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This work reports the nonlinear dynamics of a mid-infrared interband cascade laser (ICL) subject to optical injection. It is shown that the stable locking regime is asymmetric and broadens with increasing injection strength. Outside the locking regime, the ICL mostly produces period-one oscillations. However, three categories of periodic pulse oscillations are observed in the vicinity of the Hopf bifurcation and the saddle-node bifurcation. In particular, it is found that the ICL generates broadband chaos at a near-threshold pump current, and the chaos bandwidth is over 300 MHz.
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Near-infrared semiconductor lasers subject to optical feedback usually produce chaos with a broad bandwidth of a few GHz. However, the reported mid-infrared interband cascade lasers (ICLs) only show chaos with a limited bandwidth below 1â GHz. Here we show that an ICL with optical feedback is able to generate broadband chaos as well. The mid-infrared chaos exhibits a remarkable bandwidth of about 6â GHz, which is comparable to that of the near-infrared counterpart. In addition, the spectral coverage in the electrical domain reaches as high as 17.7â GHz. It is found that the chaos bandwidth generally broadens with increasing feedback ratio and/or increasing pump current of the laser, while it is insensitive to the feedback length.
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BACKGROUND: Coordination between osteo-/angiogenesis and the osteoimmune microenvironment is essential for effective bone repair with biomaterials. As a highly personalized and precise biomaterial suitable for repairing complex bone defects in clinical practice, it is essential to endow 3D-printed scaffold the above key capabilities. RESULTS: Herein, by introducing xonotlite nanofiber (Ca6(Si6O17) (OH)2, CS) into the 3D-printed silk fibroin/gelatin basal scaffold, a novel bone repair system named SGC was fabricated. It was noted that the incorporation of CS could greatly enhance the chemical and mechanical properties of the scaffold to match the needs of bone regeneration. Besides, benefiting from the addition of CS, SGC scaffolds could accelerate osteo-/angiogenic differentiation of bone mesenchymal stem cells (BMSCs) and meanwhile reprogram macrophages to establish a favorable osteoimmune microenvironment. In vivo experiments further demonstrated that SGC scaffolds could efficiently stimulate bone repair and create a regeneration-friendly osteoimmune microenvironment. Mechanistically, we discovered that SGC scaffolds may achieve immune reprogramming in macrophages through a decrease in the expression of Smad6 and Smad7, both of which participate in the transforming growth factor-ß (TGF-ß) signaling pathway. CONCLUSION: Overall, this study demonstrated the clinical potential of the SGC scaffold due to its favorable pro-osteo-/angiogenic and osteoimmunomodulatory properties. In addition, it is a promising strategy to develop novel bone repair biomaterials by taking osteoinduction and osteoimmune microenvironment remodeling functions into account.
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Compuestos de Calcio , Nanofibras , Silicatos , Andamios del Tejido , Andamios del Tejido/química , Hidrogeles/farmacología , Hidrogeles/química , Angiogénesis , Regeneración Ósea , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/química , Impresión Tridimensional , Osteogénesis , Ingeniería de TejidosRESUMEN
BACKGROUND: Impaired osteo-/angiogenesis, excessive inflammation, and imbalance of the osteoimmune homeostasis are involved in the pathogenesis of the alveolar bone defect caused by periodontitis. Unfortunately, there is still a lack of ideal therapeutic strategies for periodontitis that can regenerate the alveolar bone while remodeling the osteoimmune microenvironment. Quercetin, as a monomeric flavonoid, has multiple pharmacological activities, such as pro-regenerative, anti-inflammatory, and immunomodulatory effects. Despite its vast spectrum of pharmacological activities, quercetin's clinical application is limited due to its poor water solubility and low bioavailability. RESULTS: In this study, we fabricated a quercetin-loaded mesoporous bioactive glass (Quercetin/MBG) nano-delivery system with the function of continuously releasing quercetin, which could better promote the bone regeneration and regulate the immune microenvironment in the alveolar bone defect with periodontitis compared to pure MBG treatment. In particular, this nano-delivery system effectively decreased injection frequency of quercetin while yielding favorable therapeutic results. In view of the above excellent therapeutic effects achieved by the sustained release of quercetin, we further investigated its therapeutic mechanisms. Our findings indicated that under the periodontitis microenvironment, the intervention of quercetin could restore the osteo-/angiogenic capacity of periodontal ligament stem cells (PDLSCs), induce immune regulation of macrophages and exert an osteoimmunomodulatory effect. Furthermore, we also found that the above osteoimmunomodulatory effects of quercetin via macrophages could be partially blocked by the overexpression of a key microRNA--miR-21a-5p, which worked through inhibiting the expression of PDCD4 and activating the NF-κB signaling pathway. CONCLUSION: In summary, our study shows that quercetin-loaded mesoporous nano-delivery system has the potential to be a therapeutic approach for reconstructing alveolar bone defects in periodontitis. Furthermore, it also offers a new perspective for treating alveolar bone defects in periodontitis by inhibiting the expression of miR-21a-5p in macrophages and thereby creating a favorable osteoimmune microenvironment.
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FN-kappa B , Periodontitis , Humanos , Quercetina/farmacología , Periodontitis/tratamiento farmacológico , Flavonoides , Inflamación , Proteínas de Unión al ARN , Proteínas Reguladoras de la ApoptosisRESUMEN
The regeneration of diabetic bone defects remains challenging. Hyperglycemia causes inflammation state and excessive reactive oxygen species (ROS) during bone regeneration period. These two effects reinforce one another and create an endless loop that is also accompanied by mitochondrial dysfunction. However, there is still no effective and inclusive method targeting at the two aspects and breaking the vicious cycle. Herein, nanoparticles-Met@ZIF-8(metformin loaded zeolitic imidazolate frameworks) modified hydrogel that is capable of releasing metformin and Zn elements are constructed. This hydrogel treats hyperglycemia while also controlling mitochondrial function, reducing inflammation, and restoring homeostasis. In addition, the synergetic effect from metformin and Zn ions inhibits ROS-inflammation cascade generation and destroys the continuous progress by taking effects in both ROS and inflammation and further keeping organelles' homeostasis. Furthermore, with the recovery of mitochondria and breakdown of the ROS-inflammation cascade cycle, osteogenesis under a diabetic microenvironment is enhanced in vivo and in vitro. In conclusion, the study provides critical insight into the biological mechanism and potential therapy for diabetic bone regeneration.
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Diabetes Mellitus , Hiperglucemia , Estructuras Metalorgánicas , Humanos , Especies Reactivas de Oxígeno/metabolismo , HidrogelesRESUMEN
Angiogenesis and vasculogenic mimicry (VM) are crucial for the growth and metastasis of non-small-cell lung cancer (NSCLC). Most tumor angiogenesis inhibitors mainly target endothelial cell-mediated angiogenesis, ignoring tumor-cell-mediated VM and frequently leading to tumor recurrence and metastasis. Thus, development of bioactive molecules interfering with both tumor angiogenesis and VM is necessary. Identifying novel angiogenesis inhibitors from natural products is a promising strategy. Scoparasin B, a pimarane diterpene extracted from a marine-derived fungus, Eutypella sp. F0219, has an antibacterial effect. However, its effect on angiogenesis and VM remains unexplored. In this study, we first certified that scoparasin B showed a strong inhibition effect on angiogenesis and the VM process in vitro and ex vivo. Moreover, scoparasin B prominently impeded tumor growth, angiogenesis, and VM in an NCI-H1299 xenograft model. Further study revealed that scoparasin B restrained tumor angiogenesis and VM by reducing the VEGF-A level and suppressing the VEGF-A/VEGFR2 signaling pathway. This study first demonstrated scoparasin B inhibited tumor angiogenesis, VM, and tumor growth of NSCLC and revealed its underlying mechanism. These new findings further support the potential of scoparasin B as a novel angiogenesis inhibitor and give a hint for further exploring potential angiogenesis inhibitors from natural products.
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Productos Biológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Inhibidores de la Angiogénesis/farmacología , Productos Biológicos/uso terapéutico , Línea Celular Tumoral , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia , Neovascularización Patológica , Factor A de Crecimiento Endotelial VascularRESUMEN
Myocardial infarction (MI) is the leading cause of death worldwide, and oxidative stress is part of the process that causes MI. Calycosin, a naturally occurring substance with cardioprotective properties, is one of the major active constituents in Radix Astragali. In this study, effect of Calycosin was investigated in vivo and in vitro to determine whether it could alleviate oxidative stress and oxidative stress-induced cardiac apoptosis in neonatal cardiomyocytes (NCMs) via activation of aldehyde dehydrogenase 2 (ALDH2). Calycosin protected against oxidative stress and oxidative stress-induced apoptosis in NCMs. Molecular docking revealed that the ALDH2-Calycosin complex had a binding energy of -9.885 kcal/mol. In addition, molecular docking simulations demonstrated that the ALDH2-Calycosin complex was stable. Using BLI assays, we confirmed that Calycosin could interact with ALDH2 (KD = 1.9 × 10-4 M). Furthermore, an ALDH2 kinase activity test revealed that Calycosin increased ALDH2 activity, exhibiting an EC50 of 91.79 µM. Pre-incubation with ALDH2 inhibitor (CVT-10216 or disulfiram) reduced the cardio-protective properties Calycosin. In mice with MI, Calycosin therapy substantially reduced myocardial apoptosis, oxidative stress, and activated ALDH2. Collectively, our findings clearly suggest that Calycosin reduces oxidative stress and oxidative stress-induced apoptosis via the regulation of ALDH2 signaling, which supports potential therapeutic use in MI.
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Infarto del Miocardio , Miocitos Cardíacos , Ratones , Animales , Aldehído Deshidrogenasa Mitocondrial/metabolismo , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Apoptosis , Aldehído Deshidrogenasa/metabolismoRESUMEN
Delayed wound healing remains a challenge, and macrophages play an important role in the inflammatory process of wound healing. Morphological changes in macrophages can affect their phenotype, but little is known about the underlying mechanism. Aligned electrospun nanofibers have natural advantages in modulating cell morphology. Therefore, the current study constructed aligned electrospun nanofibers that could transform macrophages into elongated shapes. Our results demonstrated that aligned nanofibers without exogenous cytokines could downregulate the proinflammatory M1 phenotype and upregulate the prohealing M2 phenotype in an inflammatory environment. Importantly, our study revealed that aligned electrospun nanofibers could inhibit macrophage M1 polarization via the JAK-STAT and NF-κB pathways. Furthermore, the conditioned medium from macrophages cultured on aligned nanofibers could encourage fibroblast migration, proliferation and collagen secretion. In vivo, aligned nanofibers alleviated the inflammatory microenvironment, promoted angiogenesis and accelerated wound healing in mouse skin defects by modulating macrophage phenotypes. Collectively, aligned electrospun nanofibers can influence macrophage polarization via the JAK-STAT and NF-κB pathways and attenuate the local inflammatory response in skin wounds. This study provides a potential strategy to modulate macrophage polarization and promote wound healing by controlling the topology of biomaterials and offers a new perspective for the application of nanotechnology in wound healing.
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Nanofibras , Animales , Macrófagos/metabolismo , Ratones , FN-kappa B/metabolismo , Poliésteres , Cicatrización de HeridasRESUMEN
BACKGROUND: The repair of tissue defects has attracted considerable attention and remained a substantial challenge. Calcium silicate (CaSiO3, CS) bioceramics have attracted the interest of researchers due to their excellent biodegradability. Recent studies have demonstrated that nanoscale-modified bioactive materials with favorable biodegradability could promote bone tissue regeneration, providing an alternative approach for the repair of bone defects. However, the direct construction of biodegradable nanostructures in situ on CS bioceramics was still difficult. RESULTS: In this study, flower-like nanostructures were flexibly prepared in situ on biodegradable CS bioceramics via hydrothermal treatment. The flower-like nanostructure surfaces exhibited better hydrophilicity and more significantly stimulated cell adhesion, alkaline phosphatase (ALP) activity, and osteogenic differentiation. Furthermore, the CS bioceramics with flower-like nanostructures effectively promoted bone regeneration and were gradually replaced with newly formed bone due to the favorable biodegradability of these CS bioceramics. Importantly, we revealed an osteogenesis-related mechanism by which the FAK/p38 signaling pathway could be involved in the regulation of bone mesenchymal stem cell (BMSC) osteogenesis by the flower-like nanostructure surfaces. CONCLUSIONS: Flower-like nanostructure surfaces on CS bioceramics exerted a strong effect on promoting bone repair and regeneration, suggesting their excellent potential as bone implant candidates for improving bone regeneration.
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Nanoestructuras , Osteogénesis , Regeneración Ósea , Compuestos de Calcio , Transducción de Señal , SilicatosRESUMEN
The small molecular inhibitor-associated downregulation of autophagy can remarkably enhance the efficiency of photothermal cancer therapy. To identify a more effective autophagy inhibitor, we screened a library of 20 compounds and found chloroquine, hydroxychloroquine, dauricine, and daurisoline were more efficient than the others to improve the photothermal killing of cancer cells. Interestingly, the four agents all disturb the autophagosome formation and fusion process, indicating it is a promising target to enhance cancer therapeutic efficiency. Among the four agents, daurisoline was identified to be the most efficient one. It reduced the viability of cancer cells treated by low-energy photothermal therapy from 86.27% to 32.92%. Finally, the combination treatment mediated by nanodrugs loaded with daurisoline and indocyanine green was more efficient than the individual modalities, resulting in complete inhibition of tumor growth. The study gives new inspiration to autophagy modulation-associated photothermal therapy and other therapeutic modalities for cancer treatment.
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Antineoplásicos , Autofagia , Neoplasias , Terapia Fototérmica , Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Terapia Combinada , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Resultado del TratamientoRESUMEN
We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile ferrous iron and total iron levels escalated with age in rats. Oxidative stress markers, such as nitrite/nitrate, 3-nitrotyrosine, and 4-hydroxy-2-nonenal, accumulated in the aging ovaries due to an aberrant upregulation of the ovarian transferrin, ferritin light/heavy chains, and iron regulatory protein 2(IRP2)-mediated transferrin receptor 1 (TfR1). Ferritin inhibited estradiol biosynthesis in ovarian granulosa cells in vitro via the upregulation of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p65/p50-induced oxidative and inflammatory factor inducible nitric oxide synthase (iNOS). An in vivo study demonstrated how the age-associated activation of NF-κB induced the upregulation of iNOS and the tumor necrosis factor α (TNFα). The downregulation of the keap1-mediated nuclear factor erythroid 2-related factor 2 (Nrf2), that induced a decrease in glutathione peroxidase 4 (GPX4), was observed. The aberrant transferrin and ferritin upregulation triggered an iron accumulation via the upregulation of an IRP2-induced TfR1. This culminates in NF-κB-iNOS-mediated ovarian oxi-inflamm-aging and serum estradiol decrement in naturally aging rats. The iron accumulation and the effect on ferroptosis-related proteins including the GPX4, TfR1, Nrf2, Keap1, and ferritin heavy chain, as in testicular ferroptosis, indicated the triggering of ferroptosis. In young rats, an intraovarian injection of an adenovirus, which expressed iron regulatory proteins, upregulated the ovarian NF-κB/iNOS and downregulated the GPX4. These novel findings have contributed to a prompt translational research on the ovarian aging-associated iron metabolism and aging-associated ovarian diseases.
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Ferroptosis , FN-kappa B , Ratas , Animales , Femenino , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ferritinas/metabolismo , Regulación hacia Arriba , Nitritos/metabolismo , Transferrina/metabolismo , Estradiol/metabolismo , Nitratos/metabolismo , Ovario/metabolismo , Apoferritinas/metabolismo , Proteína 2 Reguladora de Hierro/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Envejecimiento , Estrés Oxidativo , Hierro/metabolismo , Receptores de Transferrina/metabolismoRESUMEN
Osteoporosis is a common skeletal complication of diabetes mellitus (DM). The mechanisms underlying the pathophysiology of diabetic osteoporosis are complex. Glycogen synthase kinase-3ß (GSK-3ß) is a widely expressed serine/threonine kinase and associated with both DM and bone metabolism, which arouse our concern. In this study, we established the diabetic mouse model by high-fat diet combined with streptozotocin injection. Decreased bone mass and reduced osteogenesis were observed in femurs of the mice. Besides, we identified that there is an activated expression of GSK3ß in the bone marrow mesenchymal stem cells (BMSCs) of diabetic mice. To explore the link between GSK3ß and diabetic osteoporosis, we exposed BMSCs to a high glucose microenvironment in vitro and discovered that the glucose-induced GSK3ß activation has negative osteogenic effects on BMSCs by suppressing ß-catenin/Tcf7/Ccn4 signaling axis. Inhibition of GSK3ß by specific concentrations of LiCl could reverse the impaired osteogenesis of BMSCs and increase expression of ß-catenin, Tcf7 and Ccn4. Our research indicated that abnormal activation of GSK3ß plays a role in diabetic osteoporosis and might be a potential target to treat diabetic osteoporosis.
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Diabetes Mellitus Experimental/fisiopatología , Glucosa/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células Madre Mesenquimatosas/metabolismo , Osteogénesis/fisiología , Animales , Proteínas CCN de Señalización Intercelular/genética , Proteínas CCN de Señalización Intercelular/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Dieta Alta en Grasa/efectos adversos , Activación Enzimática , Fémur/patología , Fémur/ultraestructura , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Estreptozocina , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
We simulated 3 transmission modes, including close-contact, respiratory droplets and aerosol routes, in the laboratory. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be highly transmitted among naive human angiotensin-converting enzyme 2 (hACE2) mice via close contact because 7 of 13 naive hACE2 mice were SARS-CoV-2 antibody seropositive 14 days after being introduced into the same cage with 3 infected-hACE2 mice. For respiratory droplets, SARS-CoV-2 antibodies from 3 of 10 naive hACE2 mice showed seropositivity 14 days after introduction into the same cage with 3 infected-hACE2 mice, separated by grids. In addition, hACE2 mice cannot be experimentally infected via aerosol inoculation until continued up to 25 minutes with high viral concentrations.
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Betacoronavirus , Infecciones por Coronavirus/transmisión , Neumonía Viral/transmisión , Aerosoles , Canal Anal/virología , Enzima Convertidora de Angiotensina 2 , Animales , Anticuerpos Antivirales/sangre , Betacoronavirus/genética , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , COVID-19 , Chlorocebus aethiops , Femenino , Humanos , Inmunoglobulina G/sangre , Pulmón/patología , Pulmón/virología , Masculino , Ratones , Ratones Transgénicos , Pandemias , Peptidil-Dipeptidasa A/genética , Faringe/virología , ARN Viral/aislamiento & purificación , Sistema Respiratorio/virología , Riesgo , SARS-CoV-2 , Organismos Libres de Patógenos Específicos , Factores de Tiempo , Células Vero , Carga Viral , Pérdida de PesoRESUMEN
Guizhi Fuling Formula was first seen in Synopsis of Golden Chamber by ZHANG Zhongjing. It is composed of Cinnamomi Ramulus, Poria, Moutan Cortex, Persicae Semen, Peony and other drugs, commonly used in the treatment of gynecological diseases such as hysteromyoma, ovarian cyst, endometriosis, pelvic inflammation, dysmenorrhea, etc. In addition, it is also used in internal medicine and urology. This reflects the modern doctors' recognition of the famous prescriptions in ancient books. However, whether Guizhi Fuling Formula is really suitable for these diseases still needs further study for verification. The author systematically searched CNKI, Wanfang, SinoMed, PubMed, EMbase, Cochrane Library database: 2 304 papers on clinical research of Guizhi Fuling, covering 13 systems and 128 diseases. Combined with the questionnaire of experts, we investigated the knowledge of experts of traditional Chinese medicine, Western medicine and combination of Chinese and Western medicine on the applicable indications of Guizhi Fuling Formula in this paper, systematically elaborated the clinical applications of Guizhi Fuling Formula, and summarized the applicable indications of Guizhi Fuling Formula, in order to provide a reference for the clinical rational application of Guizhi Fuling Formula, and provide a reference also for clinical medication.
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Medicamentos Herbarios Chinos , Enfermedad Inflamatoria Pélvica , Wolfiporia , Dismenorrea , Femenino , Humanos , Medicina Tradicional ChinaRESUMEN
As a bisphenol A (BPA) alternative, bisphenol F (BPF) has been detected in various products, such as paper products, personal care products, and food. More importantly, the toxicity of BPF remains underexplored. We reported an integrated method to study the immunotoxic potentials and the underlying mechanisms of BPF on cell apoptosis, macrophage polarization, reactive oxygen species generation, expression and secretion of immune-related cytokines, and reprogramming of lipid signaling. More serious to BPA, BPF induced apoptosis in macrophages. The apoptosis was induced by activating both sphingomyelin-ceramide signaling pathway and oxidative stress, which included intrinsic (bax and caspase-9) and extrinsic apoptotic pathways (tumor necrosis factor receptor 1, caspase-8, and caspase-3). BPF exposure also induced the proinflammatory phenotype of the macrophage. This alternation was shown to be closely correlated with the modulation of biosynthesis and degradation of glycerophospholipids. This study demonstrated novel evidence that BPF as a substituent of BPA induced immunotoxic effects at environmentally relevant concentrations. We also showed that the reprogramming of lipidome plays a key role in the regulation of macrophage polarization and the induction of immunotoxicity of the BPA analogue.
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Compuestos de Bencidrilo , Transducción de Señal , Lípidos , Macrófagos , Estrés Oxidativo , FenolesRESUMEN
Parkinson's disease is a progressive neurodegenerative disorder resulting from the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta. It induces a series of functional modifications in the circuitry of the basal ganglia nuclei and leads to severe motor disturbances. The amino acid glutamate, as an excitatory neurotransmitter, plays a key role in the disruption of normal basal ganglia function regulated through the interaction with its receptor proteins. It has been proven that glutamate receptors participate in the modulation of neuronal excitability, transmitter release, and long-term synaptic plasticity, in addition to being related to the altered neurotransmission in Parkinson's disease. Therefore, they are considered new targets for improving the therapeutic strategies used to treat Parkinson's disease. In this review, we discuss the biological characteristics of these receptors and demonstrate the receptor-mediated neuroprotection in Parkinson's disease. Pharmacological manipulation of these receptors during anti-Parkinsonian processes in both experimental studies and clinical trials are also summarized.
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Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Receptores de Glutamato/metabolismo , Animales , Ensayos Clínicos como Asunto , Descubrimiento de Drogas , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Ácido Glutámico/metabolismo , Humanos , Terapia Molecular Dirigida , Neurotransmisores/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Receptores de Glutamato/genética , Transducción de Señal/efectos de los fármacos , Sustancia Negra/metabolismo , Transmisión Sináptica , Resultado del TratamientoRESUMEN
BACKGROUND: Cytokine-based cancer therapies have attracted a great deal of attention in recent years. Unfortunately, resistance to treatment limits the efficacy of these therapeutics. Therefore, the aim of our study was to explore the mechanism of IL-2-based therapy for hepatocellular carcinoma in an attempt to increase the efficiency of this treatment option. METHODS: HepG2 cells were treated with IL-2. Then, siRNA against TZA was used to transfected into HepG2 cells. Cellular apoptosis was measured via MTT assay, TUNEL assay and caspase-3 activity. Cellular proliferation was evaluated via EdU assay and western blotting. Cellular migration was detected via Transwell assay. Mitochondrial function was monitored by mitochondrial potential analysis, ROS staining, immunofluorescence and western blotting. Pathway blocker and activator were used to establish the role of JNK/F-actin/mitochondrial fission signaling pathway in HepG2 cells stress response. RESULTS: Our study found that IL-2 treatment significantly reduced the viability, mobility and proliferation of HepG2 cells in vitro. We also demonstrated that IL-2 treatment was accompanied by an increase in the expression of transcriptional co-activator with PDZ-binding motif (TAZ). Interestingly, genetic ablation of TAZ in the presence of IL-2 further promoted apoptosis, inhibited mobility, and arrested proliferation in HepG2 cells. At the molecular level, IL-2 administration activated excessive mitochondrial fission via the JNK/F-actin pathway; these effects were further enhanced by TAZ deletion. Mechanistically, TAZ knockdown further increased the expression of mitochondrial fission-related proteins such as Drp1, Mff and Fis. The augmented mitochondrial fission stimulated ROS overproduction, mediated redox imbalance, interrupted mitochondrial energy generation, reduced mitochondrial membrane potential, promoted leakage of the pro-apoptotic molecule cyt-c into the nucleus, and initiated caspase-9-related mitochondrial death. Further, we demonstrated that the anti-proliferative and anti-metastatic effects of IL-2 in HepG2 cells were enhanced by TAZ deletion, suggesting that IL-2 sensitizes HepG2 cells to IL-2-based cytokine therapy. However, JNK/F-actin pathway blockade could abrogate the inhibitory effects of TAZ deletion on HepG2 migration, proliferation and survival. CONCLUSIONS: Taken together, our data indicate that the anti-tumor effects of IL-2-based therapies may be enhanced by TAZ deletion in a JNK/F-actin pathway-dependent manner. This finding provides a novel combinatorial therapeutic approach for treating hepatocellular carcinoma that might significantly increase the efficacy of cytokine-based therapies in a clinical setting.
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The investigation of the bone regeneration ability, degradation and excretion of the grafts is critical for development and application of the newly developed biomaterials. Herein, the in vivo bone-regeneration, biodegradation and silicon (Si) excretion of the new type calcium silicate (CaSiO3, CS) bioactive ceramics were investigated using rabbit femur defect model, and the results were compared with the traditional ß-tricalcium phosphate [ß-Ca3(PO4)2, ß-TCP] bioceramics. After implantation of the scaffolds in rabbit femur defects for 4, 8 and 12 weeks, the bone regenerative capacity and degradation were evaluated by histomorphometric analysis. While urine and some organs such as kidney, liver, lung and spleen were resected for chemical analysis to determine the excretion of the ionic products from CS implants. The histomorphometric analysis showed that the bioresorption rate of CS was similar to that of ß-TCP in femur defect model, while the CS grafts could significantly stimulate bone formation capacity as compared with ß-TCP bioceramics (P < 0.05). The chemical analysis results showed that Si concentration in urinary of the CS group was apparently higher than that in control group of ß-TCP. However, no significant increase of the Si excretion was found in the organs including kidney, which suggests that the resorbed Si element is harmlessly excreted in soluble form via the urine. The present studies show that the CS ceramics can be used as safe, bioactive and biodegradable materials for hard tissue repair and tissue engineering applications.
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Regeneración Ósea , Sustitutos de Huesos/química , Cerámica/química , Fémur/lesiones , Implantes Absorbibles , Animales , Compuestos de Calcio/química , Fosfatos de Calcio/química , Fémur/fisiología , Fémur/cirugía , Masculino , Ensayo de Materiales , Microscopía Electrónica de Rastreo , Porosidad , Conejos , Silicatos/química , Silicio/química , Ingeniería de Tejidos , Andamios del Tejido/químicaRESUMEN
Living organisms are known for creating complex organic-inorganic hybrid materials such as bone, teeth, and shells, which possess outstanding functions as compared to their simple mineral forms. This has inspired many attempts to mimic such structures, but has yielded few practical advances. In this study, a multilevel hierarchically ordered artificial biomineral (a composite of hydroxyapatite and gelatine) with favorable nanomechanical properties is reported. A typical optimized HAp/gelatin hybrid material in the perpendicular direction of the HAp c-axis has a modulus of 25.91 + 1.78 GPa and hardness of 0.90 + 0.10 GPa, which well matches that of human cortical bone (modulus 24.3 + 1.4 GPa, hardness 0.69 + 0.05 GPa). The bottom-up crystal constructions (from nano- to micro- to macroscale) of this material are achieved through a hard template approach by the phase transformation from DCP to HAp. The structural biomimetic material shows another way to mimic the complex hierarchical designs of sclerous tissues which have potential value for application in hard tissue engineering.
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Materiales Biomiméticos/química , Durapatita/química , Gelatina/química , Ingeniería de Tejidos/métodos , Huesos/química , Dureza , HumanosRESUMEN
Porous materials and scaffolds have wide applications in biomedical and biological fields. They can provide biological and physical cues to promote cell adhesion, proliferation, differentiation and extracellular matrix secretion to guide new tissue formation. Hybrid scaffolds of collagen and wollastonite nanowires with well controlled pore structures were prepared by using ice particulates as a porogen material. The hybrid scaffolds had interconnected large spherical pores with wollastonite nanowires embedded in the walls of the pores. The wollastonite nanowires reinforced the hybrid scaffolds and showed some stimulatory effects on cell functions. Human bone marrow-derived mesenchymal stem cells showed higher proliferation and osteogenic differentiation and expressed higher level of genes encoding angiogenesis-related genes in the hybrid scaffolds than did in the collagen scaf-. fold. The results suggest the hybrid scaffolds could facilitate osteogenic differentiation and induce angiogenesis and will be useful for bone tissue engineering.