas/metabolismoRESUMEN
The m-AAA protease preserves proteostasis of the inner mitochondrial membrane. It ensures a functional respiratory chain, by controlling the turnover of respiratory complex subunits and allowing mitochondrial translation, but other functions in mitochondria are conceivable. Mutations in genes encoding subunits of the m-AAA protease have been linked to various neurodegenerative diseases in humans, such as hereditary spastic paraplegia and spinocerebellar ataxia. While essential functions of the m-AAA protease for neuronal survival have been established, its role in adult glial cells remains enigmatic. Here, we show that deletion of the highly expressed subunit AFG3L2 in mature mouse oligodendrocytes provokes early-on mitochondrial fragmentation and swelling, as previously shown in neurons, but causes only late-onset motor defects and myelin abnormalities. In contrast, total ablation of the m-AAA protease, by deleting both Afg3l2 and its paralogue Afg3l1, triggers progressive motor dysfunction and demyelination, owing to rapid oligodendrocyte cell death. Surprisingly, the mice showed premature hair greying, caused by progressive loss of melanoblasts that share a common developmental origin with Schwann cells and are targeted in our experiments. Thus, while both neurons and glial cells are dependant on the m-AAA protease for survival in vivo, complete ablation of the complex is necessary to trigger death of oligodendrocytes, hinting to cell-autonomous thresholds of vulnerability to m-AAA protease deficiency.
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Proteasas ATP-Dependientes/genética , Enfermedades Desmielinizantes/genética , Cabello/metabolismo , Metaloendopeptidasas/genética , Mitocondrias/genética , Proteasas ATP-Dependientes/biosíntesis , ATPasas Asociadas con Actividades Celulares Diversas , Animales , Muerte Celular/genética , Supervivencia Celular/genética , Cabello/crecimiento & desarrollo , Humanos , Metaloendopeptidasas/biosíntesis , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Mutación , Vaina de Mielina/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Oligodendroglía/metabolismo , Células de Schwann/metabolismoRESUMEN
Bohai Bay, in the western region of northeastern China's Bohai Sea, receives water from large rivers containing various pollutants including dioxin-like compounds (DLCs). This study used the established zebrafish (Danio rerio) model, its known developmental toxicity endpoints and sensitive molecular analyses to evaluate sediments near and around an industrial effluent site in Bohai Bay. The primary objective was to assess the efficacy of rapid biological detection methods as an addition to chemical analyses. Embryos were exposed to various concentrations of sediment extracts as well as a 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) positive control. Exposure to sediment extract nearest the discharge site (P1) resulted in the most severe- and highest rates of change in embryos and larvae, suggesting that DLC contaminated sediment probably did not occur much beyond it. P1 extract resulted in concentration dependent increases in mortality and pericardial edema. Its highest concentration caused up-regulation of P-450 (CYP)-1A1(CYP1A) mRNA expression at 72â¯h post fertilization (hpf), an increase in its expression in gill arches as observed by whole mount in situ hybridization, and an increased signal in the Tg(cyp1a: mCherry) transgenic line. The pattern and magnitude of response was very similar to that of TCDD and supported the presence of DLCs in these sediment samples. Follow-up chemical analysis confirmed this presence and identified H7CDF, O8CDF and O8CDD as the main components in P1 extract. This study validates the use of biological assays as a rapid, sensitive, and cost-effective method to evaluate DLCs and their effects in sediment samples. Additionally, it provides support for the conclusion that DLCs have limited remobilization capacity in marine sediments.
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Dioxinas/análisis , Monitoreo del Ambiente/métodos , Sedimentos Geológicos/análisis , Contaminantes Químicos del Agua/análisis , Pez Cebra/metabolismo , Animales , China , Embrión no Mamífero/efectos de los fármacos , Desarrollo Embrionario/efectos de los fármacos , Monitoreo del Ambiente/economíaRESUMEN
Cafestol and kahweol are natural diterpenes extracted from coffee beans. In addition to the effect of raising serum lipid, in vitro and in vivo experimental results have revealed that the two diterpenes demonstrate multiple potential pharmacological actions such as anti-inflammation, hepatoprotective, anti-cancer, anti-diabetic, and anti-osteoclastogenesis activities. The most relevant mechanisms involved are down-regulating inflammation mediators, increasing glutathione (GSH), inducing apoptosis of tumor cells and anti-angiogenesis. Cafestol and kahweol show similar biological activities but not exactly the same, which might due to the presence of one conjugated double bond on the furan ring of the latter. This review aims to summarize the pharmacological properties and the underlying mechanisms of cafestol-type diterpenoids, which show their potential as functional food and multi-target alternative medicine.
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Diterpenos/farmacología , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Diterpenos/química , Humanos , Hipoglucemiantes/farmacologíaRESUMEN
The m-AAA protease subunit AFG3L2 is involved in degradation and processing of substrates in the inner mitochondrial membrane. Mutations in AFG3L2 are associated with spinocerebellar ataxia SCA28 in humans and impair axonal development and neuronal survival in mice. The loss of AFG3L2 causes fragmentation of the mitochondrial network. However, the pathogenic mechanism of neurodegeneration in the absence of AFG3L2 is still unclear. Here, we show that depletion of AFG3L2 leads to a specific defect of anterograde transport of mitochondria in murine cortical neurons. We observe similar transport deficiencies upon loss of AFG3L2 in OMA1-deficient neurons, indicating that they are not caused by OMA1-mediated degradation of the dynamin-like GTPase OPA1 and inhibition of mitochondrial fusion. Treatment of neurons with antioxidants, such as N-acetylcysteine or vitamin E, or decreasing tau levels in axons restored mitochondrial transport in AFG3L2-depleted neurons. Consistently, tau hyperphosphorylation and activation of ERK kinases are detected in mouse neurons postnatally deleted for Afg3l2. We propose that reactive oxygen species signaling leads to cytoskeletal modifications that impair mitochondrial transport in neurons lacking AFG3L2.
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Proteasas ATP-Dependientes/genética , Mitocondrias/metabolismo , Proteínas tau/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas , Acetilcisteína/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Transporte Biológico/genética , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Embrión de Mamíferos , Sistema de Señalización de MAP Quinasas/genética , Metaloproteasas/genética , Metaloproteasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/efectos de los fármacos , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fosforilación/genética , Especies Reactivas de Oxígeno/farmacologíaRESUMEN
Thiosemicarbazone, a class of compounds with excellent biological activity, especially antitumor activity, have attracted wide attention. In this study, a novel fluorinated thiosemicarbazone derivative, 2-(3,4-difluorobenzylidene) hydrazinecarbothioamide (compound 1) was synthesized and its antitumor activities were further investigated on a non-small cell lung cancer cell line (A549) along with its underlying mechanisms. Compound 1 showed significant anti-proliferative activity on A549 cells, which was further proved by colony formation experiment. Compound 1 also inhibits the invasion of A549 cells in a trans-well culture system. Moreover, compound 1 markedly induced apoptosis on A549 cells, and the ratio of Bcl-2/Bax was decreased while the amount of p53, Cleaved-Caspase 3 and Cleaved-PARP expression were increased significantly. Compound 1 decreased the mitochondrial membrane potential, while the content of reactive oxygen was increased obviously. It is revealed that compound 1 mediated cell cycle arrest in G0/G1 phase by reducing G1 phase dependent proteins, CDK4 and Cyclin D1. As a result, it is indicated that compound 1 induced apoptosis on A549 cells was realized by regulating ROS-mediated mitochondria-dependent signaling pathway.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Tiosemicarbazonas/síntesis química , Células A549 , Antineoplásicos/química , Relación Dosis-Respuesta a Droga , Compuestos de Flúor/síntesis química , Compuestos de Flúor/farmacología , Humanos , Mitocondrias/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Tiosemicarbazonas/farmacologíaRESUMEN
A series of bromophenol hybrids with N-containing heterocyclic moieties were designed, and their anticancer activities against a panel of five human cancer cell lines (A549, Bel7402, HepG2, HCT116 and Caco2) using MTT assay in vitro were explored. Among them, thirteen compounds (17a, 17b, 18a, 19a, 19b, 20a, 20b, 21a, 21b, 22a, 22b, 23a, and 23b) exhibited significant inhibitory activity against the tested cancer cell lines. The structure-activity relationships (SARs) of bromophenol derivatives were discussed. The promising candidate compound 17a could induce cell cycle arrest at G0/G1 phase and induce apoptosis in A549 cells, as well as caused DNA fragmentations, morphological changes and ROS generation by the mechanism studies. Furthermore, compound 17a suppression of Bcl-2 levels (decrease in the expression of the anti-apoptotic proteins Bcl-2 and down-regulation in the expression levels of Bcl-2) in A549 cells were observed, along with activation caspase-3 and PARP, which indicated that compound 17a induced A549 cells apoptosis in vitro through the ROS-mediated apoptotic pathway. These results might be useful for bromophenol derivatives to be explored and developed as novel anticancer drugs.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Organismos Acuáticos , Fenoles/farmacología , Animales , Antineoplásicos/química , Línea Celular Tumoral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Fenoles/química , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Bis (2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) is a natural bromophenol compound derived from marine algae. Previous reports have shown that BDDPM possesses antimicrobial activity. In the present study, we found that BDDPM has cytotoxic activity on a wide range of tumor cells, including BEL-7402 cells (IC50 = 8.7 µg/mL). Further studies have shown that prior to the onset of apoptosis, the BDDPM induces BEL-7402 cell detachment by decreasing the adherence of cells to the extracellular matrix (ECM). Detachment experiments have shown that the treatment of BEL-7402 cells with low concentrations of BDDPM (5.0 µg/mL) significantly inhibits cell adhesion to fibronectin and collagen IV as well as cell migration and invasion. High doses of BDDPM (10.0 µg/mL) completely inhibit the migration of BEL-7402 cells, and the expression level of MMPs (MMP-2 and MMP-9) is significantly decreased. Moreover, the expression of ß1-integrin and focal adhesion kinase (FAK) is found to be down-regulated by BDDPM. This study suggests that BDDPM has a potential to be developed as a novel anticancer therapeutic agent due to its anti-metastatic activity and also indicates that BDDPM, which has a unique chemical structure, could serve as a lead compound for rational drug design and for future development of anticancer agents.
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Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Hidrocarburos Bromados/farmacología , Toxinas Marinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Integrina beta1/fisiología , Neoplasias Hepáticas Experimentales , Toxinas Marinas/química , Invasividad Neoplásica/prevención & control , Metástasis de la Neoplasia/prevención & controlRESUMEN
3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-isopropoxymethyl benzyl)benzene-1,2-diol (HPN) is a bromophenol derivative from the marine red alga Rhodomela confervoides. We have previously found that HPN exerted an anti-hyperglycemic property in db/db mouse model. In the present study, we found that HPN could protect HepG2 cells against palmitate (PA)-induced cell death. Data also showed that HPN inhibited cell death mainly by blocking the cell apoptosis. Further studies demonstrated that HPN (especially at 1.0 µM) significantly restored insulin-stimulated tyrosine phosphorylation of IR and IRS1/2, and inhibited the PTP1B expression level in HepG2 cells. Furthermore, the expression of Akt was activated by HPN, and glucose uptake was significantly increased in PA-treated HepG2 cells. Our results suggest that HPN could protect hepatocytes from lipid-induced cell damage and insulin resistance via PTP1B inhibition. Thus, HPN can be considered to have potential for the development of anti-diabetic agent that could protect both hepatic cell mass and function.
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Compuestos de Bencilo/farmacología , Catecoles/farmacología , Muerte Celular/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Resistencia a la Insulina , Lípidos/efectos adversos , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Células Hep G2/efectos de los fármacos , Humanos , Hipoglucemiantes/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismoRESUMEN
A series of bromophenol derivatives containing indolin-2-one moiety were designed and evaluated that for their anticancer activities against A549, Bel7402, HepG2, HeLa and HCT116 cancer cell lines using MTT assay in vitro. Among them, seven compounds (4g-4i, 5h, 6d, 7a, 7b) showed potent activity against the tested five human cancer cell lines. Wound-healing assay demonstrated that compound 4g can be used as a potent compound for inactivating invasion and metastasis by inhibiting the migration of cancer cells. The structure-activity relationships (SARs) of bromophenol derivatives had been discussed, which were useful for exploring and developing bromophenol derivatives as novel anticancer drugs.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Indoles/síntesis química , Indoles/farmacología , Fenoles/síntesis química , Fenoles/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Invasividad Neoplásica/prevención & control , Metástasis de la Neoplasia/prevención & control , Relación Estructura-Actividad , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Bis-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) is a bromophenol first isolated from Rhodomelaceae confervoides. Our previous studies showed that BDDPM exerts PTP1B-inhibiting activity and anti-cancer activity against a wide range of tumor cells while it also showed lower cytotoxicity against normal cells. In the present study, we found that BDDPM exhibits significant activities toward angiogenesis in vitro. BDDPM inhibits multiple angiogenesis processes, including endothelial cell sprouting, migration, proliferation, and tube formation. Further kinase assays investigations found that BDDPM is a potent selective, but multi-target, receptor tyrosine kinase (RTKs) inhibitor. BDDPM (10 µM) inhibits the activities of fibroblast growth factor receptor 2 and 3 (FGFR2, 3), vascular endothelial growth factor receptor 2 (VEGFR2) and platelet-derived growth factor receptor α (PDGFRα) (inhibition rate: 57.7%, 78.6%, 78.5% and 71.1%, respectively). Moreover, BDDPM also decreases the phosphorylation of protein kinase B (PKB/Akt) and endothelial nitric oxide synthase (eNOS), as well as nitric oxide (NO) production in a dose dependent manner. These results indicate that BDDPM can be exploited as an anti-angiogenic drug, or as a lead compound for the development of novel multi-target RTKs inhibitors.
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Inhibidores de la Angiogénesis/farmacología , Hidrocarburos Bromados/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Rhodophyta/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/química , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Hidrocarburos Bromados/química , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Kidney disease is a common health problem worldwide. Acute or chronic injuries may interfere with kidney functions, eventually resulting in irreversible kidney damage. A number of recent studies have shown that the plant-derived natural products have an extensive potential for renal protection. Thymoquinone (TQ) is an essential compound derived from Nigella Sativa (NS), which is widely applied in the Middle East as a folk medicine. Previous experiments have demonstrated that TQ has a variety of potential pharmacological effects, including anti-oxidant, antibacterial, antitumor, immunomodulatory, and neuroprotective activities. In particular, the prominent renal protective efficacy of TQ has been demonstrated in both in vivo and in vitro experiments. TQ can prevent acute kidney injuries from various xenobiotics through anti-oxidation, anti-inflammatory, and anti-apoptosis effects. In addition, TQ exhibited significant pharmacological effects on renal cell carcinoma, renal fibrosis, and urinary calculi. The essential mechanisms involve scavenging ROS and increasing anti-oxidant activity, decreasing inflammatory mediators, inducing apoptosis, and inhibiting migration and invasion. The purpose of this review is to conclude the pharmacological effects and the potential mechanisms of TQ in renal protection, shedding new light on the exploration of medicinal phyto-protective agents targeting kidneys.
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Antioxidantes , Apoptosis , Benzoquinonas , Nigella sativa , Fitoterapia , Benzoquinonas/farmacología , Humanos , Nigella sativa/química , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Animales , Enfermedades Renales/prevención & control , Enfermedades Renales/tratamiento farmacológico , Riñón/efectos de los fármacos , Antiinflamatorios , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Sustancias Protectoras/farmacologíaRESUMEN
In this study, we propose a novel therapy system composed of UiO-66 nanoparticles, which contain quercetin combined with chloroquine (UQCNP), to achieve dual autophagy-ubiquitination blockade. Through UiO-66 NP drug loading, the solubility of quercetin (a proteasome inhibitor) was improved under physiological conditions, thereby increasing its effective concentration at the tumor site. The cell experiment results showed that UQCNP significantly increased the apoptosis rate of 4T1 cells by 73.6%, which was significantly higher than other groups. Transmission electron microscopy results showed that the autophagosome of cells in the UQCNP treatment group was significantly lower than that in other treatment groups. Moreover, western blot results showed that, compared with other groups, LC3 expression and proteasome activity (p < 0.01), as well as the tumor volume of mice treated with UQCNP (p < 0.01) were significantly reduced. These results indicate that UQCNP achieves effective tumor therapy by blocking the autophagy and proteasome pathways synchronously.
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Autofagia , Cloroquina , Nanopartículas , Quercetina , Ubiquitinación , Quercetina/farmacología , Quercetina/química , Cloroquina/farmacología , Cloroquina/química , Animales , Autofagia/efectos de los fármacos , Ratones , Nanopartículas/química , Ubiquitinación/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , HumanosRESUMEN
Poly-γ-glutamic acid (γ-PGA), naturally secreted from various strains of Bacillus, has anti-inflammatory activity. In inflammatory bowel disease (IBD), inflammation is promoted and sustained by angiogenesis; however, the role played by γ-PGA in this condition is unclear. Therefore, we evaluated γ-PGA effects on angiogenesis and inflammation in a dextran sulfate sodium-(DSS-) induced mouse colitis model. Experimental colitis was induced in male C57BL/6 mice by administering 3% DSS. Disease activity index (DAI), histopathological scores, microvascular density, myeloperoxidase activity, and VEGF-A and VEGFR2 expression were compared among control mice, DSS-treated mice, and mice receiving 3% DSS along with γ-PGA at 50 mg/kg body weight per day or 3% DSS with γ-PGA at 200 mg/kg body weight per day. We found that γ-PGA significantly attenuated weight loss, DAI, and colon shortening. γ-PGA also significantly reduced histopathological evidence of injury. Moreover, γ-PGA significantly attenuated DSS-induced blood vessel densities. Furthermore, γ-PGA attenuated DSS-induced expression of VEGF-A and its receptor, VEGFR2. In addition, γ-PGA treatment led to reduced recruitment of leukocytes to the inflamed colon. Therefore, our results indicate that γ-PGA has potential application in conditions marked by inflammatory-driven angiogenesis and mucosal inflammation.
Asunto(s)
Colitis/tratamiento farmacológico , Colitis/inmunología , Inflamación/tratamiento farmacológico , Ácido Poliglutámico/análogos & derivados , Animales , Western Blotting , Sulfato de Dextran/toxicidad , Técnica del Anticuerpo Fluorescente , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Patológica/prevención & control , Ácido Poliglutámico/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Pérdida de Peso/efectos de los fármacosRESUMEN
The Brayton cycle system, as a closed cycle working under high-temperature, high-pressure and high-speed conditions, presents significant prospects in many fields. However, the flow behavior and energy efficiency of supercritical CO2 is severely influenced by the structures of face seals and the sealing temperature, especially when the sealing gas experiment is the supercritical transformation process. Therefore, a numerical model was established to investigate the high-temperature flow behavior and energy consumption of face seals with different surface grooves. The effects of the operation parameters and groove structure on the temperature distribution and sealing performance are further studied. The obtained results show that the supercritical effect of the gas film has a more obvious influence on the flow velocity uθ than ur. Moreover, it can be found that the temperature distribution, heat dissipation and leakage rate of the gas face seals present a dramatic change when the working condition exceeds the supercritical point. For the spiral groove, the change rate of heat dissipation becomes larger, from 3.6% to 8.1%, with the increase in sealing pressure from 15 to 50 MPa, when the temperature grows from 300 to 320 K. Meanwhile, the open force maintains a stable state with the increasing temperature and pressure even at the supercritical point. The proposed model could provide a theoretical basis for seal design with different grooves on the supercritical change range in the future.