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Distal biaxial atropisomers are typical structures in chiral catalysts and ligands and offer a wide variety of applications in biology and materials technology, but the development of efficient synthesis of these valuable scaffolds is still in great demand. Herein, we describe a highly efficient iridium catalyzed asymmetric C-H alkylation reaction that provides a range of new distal biaxial atropisomers with excellent yields (up to 99%) and stereoselectivity (up to 99% ee and essentially one isomer). Based on this unprecedented strategy, a polycyclic skeleton with five successive chiral centers as well as C-C and C-N (or N-N) two distal chiral axes was created successfully in mild circumstances. In addition, the optically pure products bearing fluorophores show circular polarized luminescence (CPL) properties, being potential candidate materials for CPL applications.
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Composite cranial defects have individual functional and aesthetic ramifications, as well as societal burden, while posing significant challenges for reconstructive surgeons. Single-stage composite reconstruction of these deformities entail complex surgeries that bear many short- and long-term risks and complications. Current research on composite scalp-cranial defects is sparse and one-dimensional, often focusing solely on bone or skin. Thus, there is an unmet need for a simple, clinically relevant composite defect model in rodents, where there is a challenge in averting healing of the skin component via secondary intention. By utilizing a customizable (3D-printed) wound obturator, the scalp wound can be rendered non-healing for a long period (more than 6 weeks), with the cranial defect patent. The wound obturator shows minimal biotoxicity and will not cause severe endocranium-granulation adhesion. This composite defect model effectively slowed the scalp healing process and preserved the cranial defect, embodying the characteristics of a "chronic composite defect". In parallel, an autologous reconstruction model was established as the positive control. This positive control exhibited reproducible healing of the skin within 3 weeks with variable degrees of osseointegration, consistent with clinical practice. Both models provide a stable platform for subsequent research not only for composite tissue engineering and scaffold design but also for mechanistic studies of composite tissue healing.
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Approaches to regenerating bone often rely on integrating biomaterials and biological signals in the form of cells or cytokines. However, from a translational point of view, these approaches are challenging due to the sourcing and quality of the biologic, unpredictable immune responses, complex regulatory paths, and high costs. We describe a simple manufacturing process and a material-centric 3D-printed composite scaffold system (CSS) that offers distinct advantages for clinical translation. The CSS comprises a 3D-printed porous polydiolcitrate-hydroxyapatite composite elastomer infused with a polydiolcitrate-graphene oxide hydrogel composite. Using a micro-continuous liquid interface production 3D printer, we fabricate a precise porous ceramic scaffold with 60 wt% hydroxyapatite resembling natural bone. The resulting scaffold integrates with a thermoresponsive hydrogel composite in situ to fit the defect, which is expected to enhance surface contact with surrounding tissue and facilitate biointegration. The antioxidative properties of citrate polymers prevent long-term inflammatory responses. The CSS stimulates osteogenesis in vitro and in vivo. Within 4 weeks in a calvarial critical-sized bone defect model, the CSS accelerated ECM deposition (8-fold) and mineralized osteoid (69-fold) compared to the untreated. Through spatial transcriptomics, we demonstrated the comprehensive biological processes of CSS for prompt osseointegration. Our material-centric approach delivers impressive osteogenic properties and streamlined manufacturing advantages, potentially expediting clinical application for bone reconstruction surgeries.
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Recombinant adenovirus (rAdV) is a commonly used vector system for gene transfer. Efficient initial packaging and subsequent production of rAdV remains time-consuming and labor-intensive, possibly attributable to rAdV infection-associated oxidative stress and reactive oxygen species (ROS) production. Here, we show that exogenous GAPDH expression mitigates adenovirus-induced ROS-associated apoptosis in HEK293 cells, and expedites adenovirus production. By stably overexpressing GAPDH in HEK293 (293G) and 293pTP (293GP) cells, respectively, we demonstrated that rAdV-induced ROS production and cell apoptosis were significantly suppressed in 293G and 293GP cells. Transfection of 293G cells with adenoviral plasmid pAd-G2Luc yielded much higher titers of Ad-G2Luc at day 7 than that in HEK293 cells. Similarly, Ad-G2Luc was amplified more efficiently in 293G than in HEK293 cells. We further showed that transfection of 293GP cells with pAd-G2Luc produced much higher titers of Ad-G2Luc at day 5 than that of 293pTP cells. 293GP cells amplified the Ad-G2Luc much more efficiently than 293pTP cells, indicating that exogenous GAPDH can further augment pTP-enhanced adenovirus production. These results demonstrate that exogenous GAPDH can effectively suppress adenovirus-induced ROS and thus accelerate adenovirus production. Therefore, the engineered 293GP cells represent a superfast rAdV production system for adenovirus-based gene transfer and gene therapy.
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BACKGROUND: Emerging evidence suggested that S-adenosylhomocysteine (SAH) may be a better serum biomarker for cardiovascular disease than homocysteine (Hcy). However, the role of SAH in hepatocellular carcinoma (HCC) prognosis remains unclear. OBJECTIVES: We aimed to prospectively explore the relationships between serum SAH and related metabolites [Hcy, S-adenosylmethionine (SAM)] with HCC survival, and to evaluate the effect modifications by gene polymorphisms in one-carbon metabolism key enzymes. METHODS: We included 1080 newly diagnosed patients with HCC from the Guangdong Liver Cancer Cohort. Serum SAH, Hcy, and SAM were measured utilizing high-performance liquid chromatography-tandem mass spectrometry. Gene polymorphisms in one-carbon metabolism key enzymes were identified using kompetitive allele-specific polymerase chain reaction. Primary outcomes were liver cancer-specific survival (LCSS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariate Cox proportional hazards models. RESULTS: After a median follow-up of 3.6 y, 601 deaths occurred, with 552 (92%) attributed to HCC. Multivariable analysis revealed that patients in the highest quartile of serum SAH concentrations were significantly associated with worse survival compared with those in the lowest quartile, with HRs of 1.58 (95% CI: 1.19, 2.10; P-trend = 0.002) for LCSS and 1.54 (95% CI: 1.18, 2.02; P-trend = 0.001) for OS. There were no significant interactions between serum SAH concentrations and genetic variants of one-carbon metabolism key enzymes. No significant associations were found between serum Hcy, SAM concentrations, and SAM/SAH ratio with LCSS or OS. CONCLUSIONS: Higher serum SAH concentrations, rather than Hcy, were independently associated with worse survival in patients with HCC, regardless of the genetic variants of one-carbon metabolism key enzymes. These findings suggest that SAH may be a novel metabolism-related prognostic biomarker for HCC.
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BACKGROUND: Poly L-lactic acid (PLLA) can stimulate fibrous tissue regeneration to exert a filling effect. However, severe inflammatory reactions and unsatisfactory effects remain a concern. OBJECTIVE: Herein, we describe the mechanism of action, efficacy, and safety of PLLA microspheres in suspension (PLLA-b-PEG/HA) for facial contouring and soft tissue augmentation. METHODS: PLLA-b-PEG/HA, ssynthesized by copolymerization with ethylene glycol, were suspended in hyaluronic acid (HA). Physiological verification was performed using scanning electron microscopy and X-ray computed tomography. PLLA-b-PEG/HA were subcutaneously injected into the dorsal region of 4-month-old rabbits. Ultrasound assessed volumetric capacity at 3 days and 1, 2, 4, and 12 weeks. The inflammatory response, collagen production, and HA degradation were evaluated. A retrospective case series of 10 patients who received PLLA-b-PEG/HA injections was conducted to assess long-term efficacy and safety. RESULTS: PLLA-b-PEG exhibited a spherical structure with a smooth surface (20-45 µm diameter). In rabbits, implant site volume increased within 4 weeks, gradually decreasing thereafter. Fibrous capsules, microvessel density, and new collagen fiber formation progressively increased at 4, 12, and 26 weeks after injection. Clinical data demonstrated significant improvements in face contouring at months 3 and 12 after injection. All patients showed improved internal contours based on the Global Aesthetic Improvement Scale. After 12 months, 90% of the patients retained good shaping and support effects with minimal adverse reactions. CONCLUSIONS: PLLA-b-PEG/HA demonstrated superior biocompatibility and facial regeneration potential, with outstanding dual collagen-stimulating properties. The clinical efficacy and safety of PLLA-b-PEG/HA have been validated and established as a promising therapeutic option.
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To achieve high maize (Zea mays L.) yields and quality grain, it is necessary to develop stress-resistant cultivars and related cultivation practices, aiming to maximize efficiency. Thus, our objectives were (i) to investigate the impact of tillage practices and maize hybrids (which have improved over time) on yield and its components, and (ii) to characterize the response pattern of maize hybrid grain nutrient quality components to subsoiling. To achieve this, we conducted field trials with five maize hybrids from different eras under two tillage practices: rotary tillage and subsoiling. We compared grain yield, nutritional quality, and other indicators across different tillage conditions from the 1970s to the 2010s. The main results of this study are as follows: under rotary tillage conditions, the 2010s hybrid (DH618) significantly increased yields (9.37-55.89%) compared to hybrids from the 1970s-2000s. After subsoiling, the physiologically mature grains of all hybrids exhibited minimal changes in crude protein and fat content, while there was a significant reduction in the total soluble sugar content of the grains. After subsoiling, there was a substantial 8.14 to 12.79 percent increase in total starch accumulation in the grain for all hybrids during the period of 47-75 days post-anthesis. Furthermore, during the period of 47-75 days after anthesis, the consumption of grain crude protein significantly contributed to the accumulation of total starch in the grains. Ultimately, subsoiling significantly increased the yield of each hybrid and enhanced the total grain starch content at physiological maturity of all hybrids, with the 2010s hybrid (DH618) performing exceptionally well.
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To counteract the increasing severity of water pollution and purify water sources, wastewater treatment materials are essential. In particular, it is necessary to improve the bonding strength between the adsorption material and the substrate in a long-term humid environment, and resist the invasion of microorganisms to prolong the service life. In this study, an amyloid-like aggregation method of lysozyme catalyzed by microbial transglutaminase (mTGase). Lysozyme self-assembles into an amyloid-like phase-transited lysozyme (PTL) in the presence of a reducing agent. Simultaneously, mTGase catalyzes acyl transfer reactions within lysozyme molecules or between lysozyme and keratin molecules, and driving PTL assembly on the wool fiber (TG-PTL@wool). This process enhances the grafting amount and fastness of PTL on the wool. Moreover, the tensile strength of wool fabric increased to 523 N. TG-PTL@wool achieves a 97.32 % removal rate of heavy metals, maintaining a removal rate of over 95 % after 5 cycles. TG-PTL@wool has excellent antibacterial property (99 %), and it remains above 90 % after 50 times of circulating washing. This study proved that mTGase can enhance the amyloid aggregation of lysozyme and enhance the bonding strength between PTL coating and substrate. Moreover, TG-PTL@wool provides a sustainable, efficient and cleaner solution for removing heavy metals from water.
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Metales Pesados , Muramidasa , Aguas Residuales , Metales Pesados/química , Aguas Residuales/química , Animales , Muramidasa/química , Muramidasa/aislamiento & purificación , Muramidasa/metabolismo , Transglutaminasas/química , Transglutaminasas/metabolismo , Transglutaminasas/aislamiento & purificación , Lana/química , Purificación del Agua/métodos , Contaminantes Químicos del Agua/aislamiento & purificación , Contaminantes Químicos del Agua/química , Adsorción , Proteínas Amiloidogénicas/química , Proteínas Amiloidogénicas/aislamiento & purificación , Proteínas Amiloidogénicas/metabolismo , Fibra de Lana , Agregado de Proteínas , Amiloide/químicaRESUMEN
Periodontitis is an immune-inflammatory disease caused by dental plaque, and deteriorates the periodontal ligament, causes alveolar bone loss, and may lead to tooth loss. To treat periodontitis, antibacterial and anti-inflammation approaches are required to reduce bone loss. Thus, appropriate drug administration methods are significant. Due to their "syringeability", biocompatibility, and convenience, injectable hydrogels and associated methods have been extensively studied and used for periodontitis therapy. Such hydrogels are made from natural and synthetic polymer materials using physical and/or chemical cross-linking approaches. Interestingly, some injectable hydrogels are stimuli-responsive hydrogels, which respond to the local microenvironment and form hydrogels that release drugs. Therefore, as injectable hydrogels are different and highly varied, we systematically reviewed the periodontal treatment field from three perspectives: raw material sources, cross-linking methods, and stimuli-responsive methods. We then discussed current challenges and opportunities for the translation of hydrogels to clinic, which may guide further injectable hydrogel designs for periodontitis.
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Hidrogeles , Periodontitis , Periodontitis/tratamiento farmacológico , Hidrogeles/química , Humanos , Animales , Inyecciones , Antibacterianos/química , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacologíaRESUMEN
Chondrocyte hypertrophy and the expression of its specific marker, the collagen type X gene (COL10A1), constitute key terminal differentiation stages during endochondral ossification in long bone development. Mutations in the COL10A1 gene are known to cause schmid type metaphyseal chondrodysplasia (SMCD) and spondyloepiphyseal dyschondrodysplasia (SMD). Moreover, abnormal COL10A1 expression and aberrant chondrocyte hypertrophy are strongly correlated with skeletal diseases, notably osteoarthritis (OA) and osteosarcoma (OS). Throughout the progression of OA, articular chondrocytes undergo substantial changes in gene expression and phenotype, including a transition to a hypertrophic-like state characterized by the expression of collagen type X, matrix metalloproteinase-13, and alkaline phosphatase. This state is similar to the process of endochondral ossification during cartilage development. OS, the most common pediatric bone cancer, exhibits characteristics of abnormal bone formation alongside the presence of tumor tissue containing cartilaginous components. This observation suggests a potential role for chondrogenesis in the development of OS. A deeper understanding of the shifts in collagen X expression and chondrocyte hypertrophy phenotypes in OA or OS may offer novel insights into their pathogenesis, thereby paving the way for potential therapeutic interventions. This review systematically summarizes the findings from multiple OA models (e.g., transgenic, surgically-induced, mechanically-loaded, and chemically-induced OA models), with a particular focus on their chondrogenic and/or hypertrophic phenotypes and possible signaling pathways. The OS phenotypes and pathogenesis in relation to chondrogenesis, collagen X expression, chondrocyte (hypertrophic) differentiation, and their regulatory mechanisms were also discussed. Together, this review provides novel insights into OA and OS therapeutics, possibly by intervening the process of abnormal endochondral-like pathway with altered collagen type X expression.
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BACKGROUND AND AIMS: The type X collagen gene (Col10a1), is a specific molecular marker of hypertrophic chondrocytes during endochondral ossification. Col10a1 expression is known to be influenced by many regulators. In this study, we aim to investigate how DEAD-box helicase 5 (DDX5), a potential binding factor for Col10a1 enhancer, may play a role in Col10a1 expression and chondrocyte hypertrophic differentiation in vitro. METHODS: The potential binding factors of the 150-bp Col10a1 cis-enhancer were identified with the hTFtarget database. The expression of DDX5 and COL10A1 was detected by quantitative real-time PCR (qRT-PCR) and Western blot in chondrogenic ATDC5 and MCT cell models with or without Ddx5 knockdown or overexpression. Dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) were performed to determine the interaction between DDX5 and the Col10a1 enhancer. The effect and mechanism of DDX5 on chondrocyte differentiation and maturation was evaluated by alcian blue, alkaline phosphatase (ALP), and alizarin red staining in ATDC5 cell lines with stable knockdown of Ddx5. RESULTS: DDX5 was identified as a potential binding factor for the Col10a1 enhancer. The expression of DDX5 in hypertrophic chondrocytes was higher than that in proliferative chondrocytes. Knockdown of Ddx5 decreased, while overexpression of Ddx5 slightly increased COL10A1 expression. DDX5 promotes the enhancer activity of Col10a1 as demonstrated by dual-luciferase reporter assay, and the ChIP experiment suggests a direct interaction between DDX5 and the Col10a1 enhancer. Compared to the control (NC) group, we observed weaker alcian blue and ALP staining intensity in the Ddx5 knockdown group of ATDC5 cells cultured both for 7 and 14 days. Whereas weaker alizarin red staining intensity was only found in the Ddx5 knockdown group of cells cultured for 7 days. Meanwhile, knockdown of Ddx5 significantly reduced the level of runt-related transcription factor 2 (RUNX2) in related ATDC5 cells examined. CONCLUSIONS: Our results suggest that DDX5 acts as a positive regulator for Col10a1 expression and may cooperate with RUNX2 together to control Col10a1 expression and promote the proliferation and maturation of chondrocytes.
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Follicular fluid meiosis-activating sterol (FF-MAS) is a small molecule compound found in FF, named for its ability to induce oocyte resumption of meiosis. Granulosa cells (GCs) within the follicle are typically located in a hypoxic environment under physiologic conditions due to limited vascular distribution. Previous research suggests that hypoxia-induced cell cycle arrest and apoptosis in GCs may be crucial triggering factors in porcine follicular atresia. However, the impact of FF-MAS on GCs within follicles has not been explored so far. In this study, we uncovered a novel role of FF-MAS in facilitating GC survival under hypoxic conditions by inhibiting STAT4 expression. We found that STAT4 expression was upregulated in porcine GCs exposed to 1% O2. Both gain and loss of function assays confirmed that STAT4 was required for cell apoptosis under hypoxia conditions, and that the GC apoptosis caused by hypoxia was markedly attenuated following FF-MAS treatment through inhibition of STAT4 expression. Correlation analysis in vivo revealed that GC apoptosis was associated with increased STAT4 expression, while the FF-MAS content in follicular fluid was negatively correlated with STAT4 mRNA levels and cell apoptosis. These findings elucidate a novel role of FF-MAS-mediated protection of GCs by inhibiting STAT4 expression under hypoxia, which might contribute to the mechanistic understanding of follicular development.
Granulosa cells (GCs) influence follicle growth and development, with their proliferation and differentiation promoting follicle development and ovulation, while their programmed cell death and degeneration trigger follicular atresia. In this study, to investigate the effect of FF-MAS on GCs of follicles, we performed gene expression profiling in the domestic pig (Sus scrofa). We discovered STAT4 is required for GC apoptosis under hypoxia conditions both in vitro and in vivo and FF-MAS prevents porcine ovarian granulosa cells from hypoxia-induced apoptosis via inhibiting STAT4 expression.
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Apoptosis , Líquido Folicular , Células de la Granulosa , Meiosis , Factor de Transcripción STAT4 , Animales , Células de la Granulosa/efectos de los fármacos , Femenino , Apoptosis/efectos de los fármacos , Porcinos , Líquido Folicular/química , Meiosis/efectos de los fármacos , Factor de Transcripción STAT4/metabolismo , Factor de Transcripción STAT4/genética , Esteroles , Hipoxia/veterinariaRESUMEN
Periodontitis is a chronic inflammatory disease caused by plaque biofilm which shares risk factors with systemic chronic diseases such as diabetes, cardiovascular disease, and osteoporosis. Many studies have found increased prevalence and rate of progression of periodontal disease in children with common metabolic disorders. Although the causal relationship and specific mechanism between them has not been determined yet. The aim of this paper is to progress on the impact of metabolic disorders on periodontal health in children and the underlying mechanisms, which provides new evidences for the prevention and intervention of metabolic disorders and periodontitis in children.
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Nutrient handling is an essential function of the gastrointestinal tract. Hormonal responses of small intestinal enteroendocrine cells (EECs) have been extensively studied but much less is known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs. Here we show that colonic EEC deficiency leads to hyperphagia and obesity. Furthermore, colonic EEC deficiency results in altered microbiota composition and metabolism, which we found through antibiotic treatment, germ-free rederivation and transfer to germ-free recipients, to be both necessary and sufficient for the development of obesity. Moreover, studying stool and blood metabolomes, we show that differential glutamate production by intestinal microbiota corresponds to increased appetite and that colonic glutamate administration can directly increase food intake. These observations shed light on an unanticipated host-microbiota axis in the colon, part of a larger gut-brain axis, that regulates host metabolism and body weight.
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Colon , Células Enteroendocrinas , Microbioma Gastrointestinal , Obesidad , Animales , Células Enteroendocrinas/metabolismo , Ratones , Colon/microbiología , Colon/metabolismo , Obesidad/metabolismo , Obesidad/microbiología , Ratones Endogámicos C57BL , Ácido Glutámico/metabolismo , Eje Cerebro-Intestino , Hiperfagia/metabolismoRESUMEN
Urban rivers are the main receptors and transporters of microplastic pollution. Understanding the occurrence and environmental risk of microplastics in urban rivers can provide theoretical basis for further control of microplastic pollution. The Sishui River, a tributary of the Yellow River, was selected as the research object. A total of nine water samples were collected from sewage outlets of the Sishui River (Xingyang section). The microplastics in the collected samples were characterized by their sizes, shapes, and colors using a microscope. It was found that microplastics were mostly in the form of transparent fibers and fragments in the water body of sewage outlets, of which the size below 500 µm was relatively high. In addition, PET and PE polymers were identified as the main types using a laser infrared imager. The correlation analysis showed that there was a significant correlation between the PET and PE, indicating that they were similar in origin. The results of the environmental risk assessment showed that the type of microplastics was the main factor affecting the assessment results, whereas the risk values of six sewage samples containing PVC were high. However, the value of pollution load index revealed a low risk level of pollutants in the study area.
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Inorganic metal halide perovskite CsPbX3 (X = I, Br, and Cl) nanocrystals (NCs) are rapidly developed due to their excellent photophysical properties and potential applications in lighting, lasers, and scintillators. However, the materials for growing perovskite NCs are insoluble or hydrolyzed in most green solvents, limiting their further development. Based on rational chemical analysis, an alkali-metal-assisted green-solvent synthesis method for in situ growth of CsPbBr3 NCs within SAPO-34 zeolite with bright luminescence is developed. Water is the only solvent used in the whole process. Surprisingly, by the synergistic effect of the channel structure of SAPO-34 and alkali-metal ions crystallization regulation, the CsPbBr3 NCs embedded in SAPO-34 assisted by Na+ emit bright blue light under ultraviolet illumination, with a 30 nm blue shift comparing to the CsPbBr3 NCs assisted by K+. Moreover, CsPbBr3 NCs can also be grown in mesoporous SiO2 SBA-15 and zeolites including ZSM-5, AlPO-5, and SOD, indicating that the method is universal for in situ growth of luminescent perovskite NCs in porous materials. This alkali-metal-assisted green-solvent synthesis provides a new strategy for developing high-quantum-yield, tunable-emission, and stable perovskite luminescent materials.
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Dementia, with homocysteine (Hcy) as an important risk factor, is a severe public health problem in the aging society. Betaine serves as a methyl donor and plays an important role in reducing Hcy. However, the effects and mechanisms of betaine on Hcy-induced cognitive impairment remain unclear. Firstly, SD rats were injected with Hcy (400 µg/kg) through vena caudalis, and betaine (2.5 % w/v) was supplemented via drinking water for 14 days. Betaine supplementation could attenuate Hcy-induced cognitive impairment in the Y maze and novel object recognition tests by repairing brain injury. Meanwhile, microglial activation was observed to be inhibited by betaine supplementation using immunofluorescence and sholl analysis. Secondly, HMC3 cells were treated with betaine, which was found to decrease the ROS level, ameliorate cell membrane rupture, reduce the release of LDH, IL-18 and IL-1ß, and attenuate the damage of microglia to neurons. Mechanistically, betaine alleviates cognitive impairment by inhibiting microglial pyroptosis via reducing the expressions of NLRP3, ASC, pro-caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, IL-18 and IL-1ß. Betaine treatment can increase SAM/SAH ratio, confirming its enhancement on methylation capacity. Furthermore, betaine treatment was found to enhance N6-methyladenosine (m6A) modification of NLRP3 mRNA, and reduced the NLRP3 mRNA stability through increasing the expression of the m6A reader YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Finally, silencing YTHDF2 could reverse the inhibitory effect of betaine on pyroptosis. Our data demonstrated that betaine attenuated Hcy-induced cognitive impairment by suppressing microglia pyroptosis via inhibiting the NLRP3/caspase-1/GSDMD pathway in an m6A-YTHDF2-dependent manner.
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Betaína , Disfunción Cognitiva , Animales , Ratas , Ratas Sprague-Dawley , Betaína/farmacología , Piroptosis , Interleucina-18 , Microglía , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Caspasa 1 , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Homocisteína , Interleucina-1beta , InflamasomasRESUMEN
The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (ß-catenin dependent) and non-canonical (ß-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.
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Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors, osteoinductive biofactors and biocompatible scaffold materials. Mesenchymal stem cells (MSCs) represent the most promising seed cells for bone tissue engineering. As multipotent stem cells that can self-renew and differentiate into multiple lineages including bone and fat, MSCs can be isolated from numerous tissues and exhibit varied differentiation potential. To identify an optimal progenitor cell source for bone tissue engineering, we analyzed the proliferative activity and osteogenic potential of four commonly-used mouse MSC sources, including immortalized mouse embryonic fibroblasts (iMEF), immortalized mouse bone marrow stromal stem cells (imBMSC), immortalized mouse calvarial mesenchymal progenitors (iCAL), and immortalized mouse adipose-derived mesenchymal stem cells (iMAD). We found that iMAD exhibited highest osteogenic and adipogenic capabilities upon BMP9 stimulation in vitro, whereas iMAD and iCAL exhibited highest osteogenic capability in BMP9-induced ectopic osteogenesis and critical-sized calvarial defect repair. Transcriptomic analysis revealed that, while each MSC line regulated a distinct set of target genes upon BMP9 stimulation, all MSC lines underwent osteogenic differentiation by regulating osteogenesis-related signaling including Wnt, TGF-ß, PI3K/AKT, MAPK, Hippo and JAK-STAT pathways. Collectively, our results demonstrate that adipose-derived MSCs represent optimal progenitor sources for cell-based bone tissue engineering.