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Arable land is facing the growing challenge of land degradation due to intensive use and this is beginning to affect global food security. However, active and passive restoration can improve soil characteristics and reshape microbial communities. Despite the increasing focus on changes in microbial communities during restoration, the mechanisms underlying how microbes drive the soil quality index (SQI) in arable land restoration remain unclear. In this study, we selected conventional farmland (CF, heavily intensified) and two restoration strategies (AR, artificial restoration; NR, natural restoration), with the same context (including soil texture, climate, etc.), and measured the microbial indicators over 2 years to investigate the mechanisms driving SQI improvement on restored arable land. The AR and NR treatments resulted in a 50% and 58% increase in SQI, respectively, compared to CF as soil nutrient levels increased, resulting in higher microbial biomasses and enzyme activities. Microbial abundance on the AR land was approximately two times greater than on the NR land due to the introduction of legumes. Bacterial diversity declined, while fungi developed in a more diverse direction under the restoration strategies. The AR and NR areas were mainly enriched with rhizobium (Microvirga, Bradyrhizobium), which contribute to healthy plant growth. The pathogenic fungi (Gibberella, Fusarium, Volutella) were more abundant in the CF area and the plant pathogen guild was about five times higher in the restored areas. Following arable land restoration, microbial life history strategies shifted from r-to K-strategists due to the higher proportion of recalcitrant SOC (DOC/SOC decreased by 18%-30%). The altered microbial community in the restored areas created new levels of functionality, with a 2.6%-4.3% decrease in bacterial energy metabolism (oxidative phosphorylation, C fixation, and N metabolism decreased by 7%, 4%, and 6%, respectively). Structural equation modelling suggested that restoration strategy affected SQI either directly by increasing total soil nutrient levels or indirectly by altering the microbial community and that fungal community composition and bacterial diversity made the largest contributions to SQI. These results provided new insights into soil quality improvement from a microbial perspective and can help guide future arable land restoration.
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Micobioma , Suelo , Bacterias/genética , Plantas , Biomasa , Hongos , Microbiología del SueloRESUMEN
Cupric ions (Cu2+), pyrophosphate (PPi), and alkaline phosphatase (ALP) are involved in a variety of biochemical processes such as DNA replication, cellular metabolism and play an important role in human growth and development. It is of great significance to establish a method for the sensitive detection of Cu2+, PPi and ALP. In this work, polyethyleneimine-capped silver nanoclusters (PEI-AgNCs) were successfully synthesized by a one-pot method using hydrazine sulfate as reductant, exhibiting a unique strong fluorescence emission in the near-ultraviolet region at â¼339 nm. Since the fluorescence of PEI-AgNCs can be quenched by Cu2+ through inner filtering effect (IFE), then recovered by competitive binding of pyrophosphate and Cu2+, and later weakened again by catalytic hydrolysis of alkaline phosphatase, a sensitive and selective strategy based on the changes of fluorescence "ON" or "OFF" was established to detect Cu2+, PPi and ALP. The LODs of these three analytes were 36 nM, 0.2 µM, and 0.14 U L-1 at a S/N ratio of 3, respectively. A series of logic gate circuits for sensing cupric ions, pyrophosphate, and alkaline phosphatase were successfully constructed. The established methods have the potential for biosensing and environmental analysis and the specific UV-A fluorescence property of PEI-AgNCs may be helpful in photonic and optical areas.
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Fosfatasa Alcalina , Cobre , Difosfatos , Nanopartículas del Metal , Polietileneimina , Plata , Espectrometría de Fluorescencia , Plata/química , Polietileneimina/química , Cobre/química , Nanopartículas del Metal/química , Fosfatasa Alcalina/análisis , Fosfatasa Alcalina/metabolismo , Difosfatos/análisis , Difosfatos/química , Espectrometría de Fluorescencia/métodos , Límite de Detección , Humanos , Fluorescencia , Rayos UltravioletaRESUMEN
BACKGROUND: Postharvest gray mold induced by Botrytis cinerea seriously affects cherry quality, resulting in huge economic losses. The aim of this study was to isolate and purify a novel antifungal compound from the endophytic Bacillus velezensis SJ100083 of cherries to prevent postharvest gray mold. RESULTS: In this study, Baelezcin A, extracted and purified from Bacillus velezensis SJ100083, was found effective in suppressing gray mold on cherries. Furthermore, the structure of Baelezcin A was identified as a novel cyclic lipopeptide with molecular formula of C52 H91 N7 O13 through ultra-high-performance liquid chromatography quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-HRMS) and nuclear magnetic resonance (NMR). Baelezcin A treatment at 25 mg L-1 significantly decreased the disease incidence and severity of cherry gray mold, the antifungal mechanism of which was attributed to the accumulation of reactive oxygen species within the spores and the leakage of mycelium cytoplasmal contents, resulting in a low rate of spore germination. Moreover, it was proven to be biologically safe within a certain range by MTT assays. CONCLUSION: Our study demonstrated that Baelezcin A from the culture of Bacillus velezensis SJ100083 may be a promising fruit preservative for controlling postharvest gray mold caused by Botrytis cinerea. © 2023 Society of Chemical Industry.
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Antifúngicos , Bacillus , Antifúngicos/farmacología , Botrytis , Lipopéptidos/farmacología , Enfermedades de las Plantas/prevención & control , Enfermedades de las Plantas/microbiologíaRESUMEN
The regulation of fibrotic activities is key to improving pathological remodelling post-myocardial infarction (MI). Currently, in the clinic, safe and curative therapies for cardiac fibrosis and improvement of the pathological fibrotic environment, scar formation and pathological remodelling post-MI are lacking. Previous studies have shown that miR-486 is involved in the regulation of fibrosis. However, it is still unclear how miR-486 functions in post-MI regeneration. Here, we first demonstrated that miR-486 targeting SRSF3/p21 mediates the senescence of cardiac myofibroblasts to improve their fibrotic activity, which benefits the regeneration of MI by limiting scar size and post-MI remodelling. miR-486-targeted silencing has high potential as a novel target to improve fibrotic activity, cardiac fibrosis and pathological remodelling.
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MicroARNs , Infarto del Miocardio , Cicatriz/patología , Fibrosis , Humanos , MicroARNs/genética , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Infarto del Miocardio/terapia , Miocardio/patología , Miofibroblastos/patología , Factores de Empalme Serina-Arginina/genéticaRESUMEN
AIMS: This study aimed to isolate active substances from metabolites of Bacillus amyloliquefaciens SJ100001 and examine their antifungal activity against Fusarium oxysporum (F. oxysporum) SJ300024 screened from the root-soil of cucumber wilt. METHODS AND RESULTS: An active substance, anti-SJ300024, was obtained from the fermentation broth of strain SJ100001 by reversed-phase silica gel and gel chromatography, and further got its chemical structure as cyclic lipopeptide Epichlicin through nuclear magnetic resonance (NMR) and mass spectrometry (MS). In vitro experiments showed that Epichlicin had a better inhibitory rate (67.46%) against the strain SJ300024 than the commercially available fungicide hymexazol (45.10%) at the same concentration. The MTT assays proved that Epichlicin was non-cytotoxic, besides it also had good free radical scavenging ability and total reducing ability. CONCLUSIONS: Epichlicin isolated from strain SJ100001 can effectively control F. oxysporum SJ300024 screened from the root-soil of cucumber wilt. SIGNIFICANCE AND IMPACT OF THE STUDY: Epichlicin may be used as an environmentally friendly and efficient biocontrol agent for controlling Fusarium wilt of cucumber and reducing crop losses. More importantly, the non-cytotoxicity of Epichlicin can avoid harm to consumers. Additionally, Epichlicin has broad application prospects in medicine due to its antioxidant properties.
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Bacillus amyloliquefaciens , Cucumis sativus , Fusarium , Bacillus amyloliquefaciens/metabolismo , Antifúngicos/química , Antioxidantes/farmacología , Antioxidantes/metabolismo , Antibacterianos/farmacología , Lipopéptidos/química , Suelo , Enfermedades de las Plantas/prevención & control , Enfermedades de las Plantas/microbiologíaRESUMEN
Phosphorus (P) limitation is a widespread problem of primary production in dryland submitted to persistent nitrogen (N) deposition. The legume alfalfa (Medicago sativa L.), which can fix N2, might potentially strengthen P limitation in dryland ecosystems and is widely distributed as forage. However, there is still unclear how alfalfa grassland mobilizes the soil P to meet its demand. In this experiment, alfalfa introduction was used for long-term revegetation to evaluate the P uptake of plants from deep soil and assess the P limitation induced by N deposition compared with fallow. Our results showed that alfalfa introduction increased the soil P storage significantly at 0-2.4 m soil depth (+0.74 Mg ha-1), whereas it decreased at 2.4-4.8 m soil depth (-0.21 Mg ha-1) after 15-year establishment. Alfalfa establishment increased soil organic P concentration (180.9 mg kg-1 vs. 67.2 mg kg-1) and its relative contribution to total P (19.64% vs. 8.08%) at 0-4.8 m. Alfalfa establishment also increased the concentration and proportion of labile and intermediate P fractions at 0-4.8 m (9.12 mg kg-1 vs. 6.87 mg kg-1, 1.12% vs. 0.98%; 16.06 mg kg-1 vs. 8.39 mg kg-1, 1.69% vs. 1.17%). Alfalfa introduction decreased the concentrated HCl-Pi (250.66 mg kg-1 vs. 229.32 mg kg-1, 36.81% vs. 28.91%) in 2.4-4.8 m soil depth. These results indicated that the deep root system of alfalfa grassland could promote the P mobilization from deep to shallow soil. The concentrated HCl-Pi may be the main potential P source of alfalfa from 2.4-4.8 m to 0-2.4 m of soil depth, and long-term establishment of alfalfa can alleviate P limitation caused by N deposition in carbonate soil. Our results suggested that species with deep roots (such as alfalfa) could be selected as an economical way to mitigate nitrogen deposition in drylands.
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Medicago sativa , Suelo , Nitrógeno/análisis , Fósforo , Ecosistema , CarbonatosRESUMEN
Recent research has revealed that cardiac telocytes (CTs) play an important role in cardiac physiopathology and the regeneration of injured myocardium. Recently, we reported that the adult Xenopus tropicalis heart can regenerate perfectly in a nearly scar-free manner after injury via apical resection. However, whether telocytes exist in the X tropicalis heart and are affected in the regeneration of injured X tropicalis myocardium is still unknown. The present ultrastructural and immunofluorescent double staining results clearly showed that CTs exist in the X tropicalis myocardium. CTs in the X tropicalis myocardium were mainly twined around the surface of cardiomyocyte trabeculae and linked via nanocontacts between the ends of the telopodes, forming a three-dimensional network. CTs might play a role in the regeneration of injured myocardium.
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Cardiopatías/patología , Corazón/fisiología , Telocitos/patología , Xenopus/fisiología , Animales , Miocitos Cardíacos/patología , Regeneración/fisiología , Telopodos/patologíaRESUMEN
Thus far, the cellular and molecular mechanisms related to early (especially within 24 hours after acute myocardial infarct (MI)) exercise-mediated beneficial effects on MI have not yet been thoroughly established. In the present study, we demonstrated that acute MI rats that underwent early moderate exercise training beginning one day after MI showed no increase in mortality and displayed significant improvements in MI healing and ventricular remodelling, including an improvement in cardiac function, a decrease in infarct size, cardiomyocyte apoptosis, cardiac fibrosis and cardiomyocyte hypertrophy, and an increase in myocardial angiogenesis, left ventricular wall thickness and the number of cardiac telocytes in the border zone. Integrated miRNA-mRNA profiling analysis performed by the ingenuity pathway analysis system revealed that the inhibition of the TGFB1 regulatory network, activation of leucocytes and migration of leucocytes into the infarct zone comprise the molecular mechanism underlying early moderate exercise-mediated improvements in cardiac fibrosis and the pathological inflammatory response. The findings of the present study demonstrate that early moderate exercise training beginning one day after MI is safe and leads to significantly enhanced MI healing and ventricular remodelling. Understanding the mechanism behind the positive effects of this early training protocol will help us to further tailor suitable cardiac rehabilitation programmes for humans.
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Inflamación/fisiopatología , Infarto del Miocardio/fisiopatología , Condicionamiento Físico Animal/fisiología , Remodelación Ventricular/fisiología , Animales , Apoptosis/genética , Modelos Animales de Enfermedad , Ecocardiografía , Femenino , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Corazón/fisiopatología , Humanos , Inflamación/genética , Inflamación/patología , MicroARNs/genética , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , ARN Mensajero/genética , Ratas Sprague-Dawley , Remodelación Ventricular/genéticaRESUMEN
Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well.
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Bacteriófagos/genética , Dependovirus/genética , Dependovirus/metabolismo , Vectores Genéticos , Tumores Neuroendocrinos/terapia , Octreótido/administración & dosificación , Neoplasias Pancreáticas/terapia , Virus Satélites/metabolismo , Animales , Femenino , Ligandos , Masculino , Ratones , Ratones TransgénicosRESUMEN
PURPOSE: MR spectroscopy (MRS) can improve diagnosis and follow treatment in cancer. However, no study has yet reported application of in vivo (1)H-MRS in malignant pancreatic lesions. This study quantitatively determined whether in vivo (1)H-MRS on multiple endocrine neoplasia type 1 (Men1) conditional knockout (KO) mice and their wild type (WT) littermates could detect differences in total choline (tCho) levels between tumor and control pancreas. METHODS: Relative tCho levels in pancreatic tumors or pancreata from KO and WT mice were determined using in vivo (1)H-MRS at 9.4 T. The levels of Cho-containing compounds were also quantified using in vitro (1)H-NMR on extracts of pancreatic tissues from KO and WT mice, respectively, and on extracts of pancreatic tissues from patients with pancreatic neuroendocrine tumors (PNETs). RESULTS: tCho levels measured by in vivo (1)H-MRS were significantly higher in PNETs from KO mice compared to the normal pancreas from WT mice. The elevated choline-containing compounds were also identified in pancreatic tumors from KO mice and tissues from patients with PNETs via in vitro (1)H-NMR. CONCLUSION: These results indicate the potential use of tCho levels estimated via in vivo (1)H-MRS in differentiating malignant pancreatic tumors from benign tumors.
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Imagen por Resonancia Magnética/métodos , Neoplasia Endocrina Múltiple Tipo 1/química , Neoplasia Endocrina Múltiple Tipo 1/diagnóstico , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/diagnóstico , Animales , Colina/análisis , Colina/química , Colina/metabolismo , Femenino , Masculino , Ratones , Ratones Noqueados , Neoplasia Endocrina Múltiple Tipo 1/patología , Neoplasias Pancreáticas/patología , Factores de Transcripción/genéticaRESUMEN
The midterm effects of cardiac telocytes (CTs) transplantation on myocardial infarction (MI) and the cellular mechanisms involved in the beneficial effects of CTs transplantation are not understood. In the present study, we have revealed that transplantation of CTs was able to significantly decrease the infarct size and improved cardiac function 14 weeks after MI. It has established that CT transplantation exerted a protective effect on the myocardium and this was maintained for at least 14 weeks. The cellular mechanism behind this beneficial effect on MI was partially attributed to increased cardiac angiogenesis, improved reconstruction of the CT network and decreased myocardial fibrosis. These combined effects decreased the infarct size, improved the reconstruction of the LV and enhanced myocardial function in MI. Our findings suggest that CTs could be considered as a potential cell source for therapeutic use to improve cardiac repair and function following MI, used either alone or in tandem with stem cells.
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Células Intersticiales de Cajal/trasplante , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Miocardio/patología , Animales , Antígenos CD34/metabolismo , Colágeno/metabolismo , Femenino , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Infarto del Miocardio/patología , Neovascularización Fisiológica , Proteínas Proto-Oncogénicas c-kit/metabolismo , Ratas Sprague-Dawley , Trasplante de Células MadreRESUMEN
Glial cells missing homolog 2 (GCM2) is a transcription factor that is expressed predominately in the pharyngeal pouches and, at later stages, in the developing and mature parathyroid glands. In humans, loss of GCM2 function, either through recessive apomorphic mutations or dominant inhibitor mutations in the human GCM2 gene, leads to isolated hypoparathyroidism. In mice, homozygous disruption of Gcm2 by conventional gene targeting results in parathyroid aplasia and hypoparathyroidism. In this study, we report the generation and functional characterization of mice encoding a conditional null allele of Gcm2. We demonstrate the functional integrity of the conditional Gcm2 allele and report successful in vivo deletion of exon 2 using Cre recombinase. The mice with conditional deletion of Gcm2 displayed phenotypes similar to those previously described for a conventional Gcm2 knockout, including perinatal lethality, hypocalemia, low or undetectable serum levels of parathyroid hormone, and absent parathyroid glands. The production of a conditional mutant allele for Gcm2 represents a valuable resource for the study of the temporal- and spatial-specific roles for Gcm2, and for understanding the postnatal activities of GCM2 protein.
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Integrasas/metabolismo , Proteínas Nucleares/fisiología , Glándulas Paratiroides/patología , Hormona Paratiroidea/metabolismo , Factores de Transcripción/fisiología , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación/genética , Glándulas Paratiroides/metabolismo , FenotipoRESUMEN
Recently, cardiac telocytes were found in the myocardium. However, the functional role of cardiac telocytes and possible changes in the cardiac telocyte population during myocardial infarction in the myocardium are not known. In this study, the role of the recently identified cardiac telocytes in myocardial infarction (MI) was investigated. Cardiac telocytes were distributed longitudinally and within the cross network of the myocardium, which was impaired during MI. Cardiac telocytes in the infarction zone were undetectable from approximately 4 days to 4 weeks after an experimental coronary occlusion was used to induce MI. Although cardiac telocytes in the non-ischaemic area of the ischaemic heart experienced cell death, the cell density increased approximately 2 weeks after experimental coronary occlusion. The cell density was then maintained at a level similar to that observed 1-4 days after left anterior descending coronary artery (LAD)-ligation, but was still lower than normal after 2 weeks. We also found that simultaneous transplantation of cardiac telocytes in the infarcted and border zones of the heart decreased the infarction size and improved myocardial function. These data indicate that cardiac telocytes, their secreted factors and microvesicles, and the microenvironment may be structurally and functionally important for maintenance of the physiological integrity of the myocardium. Rebuilding the cardiac telocyte network in the infarcted zone following MI may be beneficial for functional regeneration of the infarcted myocardium.
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Infarto del Miocardio/patología , Infarto del Miocardio/terapia , Miocardio/patología , Regeneración/fisiología , Células del Estroma/citología , Animales , Recuento de Células , Muerte Celular , Microambiente Celular , Oclusión Coronaria/complicaciones , Femenino , Inyecciones Intramusculares , Infarto del Miocardio/etiología , Ratas , Ratas Sprague-Dawley , Células del Estroma/fisiología , Células del Estroma/trasplanteRESUMEN
Introduction: Limited water and soil phosphorus (P) availability often hampers lucerne productivity in semiarid regions. Plastic film mulch and P application typically enhance young lucerne (2-3 years) productivity by increasing soil water use and P availability. However, the prolonged impact of film mulch and P application on lucerne productivity as the stand ages remains unclear. Methods: This study conducted a 9-year field experiment on the semiarid Loess Plateau to investigate how film mulch and P application affect lucerne forage yield, soil water content, and soil fertility. The field experiment used a split-plot design with randomized blocks, in which the whole plots were with (M1) and without plastic film mulch (M0), and the split plots were four P rates (0 (P0), 9.7 (P1), 19.2 (P2), and 28.8 (P3) kg P ha-1). Results and discussion: The M1 treatment produced significantly higher lucerne forage yields than the M0 treatment during the first five years, but the yield-increasing effect of film mulch gradually diminished over time, with no effect in Years 6-8, and lower yields than the M0 treatment in Year 9. Phosphorus fertilization significantly increased forage yield after Year 3 in the M0 treatment, but only in Years 3-5 in the M1 treatment. In Years 2-5, film mulch significantly increased soil organic carbon, total nitrogen (N), inorganic N, and microbial biomass carbon in P0, P1, and P2 but not in P3. However, in Years 7-9, film mulch significantly decreased soil available potassium (K), organic carbon mineralization, lucerne density, and shoot K concentration, but did not reduce soil N and P availability at any level P of application. Moreover, plastic film mulch significantly increased the soil water content at 0-300 cm deep from Year 7 onwards. In conclusion, film mulch ceased to enhance lucerne production beyond year 6, which could not be attributed to soil water content, N or P availability but was partially associated with reduced soil K availability. Consequently, future research should focus on soil K availability, and K addition should be considered after five years in lucerne pastures mulched with plastic film in semiarid areas.
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BACKGROUND: Recently, it was reported that the adult X. tropicalis heart can regenerate in a nearly scar-free manner after injury via apical resection. Thus, a cardiac regeneration model in adult X. tropicalis provides a powerful tool for recapitulating a perfect regeneration phenomenon, elucidating the underlying molecular mechanisms of cardiac regeneration in an adult heart, and developing an interventional strategy for the improvement in the regeneration of an adult heart, which may be more applicable in mammals than in species with a lower degree of evolution. However, a noninvasive and rapid real-time method that can observe and measure the long-term dynamic change in the regenerated heart in living organisms to monitor and assess the regeneration and repair status in this model has not yet been established. RESULTS: In the present study, the methodology of echocardiographic assessment to characterize the morphology, anatomic structure and cardiac function of injured X. tropicalis hearts established by apex resection was established. The findings of this study demonstrated for the first time that small animal echocardiographic analysis can be used to assess the regeneration of X. tropicalis damaged heart in a scar-free perfect regeneration or nonperfect regeneration with adhesion manner via recovery of morphology and cardiac function. CONCLUSIONS: Small animal echocardiography is a reliable, noninvasive and rapid real-time method for observing and assessing the long-term dynamic changes in the regeneration of injured X. tropicalis hearts.
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This study indicates that brain-derived neurotrophic factor (BDNF) can promote young cardiac microvascular endothelial cells (CMECs) to migrate via the activation of the BDNF-TrkB-FL-PI3K/Akt pathway, which may benefit angiogenesis after myocardial infarction (MI). However, the ageing of CMECs led to changes in the expression of receptor Trk isoforms in that among the three isoforms (TrkB-FL, TrkB-T1 and TrkB-T2), only one of its truncated isoforms, TrkB-T1, continued to be expressed, which leads to the dysfunction of its ligand, a decrease in the migration of CMECs and increased injury in ageing hearts. This shift in receptor isoforms in aged CMECs, together with changes in the ageing microenvironment, might predispose ageing hearts to decreased angiogenic potential and increased cardiac pathology.
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Envejecimiento , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Movimiento Celular , Células Endoteliales/fisiología , Neovascularización Fisiológica/fisiología , Receptor trkB/metabolismo , Animales , Femenino , Corazón , Infarto del Miocardio , Fosfatidilinositol 3-Quinasas/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
Amino Acids are not only major nutrient sources, but also serve as chemical signals to control cellular growth. Rab1A recently emerged as a key component in amino acid sensing and signaling to activate the mTOR complex1 (mTORC1). In a recently published study [1], we generated tamoxifen-inducible, conditional whole-body Rab1A knockout in adult mice. These mice are viable but develop hyperglycemia and glucose intolerance. Interestingly, Rab1A ablation selectively reduces insulin expression and pancreatic beta-cell population. Mechanistically, branched chain amino acids (BCAA), through the Rab1A-mTORC1 complex, promote the stability and nuclear localization of Pdx1, a master transcription factor that controls growth, function and identity of pancreatic beta-cells. These findings reveal a role and underlying mechanism by which amino acids control body's glucose level through a beta-cell specific function by the Rab1A-mTORC1-Pdx1 signaling axis, which has implications in both diabetes and cancer.
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Aminoácidos , Glucemia , Aminoácidos/metabolismo , Animales , Glucemia/metabolismo , Glucosa , Insulina , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Transducción de SeñalRESUMEN
Objective: Brain-derived neurotrophic factor (BDNF) and its receptor TrkB-T1 were recently found to be expressed in cardiomyocytes. However, the functional role of cardiomyocyte-derived BDNF in heart pathophysiology is not yet fully known. Recent studies revealed that BDNF-TrkB pathway plays a critical role to maintain integrity of cardiac structure and function, cardiac pathology and regeneration of myocardial infarction (MI). Therefore, the BDNF-TrkB pathway may be a novel target for myocardial pathophysiology in the adult heart. Approach and results: In the present study, we established a cardiomyocyte-derived BDNF conditional knockout mouse in which BDNF expression in developing cardiomyocytes is ablated under the control of the Myosin heavy chain 6 (MYH6) promoter. The results of the present study show that ablation of cardiomyocyte-derived BDNF during development does not impair survival, growth or reproduction; however, in the young adult heart, it causes cardiomyocyte death, degeneration of the myocardium, cardiomyocyte hypertrophy, left atrial appendage thrombosis, decreased cardiac function, increased cardiac inflammation and ROS activity, and metabolic disorders, leading to heart failure (HF) in the adult heart and eventually resulting in a decrease in the one-year survival rate. In addition, ablation of cardiomyocyte-derived BDNF during the developmental stage leads to exacerbation of cardiac dysfunction and poor regeneration after MI in adult hearts. Conclusion: Cardiomyocyte-derived BDNF is irreplaceable for maintaining the integrity of cardiac structure and function in the adult heart and regeneration after MI. Therefore, the BDNF-TrkB pathway will be a novel target for myocardial pathophysiology in the adult heart.
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Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease. Tumors are poorly immunogenic and immunosuppressive, preventing T cell activation in the tumor microenvironment. Here, we present a microbial-based immunotherapeutic treatment for selective delivery of an immunogenic tetanus toxoid protein (TT856-1313) into PDAC tumor cells by attenuated Listeria monocytogenes. This treatment reactivated preexisting TT-specific memory T cells to kill infected tumor cells in mice. Treatment of KrasG12D,p53R172H, Pdx1-Cre (KPC) mice with Listeria-TT resulted in TT accumulation inside tumor cells, attraction of TT-specific memory CD4 T cells to the tumor microenvironment, and production of perforin and granzyme B in tumors. Low doses of gemcitabine (GEM) increased immune effects of Listeria-TT, turning immunologically cold into hot tumors in mice. In vivo depletion of T cells from Listeria-TT + GEM-treated mice demonstrated a CD4 T cell-mediated reduction in tumor burden. CD4 T cells from TT-vaccinated mice were able to kill TT-expressing Panc-02 tumor cells in vitro. In addition, peritumoral lymph node-like structures were observed in close contact with pancreatic tumors in KPC mice treated with Listeria-TT or Listeria-TT + GEM. These structures displayed CD4 and CD8 T cells producing perforin and granzyme B. Whereas CD4 T cells efficiently infiltrated the KPC tumors, CD8 T cells did not. Listeria-TT + GEM treatment of KPC mice with advanced PDAC reduced tumor burden by 80% and metastases by 87% after treatment and increased survival by 40% compared to nontreated mice. These results suggest that Listeria-delivered recall antigens could be an alternative to neoantigen-mediated cancer immunotherapy.
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Carcinoma Ductal Pancreático , Listeria , Neoplasias Pancreáticas , Animales , Carcinoma Ductal Pancreático/patología , Muerte Celular , Modelos Animales de Enfermedad , Ratones , Neoplasias Pancreáticas/tratamiento farmacológico , Toxoide Tetánico/uso terapéutico , Microambiente TumoralRESUMEN
The hedgehog (HH) family of ligands plays an important instructional role in metazoan development. HH proteins are initially produced as approximately 45-kDa full-length proteins, which undergo an intramolecular cleavage to generate an amino-terminal product that subsequently becomes cholesterol-modified (HH-Np). It is well accepted that this cholesterol-modified amino-terminal cleavage product is responsible for all HH-dependent signaling events. Contrary to this model we show here that full-length forms of HH proteins are able to traffic to the plasma membrane and participate directly in cell-cell signaling, both in vitro and in vivo. We were also able to rescue a Drosophila eye-specific hh loss of function phenotype by expressing a full-length form of hh that cannot be processed into HH-Np. These results suggest that in some physiological contexts full-length HH proteins may participate directly in HH signaling and that this novel activity of full-length HH may be evolutionarily conserved.