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Polycaprolactone (PCL) implants in large animals show great promise for tracheal transplantation. However, the longest survival time achieved to date is only about three weeks. To meet clinical application standards, it is essential to extend the survival time and ensure the complete integration and functionality of the implant. Our study investigates the use of three-dimensional (3D)-printed, biodegradable, PCL-based tracheal grafts for large-scale porcine tracheal transplantation, assessing the feasibility and early structural integrity crucial for long-term survival experiments. A biodegradable PCL tracheal graft was fabricated using a BIOX bioprinter and transplanted into large-scale porcine models. The grafts, measuring 20 × 20 × 1.5 mm, were implanted following a 2 cm circumferential resection of the porcine trachea. The experiment design was traditionally implanted in eight porcines to replace four-ring tracheal segments, only two of which survived more than three months. Data were collected on the graft construction and clinical outcomes. The 3D-printed biosynthetic grafts replicated the native organ with high fidelity. The implantations were successful, without immediate complications. At two weeks, bronchoscopy revealed significant granulation tissue around the anastomosis, which was managed with laser ablation. The presence of neocartilage, neoglands, and partial epithelialization near the anastomosis was verified in the final pathology findings. Our study demonstrates in situ regenerative tissue growth with intact cartilage following transplantation, marked by neotissue formation on the graft's exterior. The 90-day survival milestone was achieved due to innovative surgical strategies, reinforced with strap muscle attached to the distal trachea. Further improvements in graft design and granulation tissue management are essential to optimize outcomes.
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The integrated stress response (ISR) is a key cellular signaling pathway activated by environmental alterations that represses protein synthesis to restore homeostasis. To prevent sustained damage, the ISR is counteracted by the upregulation of growth arrest and DNA damage-inducible 34 (GADD34), a stress-induced regulatory subunit of protein phosphatase 1 that mediates translation reactivation and stress recovery. Here, we uncover a novel ISR regulatory mechanism that post-transcriptionally controls the stability of PPP1R15A mRNA encoding GADD34. We establish that the 3' untranslated region of PPP1R15A mRNA contains an active AU-rich element (ARE) recognized by proteins of the ZFP36 family, promoting its rapid decay under normal conditions and stabilization for efficient expression of GADD34 in response to stress. We identify the tight temporal control of PPP1R15A mRNA turnover as a component of the transient ISR memory, which sets the threshold for cellular responsiveness and mediates adaptation to repeated stress conditions.
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Regiones no Traducidas 3' , Proteína Fosfatasa 1 , Animales , Humanos , Ratones , Regiones no Traducidas 3'/genética , Adaptación Fisiológica/genética , Elementos Ricos en Adenilato y Uridilato/genética , Células HEK293 , Proteína Fosfatasa 1/metabolismo , Proteína Fosfatasa 1/genética , Estabilidad del ARN/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , Estrés Fisiológico/genética , Tristetraprolina/metabolismo , Tristetraprolina/genéticaRESUMEN
It is estimated that millions of people around the world experience various types of tissue injuries every year. Regenerative medicine was born and developed for understanding and application with the aim of replacing affected organs or some cells. The research, manufacture, production, and distribution of RNA in cells have acted as a basic foundation for the development and testing of therapies and treatments that are widely applied in different fields of medicine. Vaccines against COVID-19 are considered one of the brilliant and outstanding successes of RNA therapeutics research. With the characteristics of bio-derived RNA therapeutics, the mechanism of rapid implementation, safe production, and flexibility to create proteins depending on actual requirements. Based on the advantages above in this review, we discuss RNA therapeutics for regenerative medicine, and the types of RNA therapies currently being used for regenerative medicine. The relationship between disease and regenerative medicine is currently being studied or tested in RNA therapeutics. We have also covered the mechanisms of action of RNA therapy for regenerative medicine and some of the limitations in our current understanding of the effects of RNA therapy in this area. Additionally, we have also covered developing RNA therapeutics for regenerative medicine, focusing on RNA therapeutics for regenerative medicine. As a final point, we discuss potential applications for therapeutics for regenerative medicine in the future, as well as their mechanisms.
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ARN , Medicina Regenerativa , Humanos , ARN/uso terapéutico , Vacunas contra la COVID-19RESUMEN
The prevalence of metabolic disorders is increasing exponentially and has recently reached epidemic levels. Over the decades, a large number of therapeutic options have been proposed to manage these diseases but still show several limitations. In this circumstance, RNA therapeutics have rapidly emerged as a new hope for patients with metabolic diseases. 57 years have elapsed from the discovery of mRNA, a large number of RNA-based drug candidates have been evaluated for their therapeutic effectiveness and clinical safety under clinical studies. To date, there are seven RNA drugs for treating metabolic disorders receiving official approval and entering the global market. Their targets include hereditary transthyretin-mediated amyloidosis (hATTR), familial chylomicronemia syndrome, acute hepatic porphyria, primary hyperoxaluria type 1 and hypercholesterolemia, which are all related to liver proteins. All of these seven RNA drugs are antisense oligonucleotides (ASO) and small interfering RNA (siRNA). These two types of treatment are both based on oligonucleotides complementary to target RNA through Watson-Crick base-pairing, but their mechanisms of action include different nucleases. Such treatments show greatest potential among all types of RNA therapeutics due to consecutive achievements in chemical modifications. Another method, mRNA therapeutics also promise a brighter future for patients with a handful of drug candidates currently under development.
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Neuropatías Amiloides Familiares , Oligonucleótidos Antisentido , Oligonucleótidos , Humanos , Oligonucleótidos/uso terapéutico , Oligonucleótidos Antisentido/uso terapéutico , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/uso terapéutico , ARN MensajeroRESUMEN
Human adipose-derived stem cells (ASCs) have shown immense potential for regenerative medicine. Our previous work demonstrated that chitosan nano-deposited surfaces induce spheroid formation and differentiation of ASCs for treating sciatic nerve injuries. However, the underlying cell fate and differentiation mechanisms of ASC-derived spheroids remain unknown. Here, we investigate the epigenetic regulation and signaling coordination of these therapeutic spheroids. During spheroid formation, we observed significant increases in histone 3 trimethylation at lysine 4 (H3K4me3), lysine 9 (H3K9me3), and lysine 27 (H3K27me3), accompanied by increased histone deacetylase (HDAC) activities and decreased histone acetyltransferase activities. Additionally, HDAC5 translocated from the cytoplasm to the nucleus, along with increased nuclear HDAC5 activities. Utilizing single-cell RNA sequencing (scRNA-seq), we analyzed the chitosan-induced ASC spheroids and discovered distinct cluster subpopulations, cell fate trajectories, differentiation traits, and signaling networks using the 10x Genomics platform, R studio/language, and the Ingenuity Pathway Analysis (IPA) tool. Specific subpopulations were identified within the spheroids that corresponded to a transient reprogramming state (Cluster 6) and the endpoint cell state (Cluster 3). H3K4me3 and H3K9me3 were discovered as key epigenetic regulators by IPA to initiate stem cell differentiation in Cluster 6 cells, and confirmed by qPCR and their respective histone methyltransferase inhibitors: SNDX-5613 (a KMT2A inhibitor for H3K4me3) and SUVi (an SUV39H1 inhibitor for H3K9me3). Moreover, H3K9me3 and HDAC5 were involved in regulating downstream signaling and neuronal markers during differentiation in Cluster 3 cells. These findings emphasize the critical role of epigenetic regulation, particularly H3K4me3, H3K9me3, and HDAC5, in shaping stem cell fate and directing lineage-specific differentiation.
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Quitosano , Histonas , Humanos , Histonas/metabolismo , Epigénesis Genética , Lisina/metabolismo , Diferenciación Celular , Células Madre , Histona DesacetilasasRESUMEN
Introduction: Compressive neuropathy, a common chronic traumatic injury of peripheral nerves, leads to variable impairment in sensory and motor function. Clinical symptoms persist in a significant portion of patients despite decompression, with muscle atrophy and persistent neuropathic pain affecting 10%-25% of cases. Excessive inflammation and immune cell infiltration in the injured nerve hinder axon regeneration and functional recovery. Although adipose-derived stem cells (ASCs) have demonstrated neural regeneration and immunomodulatory potential, their specific effects on compressive neuropathy are still unclear. Methods: We conducted modified CCI models on adult male Sprague-Dawley rats to induce irreversible neuropathic pain and muscle atrophy in the sciatic nerve. Intraneural ASC injection and nerve decompression were performed. Behavioral analysis, muscle examination, electrophysiological evaluation, and immunofluorescent examination of the injured nerve and associated DRG were conducted to explore axon regeneration, neuroinflammation, and the modulation of inflammatory gene expression. Transplanted ASCs were tracked to investigate potential beneficial mechanisms on the local nerve and DRG. Results: Persistent neuropathic pain was induced by chronic constriction of the rat sciatic nerve. Local ASC treatment has demonstrated robust beneficial outcomes, including the alleviation of mechanical allodynia, improvement of gait, regeneration of muscle fibers, and electrophysiological recovery. In addition, locally transplanted ASCs facilitated axon remyelination, alleviated neuroinflammation, and reduced inflammatory cell infiltration of the injured nerve and associated dorsal root ganglion (DRG). Trafficking of the transplanted ASC preserved viability and phenotype less than 7 days but contributed to robust immunomodulatory regulation of inflammatory gene expression in both the injured nerve and DRG. Discussion: Locally transplanted ASC on compressed nerve improve sensory and motor recoveries from irreversible chronic constriction injury of rat sciatic nerve via alleviation of both local and remote neuroinflammation, suggesting the promising role of adjuvant ASC therapies for clinical compressive neuropathy.
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Cancer is a dangerous disease and one of the leading causes of death in the world. In 2020, there were nearly 10 million cancer deaths and approximately 20 million new cases. New cases and deaths from cancer are expected to increase further in the coming years. To have a deeper insight into the mechanism of carcinogenesis, epigenetics studies have been published and received much attention from scientists, doctors, and patients. Among alterations in epigenetics, DNA methylation and histone modification are studied by many scientists. They have been reported to be a major contributor in tumor formation and are involved in metastasis. From the understanding of DNA methylation and histone modification, effective, accurate and cost-effective methods for diagnosis and screening of cancer patients have been introduced. Furthermore, therapeutic approaches and drugs targeting altered epigenetics have also been clinically studied and have shown positive results in combating tumor progression. Several cancer drugs that rely on DNA methylation inactivation or histone modification have been approved by the FDA for the treatment of cancer patients. In summary, epigenetics changes such as DNA methylation or histone modification are take part in tumor growth, and they also have great prospect to study diagnostic and therapeutic methods of this dangerous disease.
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Carcinogénesis , Epigénesis Genética , Epigenómica , Neoplasias , Humanos , Carcinogénesis/genética , Metilación de ADN/genética , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patología , Neoplasias/terapia , Histonas/metabolismoRESUMEN
Over the last decade, stem cell-associated therapies are widely used because of their potential in self-renewable and multipotent differentiation ability. Stem cells have become more attractive for aesthetic uses and plastic surgery, including scar reduction, breast augmentation, facial contouring, hand rejuvenation, and anti-aging. The current preclinical and clinical studies of stem cells on aesthetic uses also showed promising outcomes. Adipose-derived stem cells are commonly used for fat grafting that demonstrated scar improvement, anti-aging, skin rejuvenation properties, etc. While stem cell-based products have yet to receive approval from the FDA for aesthetic medicine and plastic surgery. Moving forward, the review on the efficacy and potential of stem cell-based therapy for aesthetic and plastic surgery is limited. In the present review, we discuss the current status and recent advances of using stem cells for aesthetic and plastic surgery. The potential of cell-free therapy and tissue engineering in this field is also highlighted. The clinical applications, advantages, and limitations are also discussed. This review also provides further works that need to be investigated to widely apply stem cells in the clinic, especially in aesthetic and plastic contexts.
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Cirugía Plástica , Humanos , Tejido Adiposo/trasplante , Cicatriz , Células Madre , EstéticaRESUMEN
Mitral regurgitation (MR), the disruption of the mitral valve, contributes to heart failure (HF). Under conditions of volume overload, excess mineralocorticoids promote cardiac fibrosis. The mineralocorticoid receptor antagonist spironolactone is a potassium-sparing diuretic and a guideline-recommended therapy for HF, but whether it can ameliorate degenerative MR remains unknown. Herein, we investigate the efficacy of spironolactone in improving cardiac remodeling in MR-induced HF compared with that of a loop diuretic, furosemide. Using a novel and mini-invasive technique, we established a rat model of MR. We treated the rats with spironolactone or furosemide for twelve weeks. The levels of cardiac fibrosis, apoptosis, and stress-associated proteins were then measured. In parallel, we compared the cardiac remodeling of 165 patients with degenerative MR receiving either spironolactone or furosemide. Echocardiography was performed at baseline and at six months. In MR rats treated with spironolactone, left ventricular function-especially when strained-and the pressure volume relationship significantly improved compared to those of rats treated with furosemide. Spironolactone treatment demonstrated significant attenuation of cardiac fibrosis and apoptosis in left ventricular tissue compared to furosemide. Further, spironolactone suppressed the expression of apoptosis-, NADPH oxidase 4 (NOX4)- and inducible nitric oxide synthase (iNOS)-associated proteins. Similarly, compared with MR patients receiving furosemide those prescribed spironolactone demonstrated a trend toward reduction in MR severity and showed improvement in left ventricular function. Collectively, MR-induced cardiovascular dysfunction, including fibrosis and apoptosis, was effectively attenuated by spironolactone treatment. Our findings suggest a potential therapeutic option for degenerative MR-induced HF.
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Insuficiencia Cardíaca , Insuficiencia de la Válvula Mitral , Animales , Fibrosis , Furosemida , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Insuficiencia de la Válvula Mitral/complicaciones , Insuficiencia de la Válvula Mitral/tratamiento farmacológico , Ratas , Receptores de Mineralocorticoides/metabolismo , Espironolactona/farmacología , Espironolactona/uso terapéutico , Remodelación Ventricular/fisiologíaRESUMEN
In the large full-thickness mouse skin regeneration model, wound-induced hair neogenesis (WIHN) occurs in the wound center. This implies a spatial regulation of hair regeneration. The role of mechanotransduction during tissue regeneration is poorly understood. Here, we created wounds with equal area but different shapes to understand if perturbing mechanical forces change the area and quantity of de novo hair regeneration. Atomic force microscopy of wound stiffness demonstrated a stiffness gradient across the wound with the wound center softer than the margin. Reducing mechanotransduction signals using FAK or myosin II inhibitors significantly increased WIHN and, conversely, enhancing these signals with an actin stabilizer reduced WIHN. Here, α-SMA was downregulated in FAK inhibitor-treated wounds and lowered wound stiffness. Wound center epithelial cells exhibited a spherical morphology relative to wound margin cells. Differential gene expression analysis of FAK inhibitor-treated wound RNAseq data showed that cytoskeleton-, integrin-, and matrix-associated genes were downregulated, while hair follicular neogenesis, cell proliferation, and cell signaling genes were upregulated. Immunohistochemistry staining showed that FAK inhibition increased pSTAT3 nuclear staining in the regenerative wound center, implying enhanced signaling for hair follicular neogenesis. These findings suggest that controlling wound stiffness modulates tissue regeneration encompassing epithelial competence, tissue patterning, and regeneration during wound healing.
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In this study, [Sr0.99Eu0.01]3MgSi2O8 phosphors were sintered at 1200-1400 °C for 1-5 h by using the solid-state reaction method. The crystallinity and morphology of these phosphors were characterized through X-ray diffraction analysis and field-emission scanning electron microscopy, respectively, to determine their luminescence. The photoluminescence properties, including the excitation and emission properties, of the prepared phosphors were investigated through fluorescence spectrophotometry. The α-Sr2SiO4, Sr2MgSi2O7, and Sr3MgSi2O8 phases coexisted in the [Sr0.99Eu0.01]3MgSi2O8 phosphors, which were synthesized at low temperatures. The particles of these phosphors had many fine hairs on their surface and resembled Clavularia viridis, which is a coral species. Transmission electron microscopy and energy dispersive X-ray spectroscopy indicated that the fine hairs contained the Sr2SiO4 and Sr2MgSi2O7 phases. However, when the [Sr0.99Eu0.01]3MgSi2O8 phosphors were sintered at 1400 °C, the Sr3MgSi2O8 phase was observed, and the Eu2+-doped Sr3MgSi2O8 phase dominated the only broad emission band, which had a central wavelength of 457 nm (blue light). The emission peaks at this wavelength were attributed to the 4f65d1-4f7 transition at the Sr2+(I) site, where Sr2+ was substituted by Eu2+. The average decay time of the synthesized phosphors was calculated to be 1.197 ms. The aforementioned results indicate that [Sr0.99Eu0.01]3MgSi2O8 can be used as a blue-emitting phosphor in ultraviolet-excited white light-emitting diodes.
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The failure of peripheral nerve regeneration is often associated with the inability to generate a permissive molecular and cellular microenvironment for nerve repair. Autologous therapies, such as platelet-rich plasma (PRP) or its derivative platelet-rich growth factors (PRGF), may improve peripheral nerve regeneration via unknown mechanistic roles and actions in macrophage polarization. In the current study, we hypothesize that excessive and prolonged inflammation might result in the failure of pro-inflammatory M1 macrophage transit to anti-inflammatory M2 macrophages in large nerve defects. PRGF was used in vitro at the time the unpolarized macrophages (M0) macrophages were induced to M1 macrophages to observe if PRGF altered the secretion of cytokines and resulted in a phenotypic change. PRGF was also employed in the nerve conduit of a rat sciatic nerve transection model to identify alterations in macrophages that might influence excessive inflammation and nerve regeneration. PRGF administration reduced the mRNA expression of tumor necrosis factor-α (TNFα), interleukin-1ß (IL-1ß), and IL-6 in M0 macrophages. Increased CD206 substantiated the shift of pro-inflammatory cytokines to the M2 regenerative macrophage. Administration of PRGF in the nerve conduit after rat sciatic nerve transection promoted nerve regeneration by improving nerve gross morphology and its targeted gastrocnemius muscle mass. The regenerative markers were increased for regrown axons (protein gene product, PGP9.5), Schwann cells (S100ß), and myelin basic protein (MBP) after 6 weeks of injury. The decreased expression of TNFα, IL-1ß, IL-6, and CD68+ M1 macrophages indicated that the inflammatory microenvironments were reduced in the PRGF-treated nerve tissue. The increase in RECA-positive cells suggested the PRGF also promoted angiogenesis during nerve regeneration. Taken together, these results indicate the potential role and clinical implication of autologous PRGF in regulating inflammatory microenvironments via macrophage polarization after nerve transection.
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Long considered as no more than biological waste meant to be eliminated in urine, glucuronides have recently contributed to tremendous developments in the biomedical field, particularly against cancer. While glucuronide prodrugs monotherapy and antibody-directed enzyme prodrug therapy have been around for some time, new facets have emerged that combine the unique properties of glucuronides notably in the fields of antibody-drug conjugates and nanomedicine. In both cases, glucuronides are utilized as a vector to improve pharmacokinetics and confer localized activation of potent drugs at tumor sites while also decreasing systemic toxicity. Here we will discuss some of the most promising strategies using glucuronides to promote successful anti-tumor therapeutic treatments.
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Inmunoconjugados , Neoplasias , Profármacos , Glucuronidasa , Glucurónidos , Humanos , Inmunoconjugados/uso terapéutico , Neoplasias/tratamiento farmacológico , Profármacos/farmacocinéticaRESUMEN
The perceived size of an object depends on its spatial context, in addition to its projected image on the retina and perceived distance. However, how these factors interact with each other to affect perceived object size is still not clear. In this study, we manipulated the binocular disparity of images to assess the effect of perceived distance on perceived object size, as well as background element size to assess the effect of context. The perceived target size under different combinations of perceived distance and context was measured with a two-interval forced-choice paradigm, in which one interval contained a standard disk with a textured background while the other contained a comparison disk on a blank background in each trial. The observers were instructed to indicate which interval contained a larger disk. A staircase procedure was used to measure the point of subjective equality for the perceived target size. Our results showed that the perceived target size increased with the perceived distance while decreased with background element size. In addition, context modulated the relationship between the perceived target size and perceived distance. The data can be explained by a computational model that incorporates several size selective channels whose size sensitivity to a stimulus can be modulated by its disparity. The target response of each channel is subjected to the divisive inhibition signal from the size information in the context. The perceived size is determined by the weighted average of the responses of these size channels. This model can explain more than 91% of variability in the averaged data. Thus, while both perceived distance and context can affect the perceived size of an object, they exert the effect through different mechanisms.
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Percepción de Distancia , Disparidad Visual , Percepción de Distancia/fisiología , Humanos , Percepción del Tamaño/fisiologíaRESUMEN
In this study, a new class of thermosensitive poly(N-isopropylacrylamide)-co-poly(acrylic acid) (P(NIPAAm-co-AAc))-grafted modified silica (m-silica) nanocomposites was prepared using a sol-gel technique. The addition of silica to P(NIPAAm-co-AAc) copolymer hydrogel has the potential to open up new applications in the development of thermosensitive building materials by leveraging the favorable thermal characteristics of P(NIPAAm-co-AAc). The silica was prepared using 3-aminopropyltriethoxysilane and 4,4'-azobis(4-cyanovaleric acid) to form the m-silica powder, which increased the adhesion between the organic and inorganic hybrid materials. The P(NIPAAm-co-AAc) copolymer hydrogel was mixed with the m-silica to form the P(NIPAAm-co-AAc)-grafted m-silica nanocomposites. Scanning electron microscopy, X-ray diffraction analysis, thermogravimetric analysis, Fourier-transform infrared spectroscopy, and thermosensitive measurement were conducted to evaluate the structure and water-holding capacity of the nanocomposites. The results indicated that the P(NIPAAm-co-AAc)-grafted m-silica nanocomposites could retain water for more than 300 min at temperatures higher than the lower critical solution temperature. The P(NIPAAm-co-AAc)-grafted m-silica nanocomposites exhibited favorable thermosensitive properties and may therefore be applied in smart architectural coatings.
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The current protocol aims to showcase the technology integration, providing a detailed description of adopting the HealthCloud app, developed by the Healthy Landscape and Healthy People Lab, National Taiwan University (HLHP-NTU), on smartphones and smartwatches to collect data on users' real-time psychological and physiological responses and environmental information. A flexible and integrated research method was proposed because it can be difficult to measure multi-dimensional aspects of personal data in on-site studies in landscape and outdoor recreation research. An on-site study conducted in 2020 at the National Taiwan University campus was used as an application example. A dataset of 385 participants was used after excluding invalid samples. During the experiment, participants were asked to walk around campus for 30 min when their heart rate and psychological-scale items were measured, together with several environmental metrics. This work aimed to provide a possible solution to help on-site studies track real-time human responses that match ambient factors. Due to the app's flexibility, its use on wearable devices shows excellent potential for multidisciplinary research studies.
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Aplicaciones Móviles , Dispositivos Electrónicos Vestibles , Estado de Salud , Humanos , Monitoreo Fisiológico , Teléfono InteligenteRESUMEN
Right ventricular (RV) failure is a major cause of mortality in pulmonary arterial hypertension (PAH), but its mechanism remains largely unknown. MicroRNA-21 (miR-21) is involved in flow-mediated stress in the vasculature, but its effects on RV remodeling require investigations. Herein, we aim to study the mechanism of miR-21 in the early (compensated) and late (decompensated) phases of PAH-induced RV dysfunction. Using aorto-venous fistula (AVS) surgery, we established a rat model of PAH. To mimic the microenvironment of PAH, we treated cardiomyocytes with flow-mediated shear stress in 6 dyne for 3 and 8 h. To evaluate whether miR-21 could be a biomarker, we prospectively collected the sera of patients with congenital heart disease- (CHD) related PAH. Additionally, clinical, echocardiographic and right heart catheterization information was collected. The primary endpoint was hospitalization for decompensated heart failure (HF). It is of note that, despite an initial increase in miR-21 expression in hypertrophic RV post AVS, miR-21 expression decreased with RV dysfunction thereafter. Likewise, the activation of miR-21 in cardiomyocytes under shear stress at 3 h was downregulated at 6 h. The downregulated miR-21 at the late phase was associated with increased apoptosis in cardiomyocytes while miR-21 mimic rescued it. Among 76 CHD-induced PAH patients, 19 who were hospitalized for heart failure represented with a significantly lower expression of circulating miR-21. Collectively, our study revealed that the upregulation of miR-21 in the early phase (RV hypertrophy) and downregulation in the late phase (RV dysfunction) under PAH triggered a biphasic regulation of cardiac remodeling and cardiomyocyte apoptosis.
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Cardiopatías Congénitas , Insuficiencia Cardíaca , MicroARNs , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Animales , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Humanos , Hipertrofia Ventricular Derecha/metabolismo , MicroARNs/metabolismo , Hipertensión Arterial Pulmonar/genética , Ratas , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/metabolismoRESUMEN
Fibroblast growth factor 9 (FGF9) modulates cell proliferation, differentiation and motility for development and tissue repair in normal cells. Growing evidence shows that abnormal activation of FGF9 signaling is associated with tumor malignancy. We have previously reported that FGF9 increases MA-10 mouse Leydig tumor cell proliferation, in vitro, and tumor growth, in vivo. Also, FGF9 promotes the tumor growth and liver metastasis of mouse Lewis lung cancer cells, in vivo. However, the effects of FGF9 in the early stage of tumorigenesis remains elusive. In this study, TM3 mouse Leydig progenitor cells, that are not tumorigenic in immunocompromised mice, were used as a model cell line to investigate the role of FGF9 in tumorigenesis. The results demonstrated that FGF9 significantly induced cell proliferation and activated the MAPK, PI3K and PLCγ signaling pathways in TM3 cells. The percentage of the cell number in G1 phase was reduced and that in S and G2/M phases was increased after FGF9 stimulation in TM3 cells. Cyclin D1, cyclin A1, CDK2, CDK1, and p21 expressions and the phosphorylation level of Rb were all induced in FGF9-treated TM3 cells. In addition, FGF9 increased the expression of FGF receptor 1-4 in TM3 cells, suggesting the positive feedback loop between FGF9 and FGFRs. Furthermore, in the allograft mouse model, FGF9 promoted the tumorigenesis of TM3 cells characterized by higher expression of tumor markers, such as tumor necrosis factor alpha (TNFα) and α-fetoprotein (AFP), in the subcutaneously inoculated TM3 cell tissue. Conclusively, FGF9 induced cell cycle to increase cell proliferation of TM3 cells through FAK, MAPK, PI3K/Akt and PLCγ signaling pathways, in vitro, and promoted the tumorigenesis of TM3 cell allograft tissue, in vivo, which is a potential marker for tumor as well as a target for cancer therapeutic strategies.
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Escherichia coli is one of the most prevalent pathogens, causing a variety of infections including bloodstream infections. At the same time, it can be found as a commensal, being part of the intestinal microflora. While it is widely accepted that pathogenic strains can evolve from colonizing E. coli strains, the evolutionary route facilitating the commensal-to-pathogen transition is complex and remains not fully understood. Identification of the underlying mechanisms and genetic changes remains challenging. To investigate the factors involved in the transition from intestinal commensal to invasive E. coli causing bloodstream infections, we compared E. coli isolated from blood culture to isolates from the rectal flora of the same individuals by whole genome sequencing to identify clonally related strains and potentially relevant virulence factors. in vitro invasion assays using a Caco- 2 cell intestinal epithelial barrier model and a gut organoid model were performed to compare clonally related E. coli. The experiments revealed a correlation between the presence of an IncFII plasmid carrying hha and the degree of invasiveness. In summary, we provide evidence for the role of an IncFII plasmid in the transition of colonization to invasion in clinical E. coli isolates.
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COVID-19 is one of the most severe global health crises that humanity has ever faced. Researchers have restlessly focused on developing solutions for monitoring and tracing the viral culprit, SARS-CoV-2, as vital steps to break the chain of infection. Even though biomedical engineering (BME) is considered a rising field of medical sciences, it has demonstrated its pivotal role in nurturing the maturation of COVID-19 diagnostic technologies. Within a very short period of time, BME research applied to COVID-19 diagnosis has advanced with ever-increasing knowledge and inventions, especially in adapting available virus detection technologies into clinical practice and exploiting the power of interdisciplinary research to design novel diagnostic tools or improve the detection efficiency. To assist the development of BME in COVID-19 diagnosis, this review highlights the most recent diagnostic approaches and evaluates the potential of each research direction in the context of the pandemic.