RESUMEN
Type 2 diabetic osteoporosis (T2DOP) is a skeletal metabolic syndrome characterized by impaired bone remodeling due to type 2 diabetes mellitus, and there are drawbacks in the present treatment. Osteoking (OK) is widely used for treating fractures and femoral head necrosis. However, OK is seldom reported in the field of T2DOP, and its role and mechanism of action need to be elucidated. Consequently, this study investigated whether OK improves bone remodeling and the mechanisms of diabetes-induced injury. We used db/db mice as a T2DOP model and stimulated MC3T3-E1 cells (osteoblast cell line) with high glucose (HG, 50 mM) and advanced glycation end products (AGEs, 100 µg/mL), respectively. The effect of OK on T2DOP was assessed using a combined 3-point mechanical bending test, hematoxylin and eosin staining, and enzyme-linked immunosorbent assay. The effect of OK on enhancing MC3T3-E1 cell differentiation and mineralization under HG and AGEs conditions was assessed by an alkaline phosphatase activity assay and alizarin red S staining. The AGEs/insulin-like growth factor-1(IGF-1)/ß-catenin/osteoprotegerin (OPG) pathway-associated protein levels were assayed by western blot analysis and immunohistochemical staining. We found that OK reduced hyperglycemia, attenuated bone damage, repaired bone remodeling, increased tibial and femoral IGF-1, ß-catenin, and OPG expression, and decreased receptor activator of nuclear kappa B ligand and receptor activator of nuclear kappa B expression in db/db mice. Moreover, OK promoted the differentiation and mineralization of MC3T3-E1 cells under HG and AGEs conditions, respectively, and regulated the levels of AGEs/IGF-1/ß-catenin/OPG pathway-associated proteins. In conclusion, our results suggest that OK may lower blood glucose, alleviate bone damage, and attenuate T2DOP, in part through activation of the AGEs/IGF-1/ß-catenin/OPG pathway.
RESUMEN
d-Galactose (d-gal) and l-glutamate (l-glu) impair learning and memory. The mechanism of interaction between the gut microbiome and brain remains unclear. In this study, a model of cognitive impairment was induced in tree shrews by intraperitoneal (ip) injection of d-gal (600 mg/kg/day), intragastric (ig) administration with l-glu (2000 mg/kg/day), and the combination of d-gal (ip, 600 mg/kg/day) and l-glu (ig, 2000 mg/kg/day). The cognitive function of tree shrews was tested by the Morris water maze method. The expression of Aß1-42 proteins, the intestinal barrier function proteins occludin and P-glycoprotein (P-gp), and the inflammatory factors NF-κB, TLR2, and IL-18 was determined by immunohistochemistry. The gut microbiome was analyzed by 16SrRNA high-throughput sequencing. After administering d-gal and l-glu, the escape latency increased (p < .01), and the times of crossing the platform decreased (p < .01). These changes were greater in the combined administration of d-gal and l-glu (p < .01). The expression of Aß1-42 was higher in the perinuclear region of the cerebral cortex (p < .01) and intestinal cell (p < .05). There was a positive correlation between the cerebral cortex and intestinal tissue. Moreover, the expression of NF-κB, TLR2, IL-18, and P-gp was higher in the intestine (p < .05), while the expression of occludin and the diversity of gut microbes were lower, which altered the biological barrier of intestinal mucosal cells. This study indicated that d-gal and l-glu could induce cognitive impairment, increase the expression of Aß1-42 in the cerebral cortex and intestinal tissue, decrease the gut microbial diversity, and alter the expression of inflammatory factors in the mucosal intestines. The dysbacteriosis may produce inflammatory cytokines to modulate neurotransmission, causing the pathogenesis of cognitive impairment. This study provides a theoretical basis to explore the mechanism of learning and memory impairment through the interaction of microbes in the gut and the brain.
Asunto(s)
Disfunción Cognitiva , Galactosa , Animales , Galactosa/toxicidad , Galactosa/metabolismo , Ácido Glutámico/metabolismo , Interleucina-18/efectos adversos , Interleucina-18/metabolismo , FN-kappa B/metabolismo , Tupaiidae/metabolismo , Ocludina/metabolismo , Receptor Toll-Like 2/metabolismo , Encéfalo/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/patología , Aprendizaje por LaberintoRESUMEN
Abnormal accumulation of lipids and massive deposition of foam cells is a primary event in the pathogenesis of atherosclerosis. Recent studies have demonstrated that autophagy and lysosomal function of atherosclerotic macrophages are impaired, which exacerbates the accumulation of lipid in macrophages and formation of foam cells. Gastrodin, a major active component of Gastrodia elata Bl., has exerted a protective effect on nervous system, but the effect of gastrodin on atherosclerotic vascular disease remains unknown. We aimed to evaluate the effect of gastrodin on autophagy and lysosomal function of foam cells and explored the mechanism underlying gastrodin's effect on the formation of foam cells. In an in vitro foam cell model constructed by incubating macrophages with oxygenized low-density lipoproteins (ox-LDL), our results showed that lysosomal function and autophagy of foam cells were compromised. Gastrodin restored lysosomal function and autophagic activity via the induction of lysosomal biogenesis and autophagy. The restoration of lysosomal function and autophagic activity enhanced cholesterol efflux from macrophages, therefore, reducing lipid accumulation and preventing formation of foam cells. AMP-activated protein kinase (AMPK) was activated by gastrodin to promote phosphorylation and nuclear translocation of forkhead box O1 (FoxO1), subsequently resulting in increased transcription factor EB (TFEB) expression. TFEB was activated by gastrodin to promote lysosomal biogenesis and autophagy. Our study revealed that the effect of gastrodin on foam cell formation and that induction of lysosomal biogenesis and autophagy of foam cells through AMPK-FoxO1-TFEB signalling axis may be a novel therapeutic target of atherosclerosis.
Asunto(s)
Aterosclerosis/prevención & control , Autofagia , Alcoholes Bencílicos/farmacología , Células Espumosas/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glucósidos/farmacología , Lisosomas/efectos de los fármacos , Macrófagos/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Células Espumosas/metabolismo , Células Espumosas/patología , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Lisosomas/metabolismo , Lisosomas/patología , Macrófagos/metabolismo , Macrófagos/patología , RatonesRESUMEN
BACKGROUND: It is extremely difficult to develop targeted treatments for triple-negative breast (TNB) cancer, because these cells do not express any of the key biomarkers usually exploited for this goal. RESULTS: In this work, we develop a solution in the form of a cascade responsive nanoplatform based on thermo-sensitive poly(N-vinylcaprolactam) (PNVCL)-chitosan (CS) nanoparticles (NPs). These are further modified with the cell penetrating peptide (CPP) and loaded with the chemotherapeutic drug doxorubicin (DOX). The base copolymer was optimized to undergo a phase change at the elevated temperatures of the tumor microenvironment. The acid-responsive properties of CS provide a second trigger for drug release, and the inclusion of CPP should ensure the formulations accumulate in cancerous tissue. The resultant CPP-CS-co-PNVCL NPs could self-assemble in aqueous media into spherical NPs of size < 200 nm and with low polydispersity. They are able to accommodate a high DOX loading (14.8% w/w). The NPs are found to be selectively taken up by cancerous cells both in vitro and in vivo, and result in less off-target cytotoxicity than treatment with DOX alone. In vivo experiments employing a TNB xenograft mouse model demonstrated a significant reduction in tumor volume and prolonging of life span, with no obvious systemic toxicity. CONCLUSIONS: The system developed in this work has the potential to provide new therapies for hard-to-treat cancers.
Asunto(s)
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Quitosano/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Línea Celular , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos/efectos de los fármacos , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7 , Ratones , Nanopartículas/química , Ratas , Ratas Wistar , Microambiente Tumoral/efectos de los fármacosRESUMEN
Alzheimer's disease (AD) is a chronic neurodegenerative disorder which can contribute to memory loss and cognitive damage in the elderly; moreover, evidence from clinical and animal studies demonstrated that AD always exhibit severe cognitive deficits. However, the effects of donepezil medications on cognition are controversial. Additionally, it is unclear whether donepezil can protect neurons to improve cognitive function through the brain-derived neurotropic factor (BDNF)/tyrosine receptor kinase B (TrkB) signalling pathway in the tree shrew (TS), which has a closer evolutionary relationship to primates than rodents. Here, we designed a study on an amyloid-ß1-40 (Aß1-40)-induced TS model of AD and investigated the molecular mechanism by which donepezil protects neurons and improves cognitive function through activating the BDNF/TrkB signalling pathway. The results showed that donepezil could rescue Aß1-40-induced spatial cognition deficits, and reverse Aß1-40-induced temporal horn along with ADC enlargement in the TS brain. Meanwhile, it suppressed Aß1-40-induced neuronal damage and loss of body weight. Intriguingly, donepezil could increase the choline acetyl transferase (ChAT) expression level and reduce the fibrillary acid protein (GFAP) expression level in the hippocampus and cortex of TS. Additionally, donepezil significantly upregulated the expression level of BDNF, as well as the phosphorylated level of TrkB. These results suggested that donepezil could protect neurocytes from senility and ameliorate learning and memory impairment in the TS model of AD, which appeared to be through regulating the cholinergic system and inhibiting the BDNF/TrkB-dependent signalling pathway. Moreover, the study underlines the potency of TS to be a novel animal model for research on AD, and it deserves intensive attention.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/toxicidad , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Donepezilo/uso terapéutico , Fragmentos de Péptidos/toxicidad , Receptor trkB/metabolismo , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Donepezilo/farmacología , Masculino , Nootrópicos/farmacología , Nootrópicos/uso terapéutico , Distribución Aleatoria , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , TupaiidaeRESUMEN
Clinical use of small-diameter vascular grafts remains a challenging issue in neovessel regeneration in view of thrombosis and intimal hyperplasia. Developing a vascular graft with structure and function similar to those of the native vessels necessitates a major direction of vascular tissue regeneration. Thus, this study sought to design and fabricate a range of tri-phasic scaffolds (0, 2, and 5 wt% gastrodin-polyurethane (PU)) with spatiotemporally defined structure and gastrodin-release for regulating the highly coordinated processes in growth of the intima and media. While the small pores of inner layer guided infiltration of human umbilical vein endothelial cells (HUVECs), the bigger pores of medial layer could offer smooth muscle cell (SMC)-friendly habitat, and external fibers conferred adequate mechanical properties. Correspondingly, spatial distribution and differential regulation of key proteins in HUVECs and SMCs were mediated by hierarchical release of gastrodin, of which rapid release in inner layer elicited enhanced HUVEC proliferation and migration against those of the SMC via activated endothelial nitric oxide synthase (eNOS) and heat shock protein 70 (HSP70) signal. Of note, superior anti-coagulation was reflected in 2 wt% gastrodin-PU ex vivo extracorporeal blood circulation experiment. After in vivo implantation for 12 weeks, there was no formation of obvious thrombosis and intimal hyperplasia in 2 wt% gastrodin-PU. The scaffold maintained high patency and improved vascular remodeling, including the formation of thin endothelialization in lumen and dense extracellular matrix deposition in medial layer. Taken together, the results demonstrate the positive function of hierarchical releasing system that responded to tri-phasic structure, which not only suppressed intimal thickening but also tightly controlled tissue regeneration.
RESUMEN
In order to facilitate the observation in the process of secondary equipment operation and maintenance supervision and the detection and tracking of operation and maintenance personnel, a secondary operation and maintenance supervision system based on AR modeling and indoor positioning is designed. The whole system is divided into seven levels and a unified information base, in which the basic level contains all kinds of secondary equipment; AR modeling layer uses augmented reality technology to create models for each secondary equipment in the basic layer, and determines the equipment position information based on ranging positioning technology; The data acquisition layer collects all kinds of original management data based on the constructed secondary equipment model; The data analysis layer reads and analyzes the information of the data acquisition layer through the data bus; The process support layer provides task scheduling support for the integrated management application based on the data analysis results; The integrated application layer uniformly monitors the secondary equipment based on the task scheduling results; The presentation layer is responsible for the interface presentation of all operation and maintenance and security management information of the system, and the unified information base provides data support for the whole system. The experimental results show that the secondary equipment model in the designed system has high definition, can obtain more image details, can realize the 3D display and real-time interaction of the secondary equipment operation and maintenance supervision results, and accurately mark the target and track for the staff.
Asunto(s)
Realidad Aumentada , Cirugía Asistida por Computador , Humanos , Cirugía Asistida por Computador/métodos , TecnologíaRESUMEN
Wound healing is a highly orchestrated process involving a variety of cells, including immune cells. Developing immunomodulatory biomaterials for regenerative engineering applications, such as bone regeneration, is an appealing strategy. Herein, inspired by the immunomodulatory effects of gastrodin (a bioactive component in traditional Chinese herbal medicine), a series of new immunomodulatory gastrodin-comprising biodegradable polyurethane (gastrodin-PU) and nano-hydroxyapatite (n-HA) (gastrodin-PU/n-HA) composites were developed. RAW 264.7 macrophages, rat bone marrow mesenchymal stem cells (rBMSCs), and human umbilical vein endothelial cells (HUVECs) were cultured with gastrodin-PU/n-HA containing different concentrations of gastrodin (0.5%, 1%, and 2%) to decipher their immunomodulatory effects on osteogenesis and angiogenesis in vitro. Results demonstrated that, compared with PU/n-HA, gastrodin-PU/n-HA induced macrophage polarization toward the M2 phenotype, as evidenced by the higher expression level of pro-regenerative cytokines (CD206, Arg-1) and the lower expression of pro-inflammatory cytokines (iNOS). The expression levels of osteogenesis-related factors (BMP-2 and ALP) in the rBMSCs and angiogenesis-related factors (VEGF and BFGF) in the HUVECs were significantly up-regulated in gastrodin-PU/n-HA/macrophage-conditioned medium. The immunomodulatory effects of gastrodin-PU/n-HA to reprogram macrophages from a pro-inflammatory (M1) phenotype to an anti-inflammatory and pro-healing (M2) phenotype were validated in a rat subcutaneous implantation model. And the 2% gastrodin-PU/n-HA significantly decreased fibrous capsule formation and enhanced angiogenesis. Additionally, 2% gastrodin-PU/n-HA scaffolds implanted in the rat femoral condyle defect model showed accelerated osteogenesis and angiogenesis. Thus, the novel gastrodin-PU/n-HA scaffold may represent a new and promising immunomodulatory biomaterial for bone repair and regeneration.
RESUMEN
Myocardial ischemia/reperfusion (I/R) injury after percutaneous coronary intervention (PCI) is common in acute myocardial infarction. Aspirin is commonly prescribed as anti-thrombotic therapy with coronary heart disease (CHD). However, long-term use of aspirin causes severe gastric mucosal damage. Gastrodin is a Chinese natural medicine with anti-inflammatory and anti-oxidative properties. In this study, we investigated the effects of combined therapy with aspirin and gastrodin on the myocardial and gastric mucosal injury in response to myocardial I/R injury and underlying mechanisms using the Sprague-Dawley (SD) rat model. Our results demonstrated that myocardial I/R caused significant cardiac dysfunction and gastric mucosal damage. Administration of aspirin led to significantly reduce myocardial infarction size and myocardial enzyme release, as well as significantly improved cardiac function through exerting anti-inflammatory effects. However, aspirin exacerbated gastric mucosal damage by increasing the levels of inflammatory mediators and endothelin (ET) while reducing prostaglandin E2 (PGE2) levels. The combined treatment with aspirin and gastrodin not only significantly protected gastric mucosa by normalizing the expression levels of the inflammatory factors, ET and PGE2, but also significantly reduced myocardial infarction size and improved cardiac function by inhibiting inflammation in response to I/R. The combination therapy also dramatically down-regulated the levels of pyroptosis-related proteins in the myocardium and gastric mucosa. The combination therapy showed obviously reduced level of thromboxane B2 (TXB2), which was simultaneously accompanied with increased levels of the tissue plasminogen activator (t-PA). This suggested that gastrodin did not inhibit the anti-thrombotic function of aspirin. Accordingly, aspirin in combination with gasrtodin protected the structural and functional integrity of the heart and stomach by suppressing pyroptosis and inflammation. Therefore, combination of aspirin and gastrodin is a promising treatment for cardiac dysfunction and gastric mucosa injury after myocardial I/R.
RESUMEN
Osteoporosis is a systemic bone disease characterized by reduced bone mass and destruction of bone microarchitecture, leading to increased bone fragility and susceptibility to fracture. However, the pathogenesis and molecular mechanisms of this disease remain unclear. Extracellular vesicles, structures originating from the plasma membrane and ranging from 30 nm to 5 µm in diameter, play an important role in intercellular communication in the bone microenvironment. Exosomes are extracellular vesicles that deliver cargo molecules, including endogenous proteins, lipids and nucleic acids. These cargo molecules are encapsulated in a lipid bilayer and internalized by target cells through receptor-ligand interactions or lipid membrane fusion. With the advancement of exosome research, exosome therapy for osteoporosis is fast becoming a research hotspot for researchers. This review aims to discuss the role of exosomes in the pathogenesis of osteoporosis. In addition, emerging diagnostic and therapeutic properties of exosomes are described to highlight the potential role of exosomes in osteoporosis.
Asunto(s)
Exosomas , Vesículas Extracelulares , Osteoporosis , Humanos , Exosomas/metabolismo , Huesos , Comunicación Celular , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismoRESUMEN
Alzheimer's disease (AD) is a chronic neurodegenerative disorder that can cause cognitive impairment. Ginsenoside Rg1 (Rg1) has a significant neuroprotective effect on animals with memory impairment. However, the mechanism of how Rg1 mediates the Wnt signaling pathway and improves cognitive function by regulating oxidative stress, apoptosis, and neuroinflammation is still unclear. In this study, the spatial memory ability of tree shrews was tested by Morris water maze, the expression levels of amyloid protein (Aß1-42), ionized calcium-binding adapter molecule 1 (iba-1), nitrotyrosine (NT), and 8-hydroxyguanine (8-OHG) were detected by immunohistochemistry. Subsequently, the activity of catalase (CAT) and the glutathione peroxidase (GSH-Px) was, respectively, measured by the ammonium molybdate method and the 5,5'-dithiobis (2-nitrobenzoic acid). Furthermore, the malondialdehyde (MDA) concentration was determined by the thiobarbituric acid test. Finally, the expression levels of Beta-secretase (BACE1), superoxide dismutase (SOD), BCL2-Associated X (Bax), B-cell lymphoma-2 (Bcl-2), caspase-anti-apoptotic factor Cleaved-caspase-3 (Caspase-3), microtubule-associated proteins 2 (MAP2), Neuronal nuclear antigen (NeuN), as well as the phosphorylation of GSK-3ß and ß-catenin were detected by Western blot. This study implied that Rg1 reduced the phosphorylation of Tau protein, the deposition of Aß1-42, and the expression of BACE1. It also showed that Rg1 increased the antioxidant activity of SOD, CAT, GPx, and instead reduced the oxidation products of NT, 8-OHG, and MDA, as wells as the inflammatory factor interleukin-1 and iba-1. It further showed that Rg1 increased the ratio of Bcl-2 to Bax and expression of neuronal markers MAP2 and NeuN, but instead reduced the expression of Caspase-3, GSK-3ß, and ß-catenin. In conclusion, by regulating the Wnt/GSK-3ß/ß-catenin signaling pathway, Rg1 of moderate and high dose could alleviate oxidative stress damage, improve neuroinflammation, protect neurons, finally improve the cognitive impairment of the AD tree shrew. This study provides theoretical basis for the Rg1 clinical application in AD.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Apoptosis , Ácido Aspártico Endopeptidasas/metabolismo , Caspasa 3/metabolismo , Ginsenósidos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Enfermedades Neuroinflamatorias , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Superóxido Dismutasa/metabolismo , Vía de Señalización Wnt , Proteína X Asociada a bcl-2/metabolismo , beta Catenina/metabolismoRESUMEN
Existing tissue adhesives and sealants are far from satisfactory when applied on wet and dynamic tissues. Herein, we report a strategy for designing biodegradable super-strong aqueous glue (B-Seal) for surgical uses inspired by an English ivy adhesion strategy and a cement particle packing theory. B-Seal is a fast-gelling, super-strong, and elastic adhesive sealant composed of injectable water-borne biodegradable polyurethane (WPU) nanodispersions with mismatched particle sizes and counterions in its A-B formulation. B-Seal showed 24-fold greater burst pressure than DuraSeal®, 138-fold greater T-pull adhesive strength than fibrin glue, and 16-fold greater lap shear strength than fibrin glue. In vivo evaluation on a rat cerebrospinal fluid (CSF) rhinorrhea model and a porcine craniotomy model validated the safety and efficacy of B-Seal for effective CSF leak prevention and dura repair. The plant-inspired adhesion strategy combined with particle packing theory represents a new direction of designing the next-generation wet tissue adhesives for surgeries.
RESUMEN
Ginsenoside Rg1 (Rg1) is traditional Chinese medicine with neuroprotective activity. Previous studies have demonstrated that Rg1 improves Alzheimer's disease (AD) and alters gut microbiology, but its mechanism remains to be elucidated, and thus far, its use in the treatment of AD has not been satisfactory. The present study investigated the improvement effects of Rg1 and its association with the microbiota of the large intestine. Following treatment with Rg1 in AD tree shrews, the treatment group demonstrated significantly shorter escape latency and crossed a platform more frequently in a water maze test. Western blotting demonstrated that Rg1 inhibited the expression of ß-secretase 1, while increasing microtubule-associated protein 2 and Fox-3 in the hippocampus. Immunohistochemical analysis revealed that Rg1 decreased the expression of amyloid ß, tau phosphorylated at serine 404 and pro-apoptotic factor Bax, while increasing the expression of Bcl-2 in the hippocampus and cortex. High throughput sequencing of 16S rRNA demonstrated that Rg1 altered the microbiota abundance of the large intestine. In conclusion, Rg1 affected the expression of apoptosis proteins, possessed a neuroprotective effect and may have a close association with the microbiota of large intestine by significantly reducing the abundance of Bacteroidetes and increasing the energy requirement of tree shrews.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Microbioma Gastrointestinal/efectos de los fármacos , Ginsenósidos/farmacología , Intestino Grueso/efectos de los fármacos , Enfermedad de Alzheimer/microbiología , Enfermedad de Alzheimer/psicología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Antígenos Nucleares/metabolismo , Intestino Grueso/microbiología , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Fármacos Neuroprotectores/farmacología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Tupaiidae , Proteína X Asociada a bcl-2/metabolismo , Proteínas tau/metabolismoRESUMEN
Ginsenoside Rg1 (GRg1) has neuroprotective effects on Alzheimer's disease (AD). The occurrence and progression of AD are closely related to gut microbiota. Few studies have learned the direct relationship between GRg1 and gut microbiota. In this study, we found an original way to research this relationship by using GRg1 in the AD model of tree shrews. Morris water maze and immunohistochemistry were performed to test the cognition repairing function of GRg1 by tree shrews and 16S ribosomal RNA sequencing was used to explore the composition and abundance of gut microbiota. After GRg1 treatment, the result of Morris water maze showed an improvement in cognitive function, and immunohistochemistry revealed a decrease in tau protein. Moreover, 16SrRNA sequencing results showed the abundances of Proteobacteria and Verrucomicrobia were significantly different, and Lactobacillaceae was significantly increased in the GRg1 treatment group. It also showed that the gut microbiome with middle and high doses of GRg1 was close to the normal group. In conclusion, this study suggests that GRg1 at middle and high doses may change the abundance of gut microbiota to improve AD, and thatProteobacteria and Verrucomicrobia are key microbiota. This is the first report that has ever studied the relationship between GRg1 and gut microbiota in tree shrews.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Ginsenósidos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/microbiología , Enfermedad de Alzheimer/fisiopatología , Animales , Bacterias/clasificación , Bacterias/efectos de los fármacos , Bacterias/genética , Bacterias/aislamiento & purificación , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Ginsenósidos/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Tupaiidae , Proteínas tau/metabolismoRESUMEN
Outbreaks of avian influenza virus continue to pose threats to human health. Animal models such as the mouse, ferret, and macaque are used to understand the pathogenesis of avian influenza virus infection in humans. We previously reported that the tree shrew (Tupaia belangeri, family Tupaiidae), which is regarded as a "low-level primate", has α2,3- and α2,6-linked sialic acid receptor distributions similar to those of humans and is potentially a useful mammalian model for studying mild human influenza (H1N1) virus infection. In this study, we used the tree shrew experimental model to investigate the pathogenesis of avian influenza A (H9N2) virus infection and the effect of the E627K mutation in the PB2 gene, an adaptation to mammalian hosts. Evidence of disease, virus titers in the upper and lower respiratory tract, histopathology and induction of proinflammatory cytokines are described. We also established ex vivo culture models of tree shrew respiratory tissues to study the tropism and replication of the H9N2 virus. Our results demonstrated that the tree shrew is a viable new in vivo experimental model for avian influenza research that provides results comparable to those observed in ferrets. The disease spectrum and pathogenesis in tree shrews correlate well with what is observed in humans.
Asunto(s)
Modelos Animales de Enfermedad , Subtipo H9N2 del Virus de la Influenza A/fisiología , Gripe Humana/virología , Tupaiidae , Animales , Citocinas/genética , Citocinas/inmunología , Femenino , Hurones , Humanos , Subtipo H9N2 del Virus de la Influenza A/genética , Gripe Humana/genética , Gripe Humana/inmunología , Gripe Humana/patología , Masculino , Tupaiidae/virología , Tropismo Viral , Replicación ViralRESUMEN
Tree shrew has increasingly become an attractive experimental animal model for human diseases, particularly for breast cancer due to spontaneous breast tumours and their close relationship to primates and by extension to humans. However, neither normal mammary glands nor breast tumours have been well characterised in the Chinese tree shrew (Tupaia belangeri chinensis). In this study, normal mammary glands from four different developmental stages and 18 spontaneous breast tumours were analysed. Haematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) showed that normal mammary gland morphology and structures of tree shrews were quite similar to those found in humans. Spontaneous breast tumours of tree shrews were identified as being intraductal papilloma, papillary carcinoma, and invasive ductal carcinoma with or without lung metastasis. To further analyse breast cancer tumours among tree shrews, 40 3-4 month-old female tree shrews were orally administrated 20 mg 7,12-dimethylbenz(a)anthracene (DMBA) or peanut oil thrice, and then, 15 of these DMBA administrated tree shrews were implanted with medroxyprogesterone acetate (MPA) pellets. DMBA was shown to induce breast tumours (12%) while the addition of MPA increased the tumour incidence (50%). Of these, three induced breast tumours were intraductal papillary carcinomas and one was invasive ductal carcinoma (IDC). The PTEN/PIK3CA (phosphatase and tensin homologue/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), but not TP53 and GATA3, genes are frequently mutated in breast tumours, and the PTEN/PIK3CA gene mutation status correlated with the expression of pAKT in tree shrew breast tumours. These results suggest that tree shrews may be a promising animal model for a subset of human breast cancers with PTEN/PIK3CA gene mutations.
Asunto(s)
Modelos Animales de Enfermedad , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Experimentales/genética , Mutación/genética , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasa/genética , 9,10-Dimetil-1,2-benzantraceno , Animales , Carcinógenos , Carcinoma Ductal de Mama/genética , Carcinoma Papilar/genética , Estrógenos/metabolismo , Femenino , Glándulas Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/inducido químicamente , Neoplasias Mamarias Experimentales/inducido químicamente , Acetato de Medroxiprogesterona , Papiloma Intraductal/genética , Progesterona/metabolismo , Distribución Aleatoria , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , TupaiidaeRESUMEN
Anatomical parameter values in tree shrews are major biological characteristic indicators in laboratory animals. Body size, bones and mammilla, organ weights, coefficient intestinal canal and other anatomical data were measured and analyzed in laboratory domesticated tree shrews (7 to 9 months of age). Measurement of 31 anatomical parameters showed that body height, width of the right ear, ileum and colon had significant differences between males and females (P<0.05). Highly significant differences were also found in body slanting length, chest depth, torso length, left and right forelimb length, right hind limb length, left and right ear length, left ear width, keel bone length, left and right tibia length, duodenum and jejunum (P<0.01). With body length as the dependent variable, and tail length, torso length, right and left forelimb length, and left and right hind limb length as independent variables for stepwise regression analysis, the regression equation for body length = 13.90 + tail length × 0.16. The results of 37 organs weights between female and male tree shrews showed very significant differences (P<0.01) for weight of heart, lungs, spleen, left and right kidney, bladder, left and right hippocampus, left submandibular gland, and left and right thyroid gland, as well as significant (P<0.05) differences in the small intestine, right submandibular gland, and left adrenal gland. The coefficient of heart, lung, stomach, bladder, small and large intestine, brain, right hippocampus, and left adrenal gland showed highly significant differences (P<0.01), while differences in the right kidney, left hippocampus, left submandibular gland, right adrenal gland, and left and right thyroid gland were significant (P<0.05). With animal weight as the dependent variable and indicators of heart, lung, liver, spleen, left and right kidney and brain as independent variables for stepwise regression analysis, the regression equation showed that weight = 62.73 + left kidney × 79.21 + heart × 24.09. Female and male laboratory domesticated tree shrews showed certain influences in body size, organ weight and coefficient, and intestinal canal regarding anatomical parameters. This experiment provides basic data for studies on laboratory tree shrews and animal models.
Asunto(s)
Tupaiidae/anatomía & histología , Tupaiidae/crecimiento & desarrollo , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Tamaño de los ÓrganosRESUMEN
Breast cancer is a common malignant tumor. It is essential to develop suitable animal models for discovering novel preventive and therapeutic approaches. Tree shrews (Tupaia belangeri chinensis) have a closer evolutionary relationship with humans than do rodents, which have been widely used in laboratory research. Spontaneous breast tumors were identified in tree shrews in 1960s; however, no detailed studies about tree shrew breast tumors have been conducted to date. Here, we characterized a spontaneous breast tumor from tree shrews by Haematoxylin Eosin (H&E) staining. This tumor was identified as a papillary tumor. Immunohistochemical staining (IHC) for progesterone receptor (PR), Ki-67 and cleaved caspase-3 showed that tumor cells were positive for PR, highly proliferative, and less apoptotic compared to normal breast epithelial cells. Thus, the spontaneous tumor of tree shrew is very close to human papillary tumors in terms of morphology and pathology and we concluded that tree shrew may be a suitable animal model for breast cancer research.
Asunto(s)
Neoplasias de la Mama/patología , Neoplasias de la Mama/veterinaria , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/patología , Tupaia/metabolismo , Animales , Apoptosis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/fisiopatología , Caspasa 3/metabolismo , Proliferación Celular , Femenino , Humanos , Antígeno Ki-67/metabolismo , Glándulas Mamarias Animales/citología , Glándulas Mamarias Animales/metabolismo , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/fisiopatologíaRESUMEN
We outline the historical research on the laboratory tree shrew in China and discuss its current research trends. Five key aspects of applied research are emphasized in this review, including quality control standards for laboratory tree shrews, the establishment of an inbred colony, commercial preparation of major molecular and cellular research tools, further research on tree shrew models for human diseases, and the establishment of the tree shrew seed institution at state level.