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Despite advances in surgery and chemotherapy, the survival of patients with osteosarcoma (OS) has not been fundamentally improved over the last two decades. Microvesicles (MVs) have a high cargo-loading capacity and are emerging as a promising drug delivery nanoplatform. The aim of this study was to develop MVs as specifically designed vehicles to enable OS-specific targeting and efficient treatment of OS. Herein, we designed and constructed a nanoplatform (YSA-SPION-MV/MTX) consisting of methotrexate (MTX)-loaded MVs coated with surface-carboxyl Fe3O4 superparamagnetic nanoparticles (SPIONs) conjugated with ephrin alpha 2 (EphA2)-targeted peptides (YSAYPDSVPMMS, YSA). YSA-SPION-MV/MTX showed an effective targeting effect on OS cells, which was depended on the binding of the YSA peptide to EphA2. In the orthotopic OS mouse model, YSA-SPION-MV/MTX effectively delivered drugs to tumor sites with specific targeting, resulting in superior anti-tumor activity compared to MTX or MV/MTX. And YSA-SPION-MV/MTX also reduced the side effects of high-dose MTX. Taken together, this strategy opens up a new avenue for OS therapy. And we expect this MV-based therapy to serve as a promising platform for the next generation of precision cancer nanomedicines.
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Neoplasias Óseas , Micropartículas Derivadas de Células , Osteosarcoma , Animales , Humanos , Ratones , Neoplasias Óseas/tratamiento farmacológico , Efrinas , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Osteosarcoma/tratamiento farmacológicoRESUMEN
Metal-organic framework (MOF) membranes with rich functionality and tunable pore system are promising for precise molecular separation; however, it remains a challenge to develop defect-free high-connectivity MOF membrane with high water stability owing to uncontrollable nucleation and growth rate during fabrication process. Herein, we report on a confined-coordination induced intergrowth strategy to fabricate lattice-defect-free Zr-MOF membrane towards precise molecular separation. The confined-coordination space properties (size and shape) and environment (water or DMF) were regulated to slow down the coordination reaction rate via controlling the counter-diffusion of MOF precursors (metal cluster and ligand), thereby inter-growing MOF crystals into integrated membrane. The resulting Zr-MOF membrane with angstrom-sized lattice apertures exhibits excellent separation performance both for gas separation and water desalination process. It was achieved H2 permeance of ~1200 GPU and H2/CO2 selectivity of ~67; water permeance of ~8â L â m-2 â h-1 â bar-1 and MgCl2 rejection of ~95 %, which are one to two orders of magnitude higher than those of state-of-the-art membranes. The molecular transport mechanism related to size-sieving effect and transition energy barrier differential of molecules and ions was revealed by density functional theory calculations. Our work provides a facile approach and fundamental insights towards developing precise molecular sieving membranes.
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Joint pain is one of the most debilitating symptoms of rheumatoid arthritis (RA) and patients frequently rate improvements in pain management as their priority. RA is hallmarked by the presence of anti-modified protein autoantibodies (AMPA) against post-translationally modified citrullinated, carbamylated and acetylated proteins. It has been suggested that autoantibody-mediated processes represent distinct mechanisms contributing to pain in RA. In this study, we investigated the pronociceptive properties of monoclonal AMPA 1325:01B09 (B09 mAb) derived from the plasma cell of an RA patient. We found that B09 mAb induces pain-like behavior in mice that is not associated with any visual, histological or transcriptional signs of inflammation in the joints, and not alleviated by non-steroidal anti-inflammatory drugs (NSAIDs). Instead, we found that B09 mAb is retained in dorsal root ganglia (DRG) and alters the expression of several satellite glia cell (SGC), neuron and macrophage-related factors in DRGs. Using mice that lack activating FcγRs, we uncovered that FcγRs are critical for the development of B09-induced pain-like behavior, and partially drive the transcriptional changes in the DRGs. Finally, we observed that B09 mAb binds SGC in vitro and in combination with external stimuli like ATP enhances transcriptional changes and protein release of pronociceptive factors from SGCs. We propose that certain RA antibodies bind epitopes in the DRG, here on SGCs, form immune complexes and activate resident macrophages via FcγR cross-linking. Our work supports the growing notion that autoantibodies can alter nociceptor signaling via mechanisms that are at large independent of local inflammatory processes in the joint.
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Artritis Reumatoide , Autoanticuerpos , Animales , Ratones , Receptores de IgG , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico , DolorRESUMEN
The morphology of materials usually plays a significant role in their applications; the mechanical properties of the materials and characteristics such as specific surface area, surface energy, adsorbability, and wettability are dependent on the morphology. This study is focused on studying the effects of different tertiary butyl alcohol (TBA) aqueous solutions on the freeze-dried morphologies of chitin microspheres (CMs). By constructing a TBA/H2 O phase diagram, the underlying mechanisms of morphology change are explored. It is found that by freeze drying the CMs with 20 and 100 wt% TBA, a fine nanofiber weaved pore structure can be obtained. Away from these two ratios, the nanofibers are oppressed by the large crystals formed during the precool process or bind together due to the existence of water in the secondary drying stage, poor morphology and pore characteristics appearing. Moreover, the 20 wt% TBA freeze-drying route is conducive to split the CMs and other polysaccharide (PS) microspheres. The split method is also helpful for exploring the internal structure of the microspheres. Therefore, this study makes it possible to simplify the morphology control of CMs, which helps in the characterization of porous PS-based microspheres.
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Quitina , Alcohol terc-Butílico , Desecación , Liofilización , MicroesferasRESUMEN
BACKGROUND: To investigate the correlation between plasma D-dimer level and severity and prognosis of patients admitted to the emergency department with trauma. METHODS: A total of 168 trauma patients admitted to the department of emergency surgery of Shengzhou People's Hospital were included in this study. The general information was collected, and the plasma D-dimer level was measured within 24 hours after admission. Patients were divided into the mild traumatic group (ISS ≤ 16 points), the moderate traumatic group (16 < ISS ≤ 25 points), and the severe traumatic group (ISS > 25 points) according to the Injury Severity Score (ISS) evaluation. According to the results from a 28-day follow-up, plasma D-dimer levels were compared between the survival group and the death group. The correlation between plasma D-dimer levels and severity of trauma patients admitted to the emergency department (according to the ISS) was analyzed. The receiver operating characteristic (ROC) curve evaluated the predictive value of plasma D-dimer levels for prognosis in patients admitted to the emergency department with trauma. RESULTS: Plasma D-dimer levels successively increased from the mild traumatic group (2.51 ± 0.46 mg/L), the moderate traumatic group (4.09 ± 1.00 mg/L) to the severe traumatic group (6.58 ± 1.14 mg/L) (F = 0.659, p < 0.05). Plasma D-dimer levels were significantly and positively correlated with ISSs (r = 0.720, p < 0.001). The plasma D-dimer level in the survival group (3.72 ± 1.26 mg/L) was significantly lower than that in the death group (5.19 ± 0.87 mg/L) (t = 6.251, p < 0.001). According to the Youden index, the optimal cutoff value of plasma D-dimer was 4.00 mg/L, the AUC was 0.849, the standard error was 0.034, the 95% CI was 0.783 - 0.915, the sensitivity was 0.938, and the specificity was 0.603. CONCLUSIONS: Plasma D-dimer levels were positively correlated with the severity of patients with trauma admitted to the department of emergency surgery and can predict poor prognosis.
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Productos de Degradación de Fibrina-Fibrinógeno/análisis , Heridas y Lesiones , Adulto , Servicio de Urgencia en Hospital , Humanos , Puntaje de Gravedad del Traumatismo , Persona de Mediana Edad , Pronóstico , Curva ROC , Estudios Retrospectivos , Heridas y Lesiones/sangre , Heridas y Lesiones/diagnóstico , Heridas y Lesiones/epidemiología , Heridas y Lesiones/fisiopatología , Adulto JovenRESUMEN
Histone acetylation levels can be upregulated by treating cells with histone deacetylase inhibitors (HDACIs), which can induce autophagy. Autophagy flux in the spinal cord of rats following the left fifth lumber spinal nerve ligation (SNL) is involved in the progression of neuropathic pain. Suberoylanilide hydroxamic acid (SAHA), one of the HDACIs can interfere with the epigenetic process of histone acetylation, which has been shown to ease neuropathic pain. Recent research suggest that SAHA can stimulate autophagy via the mammalian target of rapamycin (mTOR) pathway in some types of cancer cells. However, little is known about the role of SAHA and autophagy in neuropathic pain after nerve injury. In the present study, we aim to investigate autophagy flux and the role of the mTOR pathway on spinal cells autophagy activation in neuropathic pain induced by SNL in rats that received SAHA treatment. Autophagy-related proteins and mTOR or its active form were assessed by using western blot, immunohistochemistry, double immunofluorescence staining and transmission electron microscopy (TEM). We found that SAHA decreased the paw mechanical withdrawal threshold (PMWT) of the lower compared with SNL. Autophagy flux was mainly disrupted in the astrocytes and neuronal cells of the spinal cord dorsal horn on postsurgical day 28 and was reversed by daily intrathecal injection of SAHA (n = 100 nmol/day or n = 200 nmol/day). SAHA also decreased mTOR and phosphorylated mTOR (p-mTOR) expression, especially p-mTOR expression in astrocytes and neuronal cells of the spinal dorsal horn. These results suggest that SAHA attenuates neuropathic pain and contributes to autophagy flux in astrocytes and neuronal cells of the spinal dorsal horn via the mTOR signaling pathway.
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Autofagia/efectos de los fármacos , Neuralgia/tratamiento farmacológico , Serina-Treonina Quinasas TOR/efectos de los fármacos , Vorinostat/farmacología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Modelos Animales de Enfermedad , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Masculino , Neuralgia/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Asta Dorsal de la Médula Espinal/efectos de los fármacos , Asta Dorsal de la Médula Espinal/metabolismo , Nervios Espinales/efectos de los fármacos , Nervios Espinales/lesionesRESUMEN
High strength chitin/poly(vinyl alcohol) (PVA) composite hydrogels (RCP) were constructed by adding PVA into chitin dissolved in a NaOH/urea aqueous solution, and then by cross-linking with epichlorohydrin (ECH) and freezing-thawing process. The RCP hydrogels were characterized by field emission scanning electron microscopy, FTIR, differential scanning calorimetry, solid-state (13)C NMR, wide-angle X-ray diffraction, and compressive test. The results revealed that the repeated freezing/thawing cycles induced the bicrosslinked networks consisted of chitin and PVA crystals in the composite gels. Interestingly, a jellyfish gel-like structure occurred in the RCP75 gel with 25 wt % PVA content in which the amorphous and crystalline PVA were immobilized tightly in the chitin matrix through hydrogen bonding interaction. The freezing/thawing cycles played an important role in the formation of the layered porous PVA networks and the tight combining of PVA with the pore wall of chitin. The mechanical properties of RCP75 were much higher than the other RCP gels, and the compressive strength was 20× higher than that of pure chitin gels, as a result of broadly dispersing stress caused by the orderly multilayered networks. Furthermore, the cell culture tests indicated that the chitin/PVA composite hydrogels exhibited excellent biocompatibility and safety, showing potential applications in the field of tissue engineering.
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Materiales Biocompatibles , Quitina , Cnidarios , Hidrogeles , Alcohol Polivinílico , Animales , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Línea Celular , Quitina/síntesis química , Quitina/química , Quitina/farmacología , Quitina/ultraestructura , Epiclorhidrina/química , Hidrogeles/síntesis química , Hidrogeles/química , Hidrogeles/farmacología , Espectroscopía de Resonancia Magnética , Ensayo de Materiales/métodos , Ratones , Alcohol Polivinílico/síntesis química , Alcohol Polivinílico/química , Alcohol Polivinílico/farmacologíaRESUMEN
In order to solve the problem of the low treatment efficiency of wastewater containing heavy metals in mining areas, straw biochar and graphene oxide enhanced external pressure ultrafiltration (SGU) was used to treat wastewater containing high concentrations of Pb2+. The operation parameters such as pH and temperature were optimized, and the removal efficiency of CODCr, NH3-N, turbidity and Pb2+ via SGU, straw biochar ultrafiltration (SU), ultrafiltration (UF), and conventional treatment (CT) were systematically investigated. The results showed that the pH and temperature of polluted water were 4.8-5.2 and 21-30 °C, respectively, the average removal rates of CODCr, NH3-N, turbidity and Pb2+ by SGU reached 91%, 97%, 98% and 95%, respectively, and the removal effect was better than that of other processes. In addition, under the backwash conditions of clean water, weak acid, and weak alkali, the membrane flux recovered 65%, 88%, and 89% of the new membrane, respectively. This study provides scientific and theoretical support for the advanced treatment of polluted water in mining areas.
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Pain is the leading symptom for most individuals with osteoarthritis (OA), a complex condition marked by joint discomfort. Recently, the dynamic interplay between the nervous and immune systems has become a focal point for understanding pain regulation. Despite this, there is still a substantial gap in our comprehensive understanding of the neuroimmune interactions and their effects on pain in OA. This review examines the bidirectional influences between immune cells and nerves in OA progression. It explores current approaches that target neuroimmune pathways, including promoting M2 macrophage polarization and specific neuronal receptor targeting, for effective pain reduction. Translational potential statement: This review provides a comprehensive overview of the mechanisms underlying the interplay between the immune system and nervous system during the progression of OA, as well as their contributions to pain. Additionally, it compiles existing intervention strategies targeting neuroimmunity for the treatment of OA pain. This information offers valuable insights for researchers seeking to address the challenge of OA pain.
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Osteoarthritis (OA), as a degenerative disease, leads to high socioeconomic burdens and disability rates. The knee joint is typically the most affected and is characterized by progressive destruction of articular cartilage, subchondral bone remodeling, osteophyte formation and synovial inflammation. The current management of OA mainly focuses on symptomatic relief and does not help to slow down the advancement of disease. Recently, mesenchymal stem cells (MSCs) and their exosomes have garnered significant attention in regenerative therapy and tissue engineering areas. Preclinical studies have demonstrated that MSC-derived exosomes (MSC-Exos), as bioactive factor carriers, have promising results in cell-free therapy of OA. This study reviewed the application of various MSC-Exos for the OA treatment, along with exploring the potential underlying mechanisms. Moreover, current strategies and future perspectives for the utilization of engineered MSC-Exos, alongside their associated challenges, were also discussed.
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Objectives: TANK-binding kinase 1 (TBK1) is pivotal in autoimmune and inflammatory diseases, yet its role in osteoarthritis (OA) remains elusive. This study sought to elucidate the effect of the TBK1 inhibitor BX795 on OA and to delineate the underlying mechanism by which it mitigates OA. Methods: Interleukin-1 Beta (IL-1ß) was utilized to simulate inflammatory responses and extracellular matrix degradation in vitro. In vivo, OA was induced in 8-week-old mice through destabilization of the medial meniscus surgery. The impact of BX795 on OA was evaluated using histological analysis, X-ray, micro-CT, and the von Frey test. Additionally, Western blot, RT-qPCR, and immunofluorescence assays were conducted to investigate the underlying mechanisms of BX795. Results: Phosphorylated TBK1 (P-TBK1) levels were found to be elevated in OA knee cartilage of both human and mice. Furthermore, intra-articular injection of BX795 ameliorated cartilage degeneration and alleviated OA-associated pain. BX795 also counteracted the suppression of anabolic processes and the augmentation of catabolic activity, inflammation, and senescence observed in the OA mice. In vitro studies revealed that BX795 reduced P-TBK1 levels and reversed the effects of anabolism inhibition, catabolism promotion, and senescence induction triggered by IL-1ß. Mechanistically, BX795 inhibited the IL-1ß-induced activation of the cGAS-STING and TLR3-TRIF signaling pathways in chondrocytes. Conclusions: Pharmacological inhibition of TBK1 with BX795 protects articular cartilage by inhibiting the activation of the cGAS-STING and TLR3-TRIF signaling pathways. This action attenuates inflammatory responses and cellular senescence, positioning BX795 as a promising therapeutic candidate for OA treatment. The translational potential of this article: This study furnishes experimental evidence and offers a potential mechanistic explanation supporting the efficacy of BX795 as a promising candidate for OA treatment.
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Microplastics have become an emerging threat to global ecosystems, and their efficient removal faces with serious challenges. Herein, this study introduced different hydrophilic polyaniline (PANIs) into chitin matrix to fabricate Chitin-PANIs sponge (ChPANIs) and investigated the relationship between PANIs dispersibility in chitin sponge matrix controlled by its hydrophilicity and adsorption effects on MPs. With the increase of PANIs' hydrophilicity (WCA from 153.9° to 32.8°), the removal efficiency of sponges to MPs increased from 84.0 % to 91.7 %. More hydrophilic PANIs can provide more contact surfaces and adsorption sites, which enhanced the electrostatic interactions to MPs and obtained excellent adsorption properties. The adsorption of MPs on ChPANIs accorded with the pseudo-first-order adsorption, suggesting that physical adsorption plays a dominant role. The adsorption process also conformed to Freundlich model, which displayed the MPs adsorption on ChPANI-PA could be multi-layer. The adsorption strength of ChPANIs was 0.7552, suggesting that it was a strong adsorbent. The ChPANIs also exhibited good mechanical properties and reusability, which its MPs removal efficiency just decreased from 91.7 % to 86.9 % during the five cycles. These findings expand the understanding of the adsorption mechanism analysis of MPs on sponge materials, and exist guiding significance for the design of adsorbed materials.
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Microplásticos , Contaminantes Químicos del Agua , Plásticos , Adsorción , Quitina , Ecosistema , Interacciones Hidrofóbicas e Hidrofílicas , Contaminantes Químicos del Agua/análisisRESUMEN
AIMS: Pellino1 (Peli1) has been reported to regulate various inflammatory diseases. This study aims to explore the role of Peli1 in the occurrence and development of osteoarthritis (OA), so as to find new targets for the treatment of OA. METHODS: After inhibiting Peli1 expression in chondrocytes with small interfering RNA (siRNA), interleukin (IL)-1ß was used to simulate inflammation, and OA-related indicators such as synthesis, decomposition, inflammation, and apoptosis were detected. Toll-like receptor (TLR) and nuclear factor-kappa B (NF-κB) signalling pathway were detected. After inhibiting the expression of Peli1 in macrophages Raw 264.7 with siRNA and intervening with lipopolysaccharide (LPS), the polarization index of macrophages was detected, and the supernatant of macrophage medium was extracted as conditioned medium to act on chondrocytes and detect the apoptosis index. The OA model of mice was established by destabilized medial meniscus (DMM) surgery, and adenovirus was injected into the knee cavity to reduce the expression of Peli1. The degree of cartilage destruction and synovitis were evaluated by haematoxylin and eosin (H&E) staining, Safranin O/Fast Green staining, and immunohistochemistry. RESULTS: In chondrocytes, knockdown of Peli1 produced anti-inflammatory and anti-apoptotic effects by targeting the TLR and NF-κB signalling pathways. We found that in macrophages, knockdown of Peli1 can inhibit M1-type polarization of macrophages. In addition, the corresponding conditioned culture medium of macrophages applied to chondrocytes can also produce an anti-apoptotic effect. During in vivo experiments, the results have also shown that knockdown Peli1 reduces cartilage destruction and synovial inflammation. CONCLUSION: Knockdown of Peli1 has a therapeutic effect on OA, which therefore makes it a potential therapeutic target for OA.Cite this article: Bone Joint Res 2023;12(2):121-132.
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Well-intergrown polycrystalline UiO-66 membranes were successfully synthesized on a polymeric substrate under mild synthesis conditions of a lower temperature and short synthesis time. The resulted UiO-66 membranes with fast water selective transport channels exhibited unprecedentedly high solvent dehydration performance with a permeation flux of â¼6100 g m-2 h-1 and a separation factor of â¼7500, showing great potential for intensification of esterification reaction.
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Osteoarthritis (OA) is a trauma-/age-related degenerative disease characterized by chronic inflammation as one of its pathogenic mechanisms. Mulberroside A (MA), a natural bioactive withanolide, demonstrates anti-inflammatory properties in various diseases; however, little is known about the effect of MA on OA. We aim to examine the role of MA on OA and to identify the potential mechanisms through which it protects articular cartilage. In vitro, MA improved inflammatory response, anabolism, and catabolism in IL-1ß-induced OA chondrocytes. The chondroprotective effects of MA were attributed to suppressing the MAPK, NF-κB, and PI3K-AKT-mTOR signaling pathways, as well as promoting the autophagy process. In vivo, intra-articular injection of MA reduced the cartilage destruction and reversed the change of anabolic and catabolic-related proteins in destabilized medial meniscus (DMM)-induced OA models. Thus, the study indicates that MA exhibits a chondroprotective effect and might be a promising agent for OA treatment.
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Humic acid (HA) in makeup water is one of the important safety issues of high-parameter power plants. Herein, the Zr-based metal-organic frameworks (NH2-UiO-66) was applied to remove humic acid in water. The mesoporous of NH2-UiO-66 was controlled by surfactants sodium dodecyl benzene sulfonate (SDBS) to increase the adsorption of HA. The adsorption of HA at 25°C and pH 7 increased fast at the first 0.5 h and then gradually reached equilibrium after 10 h. The maximum adsorption capacity was 108.93 mg g-1, which removal efficiency was high as 95.0%. The morphology and adsorption properties of NH2-UiO-66 were characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), surface charge, Fourier transform infrared (FT-IR), N2 adsorption-desorption, and adsorption test. The adsorption process of HA accorded with the pseudo-second-order kinetics, while the adsorption isotherm conformed to be the Langmuir model and the adsorption was proved to be monolayer adsorption. Adsorption was the spontaneous and endothermic process (ΔG°<0, ΔH°>0). The accessible surface area provided by mesopores on the 5 different Zr-MOFs was the reason for the enhanced HA adsorption capacity. These results provided useful information for effective HA removing and enhanced our understanding of the adsorption mechanism of HA on NH2-UiO-66.
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Estructuras Metalorgánicas , Contaminantes Químicos del Agua , Adsorción , Sustancias Húmicas , Cinética , Ácidos Ftálicos , Espectroscopía Infrarroja por Transformada de Fourier , Tensoactivos , Agua/química , Contaminantes Químicos del Agua/análisisRESUMEN
Cancer is one of the primary causes of death worldwide, and its morbidity and mortality rates are increasing rapidly. However, standard treatment modalities (surgery, radiotherapy, chemotherapy, and immunotherapy) often fail to achieve a satisfactory therapeutic effect. Extracellular vesicles (EVs) are natural nano-sized lipid bilayer vesicles secreted from cells. Owing to their advantages of low toxicity, high biocompatibility, low immunogenicity, and inherent targeting, EVs can be exploited as drug delivery vectors for cancer treatment. In this review, we summarize the research progress of EV-based drug delivery systems in cancer treatment by focusing on four aspects: sources, cargo types, cargo loading methods and modification strategies. Finally, current challenges and future perspectives are discussed.
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Vesículas Extracelulares , Neoplasias , Transporte Biológico , Comunicación Celular , Sistemas de Liberación de Medicamentos , Vesículas Extracelulares/metabolismo , Humanos , Neoplasias/metabolismoRESUMEN
Inflammation can influence the pluripotency and self-renewal of mesenchymal stem cells (MSCs), thereby altering their cartilage regeneration ability. Sprague-Dawley (SD) rat bone marrow mesenchymal stem cells (BMSCs) were isolated and found to be defective in differentiation potential in the interleukin-1ß- (IL-1ß-) induced inflammatory microenvironment. Glycogen synthase kinase-3ß (GSK-3ß) is an evolutionarily conserved serine/threonine kinase that plays a role in numerous cellular processes. The role of GSK-3ß in inflammation may be related to the nuclear factor-κB (NF-κB) signaling pathway and the Wnt/ß-catenin signaling pathway, whose mechanism remains unclear. In this study, we found that GSK-3ß can inhibit chondrogenesis of IL-1ß-impaired BMSCs by disrupting metabolic balance and promoting cell apoptosis. By using the inhibitors LiCl and SN50, we demonstrated that GSK-3ß regulates the chondrogenesis via the NF-κB and Wnt/ß-catenin signaling pathways and possibly mediates the cross-reaction between NF-κB and ß-catenin in the nucleus. Given the molecular mechanisms of GSK-3ß in chondrogenic differentiation in inflammation, GSK-3ß is a crucial target for the treatment of inflammation-induced cartilage disease.
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Background: This study aimed to develop an artificial neural network (ANN) model for predicting synchronous organ-specific metastasis in lung cancer (LC) patients. Methods: A total of 62,151 patients who diagnosed as LC without data missing between 2010 and 2015 were identified from Surveillance, Epidemiology, and End Results (SEER) program. The ANN model was trained and tested on an 75/25 split of the dataset. The receiver operating characteristic (ROC) curves, area under the curve (AUC) and sensitivity were used to evaluate and compare the ANN model with the random forest model. Results: For distant metastasis in the whole cohort, the ANN model had metrics AUC = 0.759, accuracy = 0.669, sensitivity = 0.906, and specificity = 0.613, which was better than the random forest model. For organ-specific metastasis in the cohort with distant metastasis, the sensitivity in bone metastasis, brain metastasis and liver metastasis were 0.913, 0.906 and 0.925, respectively. The most important variable was separate tumor nodules with 100% importance. The second important variable was visceral pleural invasion for distant metastasis, while histology for organ-specific metastasis. Conclusions: Our study developed a "two-step" ANN model for predicting synchronous organ-specific metastasis in LC patients. This ANN model may provide clinicians with more personalized clinical decisions, contribute to rationalize metastasis screening, and reduce the burden on patients and the health care system.
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BACKGROUND: Mechanical loading has been widely considered to be essential for growth plate to maintain metabolism and development. Cyclic mechanical strain has been demonstrated to induce autophagy, whereas the relationship between cyclic tensile strain (CTS) and autophagy in growth plate chondrocytes (GPCs) is not clear. The objective of this study was to investigate whether CTS can regulate autophagy in GPCs in vitro and explore the potential mechanisms of this regulation. METHODS: The 2-week-old Sprague-Dawley rat GPCs were subjected to CTS of varying magnitude and duration at a frequency of 2.0 Hz. The mRNA levels of autophagy-related genes were measured by RT-qPCR. The autophagy in GPCs was verified by transmission electron microscopy (TME), immunofluorescence and Western blotting. The fluorescence-activated cell sorting (FACS) was employed to detect the percentage of apoptotic and necrotic cells. RESULTS: In GPCs, CTS significantly increased the mRNA and protein levels of autophagy-related genes, such as LC3, ULK1, ATG5 and BECN1 in a magnitude- and time-dependent manner. There was no significant difference in the proportion of apoptotic and necrotic cells between control group and CTS group. The autophagy inhibitors, 3-methyladenine (3MA) and chloroquine (CQ) reversed the CTS-induced autophagy via promoting the formation of autophagosomes. Cytochalasin D (cytoD), an inhibitor of G-actin polymerization into F-actin, could effectively block the CTS-induced autophagy in GPCs. CONCLUSION: Cyclic mechanical strain with high-tensile triggers autophagy in GPCs, which can be suppressed by 3MA and CQ, and cytoskeletal F-actin microfilaments organization plays a key role in chondrocytes' response to mechanical loading.