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BACKGROUND: Enhanced magnetic resonance imaging (MRI) is widely used in the diagnosis, treatment and prognosis of hepatocellular carcinoma (HCC), but it can not effectively reflect the heterogeneity within the tumor and evaluate the effect after treatment. Preoperative imaging analysis of voxel changes can effectively reflect the internal heterogeneity of the tumor and evaluate the progression-free survival (PFS). AIM: To predict the PFS of patients with HCC before operation by building a model with enhanced MRI images. METHODS: Delineate the regions of interest (ROI) in arterial phase, portal venous phase and delayed phase of enhanced MRI. After extracting the combinatorial features of ROI, the features are fused to obtain deep learning radiomics (DLR)_Sig. DeLong's test was used to evaluate the diagnostic performance of different typological features. K-M analysis was applied to assess PFS in different risk groups, and the discriminative ability of the model was evaluated using the C-index. RESULTS: Tumor diameter and diolame were independent factors influencing the prognosis of PFS. Delong's test revealed multi-phase combined radiomic features had significantly greater area under the curve values than did those of the individual phases (P < 0.05).In deep transfer learning (DTL) and DLR, significant differences were observed between the multi-phase and individual phases feature sets (P < 0.05). K-M survival analysis revealed a median survival time of high risk group and low risk group was 12.8 and 14.2 months, respectively, and the predicted probabilities of 6 months, 1 year and 2 years were 92%, 60%, 40% and 98%, 90%,73%, respectively. The C-index was 0.764, indicating relatively good consistency between the predicted and observed results. DTL and DLR have higher predictive value for 2-year PFS in nomogram. CONCLUSION: Based on the multi-temporal characteristics of enhanced MRI and the constructed Nomograph, it provides a new strategy for predicting the PFS of transarterial chemoembolization treatment of HCC.
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BACKGROUND: The aim was to explore the effect of macrophage polarization and macrophage-to-myofibroblast transition (MMT) in silicosis. METHODS: Male Wistar rats were divided into a control group and a silicosis group developed using a HOPE MED 8050 dynamic automatic dusting system. Murine macrophage MH-S cells were randomly divided into a control group and an SiO2 group. The pathological changes in lung tissue were observed using hematoxylin and eosin (HE) and Van Gieson (VG) staining. The distribution and location of macrophage marker (F4/80), M1 macrophage marker (iNOS), M2 macrophage marker (CD206), and myofibroblast marker (α-smooth muscle actin [α-SMA]) were detected using immunohistochemical and immunofluorescent staining. The expression changes in iNOS, Arg, α-SMA, vimentin, and type I collagen (Col I) were measured using Western blot. RESULTS: The results of HE and VG staining showed obvious silicon nodule formation and the distribution of thick collagen fibers in the lung tissue of the silicosis group. Macrophage marker F4/80 increased gradually from 8 to 32 weeks after exposure to silica. Immunohistochemical and immunofluorescent staining results revealed that there were more iNOS-positive cells and some CD206-positive cells in the lung tissue of the silicosis group at 8 weeks. More CD206-positive cells were found in the silicon nodules of the lung tissues in the silicosis group at 32 weeks. Western blot analysis showed that the expressions of Inducible nitric oxide synthase and Arg protein in the lung tissues of the silicosis group were upregulated compared with those of the control group. The results of immunofluorescence staining showed the co-expression of F4/80, α-SMA, and Col I, and CD206 and α-SMA were co-expressed in the lung tissue of the silicosis group. The extracted rat alveolar lavage fluid revealed F4/80+α-SMA+, CD206+α-SMA+, and F4/80+α-SMA+Col I+ cells using immunofluorescence staining. Similar results were also found in MH-S cells induced by SiO2. CONCLUSIONS: The development of silicosis is accompanied by macrophage polarization and MMT.
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The pathophysiological link between diabetes and heightened propensity for the development of coronary heart disease (CHD) is well-established. Prevailing evidence confirms that small increases in low concentrations of high-sensitivity C reactive protein (hs-CRP) in the human body can determine the tendency of developing CHD. Additionally, glycated hemoglobin (HbA1c) is a well-recognized biomarker to evaluate diabetes progression. Given the positive correlation between diabetes and CHD, this research presents a notably unprecedented label-free electrochemical approach for the dual detection of %HbA1c regarding Total Hb and hs-CRP, facilitating early CHD prediction and cost-effective point-of-care diagnostics. Furthermore, a novel redox probe O-(4-Nitrophenylphosphoryl)choline (C11H17N2O6P) was used for the electrochemical detection of CRP, a method not documented in scientific literature before. The calibration curves demonstrate a limit of detection (LOD) of 5 mg/mL in PBS (pH 8) and 6 mg/mL in simulated blood (SB) for a linear range of 0-30 mg/mL of HbA1c. Conjointly, a LOD of 0.007 mg/mL and 0.008 mg/mL for measurement in PBS (pH 7.4) and SB are reported for a linear range of 0-0.05 mg/mL of CRP. The electrochemical systems presented could accurately quantify HbA1c and CRP in mixed samples, demonstrating reasonable specificity and practical applicability for complex biological samples.
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Proteína C-Reactiva , Enfermedad Coronaria , Diabetes Mellitus , Técnicas Electroquímicas , Hemoglobina Glucada , Hemoglobina Glucada/análisis , Humanos , Proteína C-Reactiva/análisis , Enfermedad Coronaria/sangre , Enfermedad Coronaria/diagnóstico , Técnicas Electroquímicas/métodos , Diabetes Mellitus/sangre , Diabetes Mellitus/diagnóstico , Límite de Detección , Biomarcadores/sangreRESUMEN
The mechanism of action of low-density lipoprotein receptor related protein 4 (LRP4) is mediated largely via the Agrin-LRP4-MuSK signalling pathway in the nervous system. LRP4 contributes to the development of synapses in the peripheral nervous system (PNS). It interacts with signalling molecules such as the amyloid beta-protein precursor (APP) and the wingless type protein (Wnt). Its mechanisms of action are complex and mediated via interaction between the pre-synaptic motor neuron and post-synaptic muscle cell in the PNS, which enhances the development of the neuromuscular junction (NMJ). LRP4 may function differently in the central nervous system (CNS) than in the PNS, where it regulates ATP and glutamate release via astrocytes. It mayaffect the growth and development of the CNS by controlling the energy metabolism. LRP4 interacts with Agrin to maintain dendrite growth and density in the CNS. The goal of this article is to review the current studies involving relevant LRP4 signaling pathways in the nervous system. The review also discusses the clinical and etiological roles of LRP4 in neurological illnesses, such as myasthenia gravis, Alzheimer's disease and epilepsy. In this review, we provide a theoretical foundation for the pathogenesis and therapeutic application of LRP4 in neurologic diseases.
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Agrina , Proteínas Relacionadas con Receptor de LDL , Proteínas Relacionadas con Receptor de LDL/metabolismo , Agrina/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Unión Neuromuscular/metabolismoRESUMEN
Unraveling the intricate relationship between mechanical factors and brain activity is a pivotal endeavor, yet the underlying mechanistic model of signaling pathways in brain mechanotransduction remains enigmatic. To bridge this gap, we introduced an in situ multi-scale platform, through which we delineate comprehensive brain biomechanical traits in white matter (WM), grey-white matter junctions (GW junction), and the pons across human brain tissue from four distinct donors. We investigate the three-dimensional expression patterns of Piezo1, Piezo2, and TMEM150C, while also examining their associated histological features and mechanotransduction signaling networks, particularly focusing on the YAP/ß-catenin axis. Our results showed that the biomechanical characteristics (including stiffness, spring term, and equilibrium stress) associated with Piezo1 vary depending on the specific region. Moving beyond Piezo1, our result demonstrated the significant positive correlations between Piezo2 expression and stiffness in the WM. Meanwhile, the expression of Piezo2 and TMEM150C was shown to be correlated to viscoelastic properties in the pons and WM. Given the heterogeneity of brain tissue, we investigated the three-dimensional expression of Piezo1, Piezo2, and TMEM150C. Our results suggested that three mechanosensitive proteins remained consistent across different vertical planes within the tissue sections. Our findings not only establish Piezo1, Piezo2, and TMEM150C as pivotal mechanosensors that regulate the region-specific mechanotransduction activities but also unveil the paradigm connecting brain mechanical properties and mechanotransduction activities and the variations between individuals.
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Canales Iónicos , Mecanotransducción Celular , Humanos , Encéfalo/metabolismo , Canales Iónicos/metabolismo , Mecanotransducción Celular/fisiologíaRESUMEN
Protein biomarkers can be used to characterize symptom classes, which describe the metabolic or immunodeficient state of patients during the progression of a specific disease. Recent literature has shown that machine learning methods can complement traditional clinical methods in identifying biomarkers. However, many machine learning frameworks only apply narrowly to a specific archetype or subset of diseases. In this paper, we propose a feature extractor which can discover protein biomarkers for a wide variety of classification problems. The feature extractor uses a special type of deep learning model, which discovers a latent space that allows for optimal class separation and enhanced class cluster identity. The extracted biomarkers can then be used to train highly accurate supervised learning models. We apply our methods to a dataset involving COVID-19 patients and another involving scleroderma patients, to demonstrate improved class separation and reduced false discovery rates compared to results obtained using traditional models.
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A large body of literature has highlighted the significance of the corticotropin-releasing factor (CRF) system in the regulation of neuropsychiatric diseases. Anxiety disorders are among the most common neuropsychiatric disorders. An increasing number of studies have demonstrated that the CRF family mediates and regulates the development and maintenance of anxiety. Thus, the CRF family is considered to be a potential target for the treatment of anxiety disorders. The prefrontal cortex (PFC) plays a role in the occurrence and development of anxiety, and both CRF and CRF-R1 are widely expressed in the PFC. This paper begins by reviewing CRF-related signaling pathways and their different roles in anxiety and related processes. Then, the role of the CRF system in other neuropsychiatric diseases is reviewed and the potential role of PFC CRF signaling in the regulation of anxiety disorders is discussed. Although other signaling pathways are potentially involved in the process of anxiety, CRF in the PFC primarily modulates anxiety disorders through the activation of corticotropin-releasing factor type1 receptors (CRF-R1) and the excitation of the cAMP/PKA signaling pathway. Moreover, the main signaling pathways of CRF involved in sex differentiation in the PFC appear to be different. In summary, this review suggests that the CRF system in the PFC plays a critical role in the occurrence of anxiety. Thus, CRF signaling is of great significance as a potential target for the treatment of stress-related disorders in the future.
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Bioreactors are advanced biomanufacturing tools that have been widely used to develop various applications in the fields of health care and cellular agriculture. In recent years, there has been a growing interest in the use of bioreactors to enhance the efficiency and scalability of these technologies. In cell therapy, bioreactors have been used to expand and differentiate cells into specialized cell types that can be used for transplantation or tissue regeneration. In cultured meat production, bioreactors offer a controlled and efficient means of producing meat without the need for animal farming. Bioreactors can support the growth of muscle cells by providing the necessary conditions for cell proliferation, differentiation, and maturation, including the provision of oxygen and nutrients. This review article aims to provide an overview of the current state of bioreactor technology in both cell therapy and cultured meat production. It will examine the various bioreactor types and their applications in these fields, highlighting their advantages and limitations. In addition, it will explore the future prospects and challenges of bioreactor technology in these emerging fields. Overall, this review will provide valuable insights for researchers and practitioners interested in using bioreactor technology to develop innovative solutions in the biomanufacturing of therapeutic cells and cultured meat.
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Reactores Biológicos , Biotecnología , Tratamiento Basado en Trasplante de Células y Tejidos , Productos de la Carne , Tratamiento Basado en Trasplante de Células y Tejidos/economía , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Productos de la Carne/economía , Biotecnología/economía , Biotecnología/métodos , Biotecnología/tendencias , Técnicas de Cultivo de CélulaRESUMEN
The kidney is critical in controlling salt and water balance, with the interstitium involved with a variety of components including immune cells in steady state. However, the roles of resident immune cells in kidney physiology are largely unknown. To help unravel some of these unknowns, we employed cell fate mapping, and identified a population of embryo-derived self-maintaining macrophages (SM-MØ) that were independent of the bone marrow in adult mouse kidneys. This kidney-specific SM-MØ population was distinctive from the kidney monocyte-derived macrophages in transcriptome and in their distribution. Specifically, the SM-MØ highly expressed nerve-associated genes; high-resolution confocal microscopy revealed that the SM-MØ in the cortex were in close association with sympathetic nerves and there was a dynamical interaction between macrophages and sympathetic nerves when live kidney sections were monitored. Kidney-specific depletion of the SM-MØ resulted in reduced sympathetic distribution and tone, leading to reduced renin secretion, increased glomerular filtration rate and solute diuresis, which caused salt decompensation and significant weight loss under a low-salt diet challenge. Supplementation of L-3,4-dihydroxyphenylserine which is converted to norepinephrine in vivo rescued the phenotype of SM-MØ-depleted mice. Thus, our findings provide insights in kidney macrophage heterogeneity and address a non-canonical role of macrophages in kidney physiology. In contrast to the well-appreciated way of central regulation, local regulation of sympathetic nerve distribution and activities in the kidney was uncovered.
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Riñón , Macrófagos , Ratones , Animales , Riñón/fisiología , Cloruro de Sodio Dietético , Sistema Nervioso Simpático , Cloruro de Sodio , AguaRESUMEN
Silicosis is a pulmonary disease caused by the inhalation of silica. There is a lack of early and effective prevention, diagnosis, and treatment methods, and addressing silicotic fibrosis is crucial. Quercetin, a flavonoid with anti-carcinogenic, anti-inflammatory, and antiviral properties, is known to have a suppressive effect on fibrosis. The present study aimed to determine the therapeutic effect of quercetin on silicotic mice and macrophage polarity. We found that quercetin suppressed silicosis in mice. It was observed that SiO2 activated macrophage polarity and the macrophage-to-myofibroblast transition (MMT) by transforming the growth factor-ß (TGF-ß)-Smad2/3 signaling pathway in silicotic mice and MH-S cells. Quercetin also attenuated the MMT and the TGF-ß-Smad2/3 signaling pathway in vivo and in vitro. The present study demonstrated that quercetin is a potential therapeutic agent for silicosis, which acts by regulating macrophage polarity and the MMT through the TGF-ß-Smad2/3 signaling pathway.
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Integration of mechanical cues in conventional 2D or 3D cell culture platforms is an important consideration for in vivo and ex vivo models of lung health and disease. Available commercial and published custom-made devices are frequently limited in breadth of applications, scalability, and customization. Herein we present a technical report on an open-source, cell and tissue (CaT) stretcher, with modularity for different in vitro and ex vivo systems, that includes the following features: 1) Programmability for modeling different breathing patterns, 2) scalability to support low to high-throughput experimentation, and 3) modularity for submerged cell culture, organ-on-chips, hydrogels, and live tissues. The strategy for connecting the experimental cell or tissue samples to the stretching device were designed to ensure that traditional biomedical outcome measurements including, but not limited to microscopy, soluble mediator measurement, and gene and protein expression remained possible. Lastly, to increase the uptake of the device within the community, the system was built with economically feasible and available components. To accommodate diverse in vitro and ex vivo model systems we developed a variety of chips made of compliant polydimethylsiloxane (PDMS) and optimized coating strategies to increase cell adherence and viability during stretch. The CaT stretcher was validated for studying mechanotransduction pathways in lung cells and tissues, with an increase in alpha smooth muscle actin protein following stretch for 24 h observed in independent submerged monolayer, 3D hydrogel, and live lung tissue experiments. We anticipate that the open-source CaT stretcher design will increase accessibility to studies of the dynamic lung microenvironment through direct implementation by other research groups or custom iterations on our designs.
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In this study, we investigate the synergistic effect of gemcitabine (Gem) and a novel DNA vaccine in the treatment of pancreatic cancer in mice and explore the anti-tumor mechanism of this combination therapy. Fibroblast activation protein α-expressing cancer-associated fibroblasts (FAPα+ CAFs), a dominant component of the tumor microenvironment (TME), have been shown to modulate the extracellular matrix (ECM) to promote the growth, invasion, and metastasis of pancreatic cancer (PC). Therefore, FAPα+ CAFs may be an ideal target for the treatment of PC. However, treatments that solely target FAPα+ CAFs do not directly affect tumor cells. We recently constructed a novel chimeric DNA vaccine (OsFS) against human FAPα and survivin, which simultaneously targets FAPα+ CAFs and tumor cells. In Panc02 tumor-bearing mice, OsFS vaccination not only reduced the proportion of immunosuppressive cells but also promoted the recruitment of tumor-infiltrating lymphocytes, which remodeled the TME to support anti-tumor immune responses. Furthermore, after depletion of regulatory T cells (Tregs) by metronomic low-dose Gem therapy, the anti-tumor effects of OsFS were enhanced. Taken together, our results indicate that the combination of the FAPα/survivin co-targeting DNA vaccine and low-dose Gem may be an effective therapy for PC.
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BACKGROUND: Pulmonary arterial hypertension maintains rapid cell proliferation and vascular remodeling through metabolic reprogramming. Recent studies suggested that circRNAs play important role in pulmonary vascular remodeling and pulmonary arterial smooth muscle cells proliferation. However, the relationship between circRNA, cell proliferation, and metabolic reprogramming in pulmonary arterial hypertension has not been investigated. METHODS: RNA-seq and qRT-PCR reveal the differential expression profile of circRNA in pulmonary arteries of pulmonary arterial hypertension rat models. Transfection was used to examine the effects of circSMOC1 on pulmonary artery smooth muscle cells, and the roles of circSMOC1 in vivo were investigated by adenoassociated virus. Mass spectrometry, RNA pull-down, RNA immunoprecipitation, and dual-luciferase reporter assay were performed to investigate the signaling pathway of circSMOC1 regulating the metabolic reprogramming. RESULTS: CircSMOC1 was significantly downregulated in pulmonary arteries of pulmonary arterial hypertension rats. CircSMOC1 knockdown promoted proliferation and migration and enhanced aerobic glycolysis of pulmonary artery smooth muscle cells. CircSMOC1 overexpression in vivo alleviates pulmonary vascular remodeling, right ventricular pressure, and right heart hypertrophy. In the nucleus, circSMOC1 directly binds to PTBP1 (polypyrimidine tract-binding protein), competitively inhibits the specific splicing of PKM (pyruvate kinase M) premRNA, resulting in the upregulation of PKM2 (pyruvate kinase M2), the key enzyme of aerobic glycolysis, to enhance glycolysis. In the cytoplasm, circSMOC1 acted as a miR-329-3p sponge, and its reduction in pulmonary arterial hypertension suppressed PDHB (pyruvate dehydrogenase E1 subunit beta) expression, leading to the impairment of mitochondrial oxidative phosphorylation. CONCLUSIONS: circSMOC1 is crucially involved in the metabolic reprogramming of pulmonary artery smooth muscle cells through PTBP1 and miR-329-3p to regulate pulmonary vascular remodeling in pulmonary arterial hypertension.
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MicroARNs , Proteína de Unión al Tracto de Polipirimidina , Hipertensión Arterial Pulmonar , ARN Circular , Animales , Ratas , Proliferación Celular/genética , MicroARNs/genética , MicroARNs/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteína de Unión al Tracto de Polipirimidina/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Hipertensión Arterial Pulmonar/genética , Arteria Pulmonar/metabolismo , Piruvato Quinasa/genética , Piruvato Quinasa/metabolismo , Piruvato Quinasa/farmacología , ARN Circular/genética , Remodelación Vascular/genéticaRESUMEN
Quercetin exerts anti-inflammatory, anti-oxidant and other protective effects. Previous studies have shown that senescent cells, such as fibroblasts and type II airway epithelial cells, are strongly implicated in the development of pulmonary fibrosis pathology. However, the role of senescent macrophages during silicosis remains unclear. We investigated the effects of quercetin on macrophage senescence and pulmonary fibrosis, and explored underlying mechanisms. Mice were randomized to six model groups. Vitro model was also established by culturing RAW264.7 macrophages with silica (SiO2). We examined the effects of quercetin on fibrosis, senescence-associated ß-galactosidase (SA-ß-Gal) activity, and senescence-specific genes (p16, p21, and p53). We showed that quercetin reduced pulmonary fibrosis and inhibited extracellular matrix (ECM) formation. Quercetin also attenuated macrophage senescence induced by SiO2 both in vitro and in vivo. In addition, quercetin significantly decreased the expressions of the senescence-associated secretory phenotype (SASP), including proinflammatory factors (interleukin-1α (Il-1α), Il-6, tumor necrosis factor-α (TNF-α), and transforming growth factor-ß1 (TGF-ß1)) and matrix metalloproteinases (MMP2, MMP9, and MMP12). In conclusion, quercetin mediated its anti-fibrotic effects by inhibiting macrophage senescence, possibly via SASP.
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Low-magnitude (≤1 g) high-frequency (≥30 Hz) (LMHF) vibration has been shown to enhance bone mineral density. However, its regulation in breast cancer bone metastasis remains controversial for breast cancer patients and elder populations. Yoda1, an activator of the mechanosensitive Piezo1 channel, could potentially intensify the effect of LMHF vibration by enhancing the mechanoresponse of osteocytes, the major mechanosensory bone cells with high expression of Piezo1. In this study, we treated osteocytes with mono- (Yoda1 only or vibration only) or combined treatment (Yoda1 and LMHF vibration) and examined the further regulation of osteoclasts and breast cancer cells through the conditioned medium. Moreover, we studied the effects of combined treatment on breast cancer cells in regulation of osteocytes. Combined treatment on osteocytes showed beneficial effects, including increasing the nuclear translocation of Yes-associated protein (YAP) in osteocytes (488.0%, p < 0.0001), suppressing osteoclastogenesis (34.3%, p = 0.004), and further reducing migration of MDA-MB-231 (15.1%, p = 0.02) but not Py8119 breast cancer cells (4.2%, p = 0.66). Finally, MDA-MB-231 breast cancer cells subjected to the combined treatment decreased the percentage of apoptotic osteocytes (34.5%, p = 0.04) but did not affect the intracellular calcium influx. This study showed the potential of stimulating Piezo1 in enhancing the mechanoresponse of osteocytes to LMHF vibration and further suppressing breast cancer migration via osteoclasts.
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Background: Anal disease has a significant impact on patients' quality of life (QoL), and surgical treatment may further diminish QoL. The purpose of this study was to conduct bibliometric analysis to investigate the profile of studies on anorectal disease-related QoL. Methods: The database of Science Citation Index Expanded (SCI-E) in Web of Science Core Collection (WOSCC) was searched. The search terms were "anal diseases" and "quality of life". The bibliometrix package of R software was used to analyze the literature on anorectal diseases and QoL. The content of the analysis included the following: the number of papers published in this field by each country, the cooperation relationship between countries, the number of papers published by institutions, the cooperation relationship between institutions, the number of papers published by researchers, the cooperation relationship between researchers, the citations of researchers, the number of articles published in journals, and the use of keywords. Results: A total of 1,130 related research literature records were retrieved in this study. An annually increasing trend was detected in the number of published papers and the number of citations. Developed countries in Europe and America, mainly the United States, the United Kingdom (UK), and Germany, were in a leading position in this field. The Cleveland Clinic Foundation and Mayo Clinic in the United States, St. Mark's Hospital in the UK, and the University of Toronto in Canada were the leading research institutions in this field. The top 3 researchers with the most published papers were Feza H. Remzi, Bo Shen, and Victor W. Fazio. Collaboration among researchers was clustered. There were more high-quality related articles in professional journals of anal diseases. The use of keywords suggested a temporal change in research focus, but randomized controlled studies were found to be lacking. Conclusions: Asian countries should participate in more collaborative research projects in the field of anorectal disease, and more randomized controlled studies should be conducted overall.
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Conventional DNA vaccine strategies usually employ a regimen of immunizations at 2-week or longer intervals to induce effective memory cell-dependent immune responses. Clinical cancer treatment requires a faster immunization strategy to contend with tumor progression. In this study, a novel fast immunization strategy was established, wherein a DNA vaccine was intramuscularly administered on days 0, 2, and 5 in a murine lung cancer model. Effector cells peaked 7 to 10 days after the last vaccination. Compared with traditional 2-week-interval immunization strategies, antigen-specific cytolysis and INF-γ secretion were significantly enhanced under the fast vaccination approach. As a result, the rapidly administered DNA vaccine elicited stronger and more prompt antitumor effects. The probable underlying mechanism of fast immunization was the accumulation of CD8+CD11c+ antigen-presenting cells at the injection site, which enhanced subsequent antigen presentation. In conclusion, the fast DNA vaccination strategy shortened vaccination time to 5 days and elicited a stronger antitumor immune response.
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BACKGROUND: Silica-induced inflammatory activation is associated with silicosis and various non-respiratory conditions. The present study was designed to examine the anti-inflammatory effects of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) on lung macrophages and bone osteoclasts after silica inhalation in rats. METHODS: Wistar rats and NR8383 and RAW 264.7 cell lines were used in the present study. The receptor activator of nuclear factor kappa-B ligand (RANKL) and toll-like receptor 4 (TLR4) signaling pathways was measured in the lung tissue of rats or NR8383/RAW 264.7 cells exposed to silica. The microarchitecture of the trabecular bone in the tibia and femur was evaluated in silicotic rats. Furthermore, the roles of Ac-SDKP on silicotic rats, silica-treated NR8383/RAW 264.7 cells, and RANKL-induced osteoclast differentiation were studied. RESULTS: The data indicated that silica inhalation might activate the RANKL and TLR4 signaling pathways in lung macrophages, thus inducing the lung inflammatory and proteolytic phenotype of macrophages and osteoclasts in lung and bone. Ac-SDKP maintained the lung elastin level by inhibiting lung inflammation and macrophage activation via the RANKL and TLR4 signaling pathways. Ac-SDKP also attenuated the reduction in femoral bone mineral density in silicotic rats by inhibiting osteoclast differentiation via the RANKL signaling pathway. CONCLUSION: Our findings support the hypothesis that inhalation of crystalline silica induces activation of lung macrophages and bone osteoclasts via the RANKL and TLR4 signaling pathways. Ac-SDKP has the potential to stabilize lung homeostasis and bone metabolism.
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Matrix stiffness is a driver of breast cancer progression and mechanosensitive transcriptional activator YAP plays an important role in this process. However, the interplay between breast cancer and matrix stiffness, and the significance of this interplay remained largely unknown. Here, we showed an increase in YAP nuclear localization and a higher proliferation rate in both highly metastatic MDA-MB-231 cells and the non-metastatic counterpart MCF-7 cells when they were exposed to the stiff matrix. However, in response to the stiff matrix highly metastatic MDA-MB-231 cells instead of MCF-7 cells exhibited upregulated mobility, which was shown to be YAP-dependent. Consistently, MDA-MB-231 cells exhibited different focal adhesion dynamics from MCF-7 cells in response to matrix stiffness. These results suggested a YAP-dependent mechanism through which matrix stiffness regulates the migratory potential of metastatic breast cancer cells.
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The ongoing COVID-19 outbreak have posed a significant threat to public health worldwide. Recently Toll-like receptor (TLR) has been proposed to be the drug target of SARS-CoV-2 treatment, the specificity and efficacy of such treatments remain unknown. In the present study we performed the investigation of repurposed drugs via a framework comprising of Search Tool for Interacting Chemicals (STITCH), Kyoto Encyclopedia of Genes and Genomes (KEGG), molecular docking, and virus-host-drug interactome mapping. Chloroquine (CQ) and hydroxychloroquine (HCQ) were utilized as probes to explore the interaction network that is linked to SARS-CoV-2. 47 drug targets were shown to be overlapped with SARS-CoV-2 network and were enriched in TLR signaling pathway. Molecular docking analysis and molecular dynamics simulation determined the direct binding affinity of TLR9 to CQ and HCQ. Furthermore, we established SARS-CoV-2-human-drug protein interaction map and identified the axis of TLR9-ERC1-Nsp13 and TLR9-RIPK1-Nsp12. Therefore, the elucidation of the interactions of SARS-CoV-2 with TLR9 axis will not only provide pivotal insights into SARS-CoV-2 infection and pathogenesis but also improve the treatment against COVID-19.