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1.
Stem Cell Res Ther ; 15(1): 102, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38589967

RESUMEN

BACKGROUND: Premature ovarian insufficiency (POI) is a major cause of infertility. In this study, we aimed to investigate the effects of the combination of bone marrow mesenchymal stem cells (BMSCs) and moxibustion (BMSCs-MOX) on POI and evaluate the underlying mechanisms. METHODS: A POI rat model was established by injecting different doses of cyclophosphamide (Cy). The modeling of POI and the effects of the treatments were assessed by evaluating estrous cycle, serum hormone levels, ovarian weight, ovarian index, and ovarian histopathological analysis. The effects of moxibustion on BMSCs migration were evaluated by tracking DiR-labeled BMSCs and analyzing the expression of chemokines stromal cell-derived factor 1 (Sdf1) and chemokine receptor type 4 (Cxcr4). Mitochondrial function and mitophagy were assessed by measuring the levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP, and the mitophagy markers (Drp1, Pink1, and Parkin). Furthermore, the mitophagy inhibitor Mdivi-1 and the mitophagy activator CCCP were used to confirm the role of mitophagy in Cy-induced ovarian injury and the underlying mechanism of combination therapy. RESULTS: A suitable rat model of POI was established using Cy injection. Compared to moxibustion or BMSCs transplantation alone, BMSCs-MOX showed improved outcomes, such as reduced estrous cycle disorders, improved ovarian weight and index, normalized serum hormone levels, increased ovarian reserve, and reduced follicle atresia. Moxibustion enhanced Sdf1 and Cxcr4 expression, promoting BMSCs migration. BMSCs-MOX reduced ROS levels; upregulated MMP and ATP levels in ovarian granulosa cells (GCs); and downregulated Drp1, Pink1, and Parkin expression in ovarian tissues. Mdivi-1 significantly mitigated mitochondrial dysfunction in ovarian GCs and improved ovarian function. CCCP inhibited the ability of BMSCs-MOX treatment to regulate mitophagy and ameliorate Cy-induced ovarian injury. CONCLUSIONS: Moxibustion enhanced the migration and homing of BMSCs following transplantation and improves their ability to repair ovarian damage. The combination of BMSCs and moxibustion effectively reduced the excessive activation of mitophagy, which helped prevent mitochondrial damage, ultimately improving ovarian function. These findings provide a novel approach for the treatment of pathological ovarian aging and offer new insights into enhancing the efficacy of stem cell therapy for POI patients.


Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Moxibustión , Insuficiencia Ovárica Primaria , Humanos , Femenino , Ratas , Animales , Mitofagia , Especies Reactivas de Oxígeno/metabolismo , Carbonil Cianuro m-Clorofenil Hidrazona/efectos adversos , Carbonil Cianuro m-Clorofenil Hidrazona/metabolismo , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/terapia , Insuficiencia Ovárica Primaria/patología , Ciclofosfamida/efectos adversos , Células Madre Mesenquimatosas/metabolismo , Mitocondrias/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Quinasas/metabolismo , Hormonas/efectos adversos , Hormonas/metabolismo , Adenosina Trifosfato/metabolismo
2.
J Ethnopharmacol ; 323: 117695, 2024 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-38163556

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Chaihu Shugan Powder (CHSGP) has significant clinical efficacy in the treatment of functional dyspepsia (FD), but the specific mechanism requires further study. AIM OF STUDY: The aim of this study was to investigate the therapeutic effect of CHSGP on FD rats and the underlying mechanism of the effect on interstitial cells of cajal (ICC) mitophagy. MATERIALS AND METHODS: The tail-clamping stimulation method was utilized to establish an FD rat model in vivo. Gastric emptying rate and small intestinal propulsion rate test, H&E staining, and Immunohistochemistry were conducted to evaluate the therapeutic effects of CHSGP on FD rats. In vitro, the regulatory effect of CHSGP on CCCP-mediated ICC mitophagy was further investigated by CCK8, Transmission electron microscope, immunofluorescence co-staining, Quantitative polymerase chain reaction and Western blot to reveal the potential mechanisms of CHSGP inhibited ICC mitophagy. RESULTS: Animal experiments provided evidence that CHSGP promoted gastric motility, increased ICC numbers, reduced Parkin expression, and elevated USP30 expression in FD rats. In vitro, further mechanism research demonstrated that CHSGP decreased LC3Ⅱ/LC3Ⅰ、PINK1、Parkin、PHB2 protein expression and increased USP30 protein expression. Furthermore, CHSGP increased Mfn2 protein expression by suppressing activation of the PINK1/Parkin pathway when USP30 is knocked down, consequently reducing CCCP-induced ICC mitophagy. CONCLUSIONS: These results suggest that CHSGP may treat FD against CCCP-induced ICC mitophagy by the up-regulation of via PINK1/Parkin pathway.


Asunto(s)
Dispepsia , Células Intersticiales de Cajal , Ratas , Animales , Mitofagia , Dispepsia/tratamiento farmacológico , Dispepsia/metabolismo , Células Intersticiales de Cajal/metabolismo , Polvos/metabolismo , Carbonil Cianuro m-Clorofenil Hidrazona/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Quinasas/metabolismo
3.
J Pediatr Surg ; 59(1): 129-133, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37858391

RESUMEN

BACKGROUND: The Center for Disease Control's Comprehensive Cancer Control Program (CCCP) funds initiatives in fifty states, the District of Columbia, seven U.S. territories, and seven tribal organizations to prevent and control cancer. These initiatives influence policy, care, research, and advocacy for cancer treatment. We performed an analysis of CCCP plans for states, U.S. territories, and tribal organizations to understand the extent of inclusion of pediatric cancer care. METHODS: We conducted a thematic and quantitative analysis of CCCP plans for states, U.S. territories, and tribal organizations. Plans were assessed by two reviewers and scored for discussion of cancer prevention, risk factors, early detection and screening, treatment and innovation, access, barriers to care, and survivorship in childhood cancer. RESULTS: Plans from fifty states, the District of Columbia, seven territories, seven tribal organizations, and one Pacific Regional (USAPI) plan were reviewed, for a total of sixty-six plans. Up-to-date CCCP plans were available through the CDC or state websites for 74% of states, 57% of territories, and 71% of tribal organizations; older plans were available for all groups without up-to-date CCCP plans. While all plans referenced children, most did so in the context of childhood exposures influencing adult cancer risks (e.g., sun, tobacco, HPV). Few plans contained a section dedicated to childhood cancer (30% states, 14.3% territories, 14.3% tribes). A minority of plans specifically discussed early detection and screening (14% states, 0% territories, 14.3% tribes), treatment and innovation (32% states, 0% territories, 28.6% tribes), access to cancer care (38% states, 28.6% territories, 28.6% tribes), reducing barriers to cancer care (28% states, 42.9% territories, 28.6% tribes), and pediatric cancer survivorship (42% states, 0% territories, 28.6% tribes). CONCLUSIONS: Promoting inclusion of pediatric cancer in CCPs will help to standardize pediatric cancer care, eliminate treatment disparities across state lines, and allow for comprehensive understanding of pediatric oncology. LEVEL OF EVIDENCE: Level IV.


Asunto(s)
Neoplasias , Adulto , Humanos , Niño , Estados Unidos , Carbonil Cianuro m-Clorofenil Hidrazona , Neoplasias/diagnóstico , Neoplasias/epidemiología , Neoplasias/prevención & control , Atención a la Salud , Factores de Riesgo
4.
J Public Health Manag Pract ; 30(2): E54-E64, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38032233

RESUMEN

CONTEXT: Opportunities to reduce the risk of cancer, including cervical, liver, and skin cancer, start early in life. To encourage adoption of primary prevention activities in childhood to reduce cancer risk later in life, Centers for Disease Control and Prevention conducted a demonstration project with 3 National Comprehensive Cancer Control Program (NCCCP) recipients. PROGRAM: Iowa, Northwest Portland Area Indian Health Board (NPAIHB), and Pennsylvania NCCCP recipients implemented evidence-based primary prevention activities for cervical, liver, and skin cancer among children using health care provider education, patient education, and policy development. IMPLEMENTATION: Iowa implemented an announcement approach to improve provider education on human papillomavirus (HPV) vaccination. Pennsylvania focused on patient education for reducing skin cancer risk and both provider and patient education for liver cancer prevention. NPAIHB created a sun safety intervention for tribal organizations, including a policy guide, media materials, and patient education. RESULTS: In Iowa, health care providers taking the announcement approach reported significantly higher mean scores on a posttest compared with a pretest regarding perceptions about HPV vaccination, self-efficacy, and behavioral intentions related to vaccination. Pennsylvania integrated sun safety education and sunscreen dispenser programs as a health and wellness initiative in 8 state parks and the Pennsylvania Department of Conservation and Natural Resources incorporated the program in its Pennsylvania Outdoor Recreation Plan. Pennsylvania also implemented health care provider education on the primary prevention of liver cancer through hepatitis B and hepatitis C screening and hepatitis B vaccination. The NPAIHB skin cancer policy guide was created and distributed for use to all 43 federally recognized tribes of Oregon, Washington, and Idaho served by NPAIHB. DISCUSSION: The identification, dissemination, and implementation of these efforts can serve as best practices for future childhood primary prevention programs. NCCCP recipients and public health professionals can use health care provider education, patient education, and policy development to reduce future risk for cervical, liver, and skin cancer among children.


Asunto(s)
Carbonil Cianuro m-Clorofenil Hidrazona/análogos & derivados , Hepatitis B , Neoplasias Hepáticas , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Neoplasias Cutáneas , Niño , Humanos , Infecciones por Papillomavirus/prevención & control , Neoplasias Cutáneas/prevención & control , Prevención Primaria , Vacunas contra Papillomavirus/uso terapéutico
5.
Lett Appl Microbiol ; 76(8)2023 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-37580156

RESUMEN

The purpose of this study was to evaluate the antimicrobial activity of indole-3-carbinol (I3C) with membrane-active agents, namely carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and ethylenediaminetetraacetic acid (EDTA) against multidrug-resistant (MDR) Gram-negative bacteria and bacterial persisters. The determination of minimal inhibitory concentration (MIC) showed that I3C was effective against Acinetobacter baumannii (3.13‒6.25 × 10-3 mol l-1), Klebsiella pneumoniae (8 × 10-3 mol l-1), Pseudomonas aeruginosa (6.25‒12.5 × 10-3 mol l-1), and Escherichia coli (6.25‒12.5 × 10-3 mol l-1). Our study demonstrated that EDTA synergistically enhanced the bactericidal activity of I3C against most MDR Gram-negative bacteria isolates and contributed to an 8- to 64-fold MIC reduction compared with that of I3C alone, yet CCCP only displayed synergy with I3C against P. aeruginosa and A. baumannii. The EDTA-I3C combination also significantly reduced the viable number of testing bacteria (P = 7.2E-05), effectively reduced bacterial persisters, and repressed bacterial growth compared with that the use of I3C alone. Our data demonstrate that use of EDTA as adjuvant molecules can effectively improve the antibacterial activity of I3C and may help to reduce the development of antimicrobial resistance.


Asunto(s)
Antibacterianos , Farmacorresistencia Bacteriana Múltiple , Ácido Edético/farmacología , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Sinergismo Farmacológico , Antibacterianos/farmacología , Bacterias , Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana
6.
Phytother Res ; 37(5): 1864-1882, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36740450

RESUMEN

Shenlian (SL) extract has been proven to be effective in the prevention and treatment of atherosclerosis and myocardial ischemia. However, the function and molecular mechanisms of SL on coronary artery no-reflow have not been fully elucidated. This study was designed to investigate the contribution of SL extract in repressing excessive mitochondrial autophagy to protect the mitochondrial function and prevent coronary artery no-reflow. The improvement of SL on coronary artery no-reflow was observed in vivo experiments and the molecular mechanisms were further explored through vitro experiments. First, a coronary artery no-reflow rat model was built by ligating the left anterior descending coronary artery for 2 hr of ischemia, followed by 24 hr of reperfusion. Thioflavin S (6%, 1 ml/kg) was injected into the inferior vena cava to mark the no-reflow area. Transmission electron microscopy was performed to observe the cellular structure, mitochondrial structure, and mitochondrial autophagy of the endothelial cells. Immunofluorescence was used to observe the microvascular barrier function and microvascular inflammation. Cardiac microvascular endothelial cells (CMECs) were isolated from rats. The CMECs were deprived of oxygen-glucose deprivation (OGD) for 2 hr and reoxygenated for 4 hr to mimic the Myocardial ischemia-reperfusion (MI/R) injury-induced coronary artery no-reflow in vitro. Mitochondrial membrane potential was assessed using JC-1 dye. Intracellular adenosine triphosphate (ATP) levels were determined using an ATP assay kit. The cell total reactive oxygen species (ROS) levels and cell apoptosis rate were analyzed by flow cytometry. Colocalization of mitochondria and lysosomes indirectly indicated mitophagy. The representative ultrastructural morphologies of the autophagosomes and autolysosomes were also observed under transmission electron microscopy. The mitochondrial autophagy-related proteins (LC3II/I, P62, PINK, and Parkin) were analyzed using Western blot analysis. In vivo, results showed that, compared with the model group, SL could reduce the no-reflow area from 37.04 ± 9.67% to 18.31 ± 4.01% (1.08 g·kg-1 SL), 13.79 ± 4.77% (2.16 g·kg-1 SL), and 12.67 ± 2.47% (4.32 g·kg-1 SL). The extract also significantly increased the left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS) (p < 0.05 or p < 0.01). The fluorescence intensities of VE-cadherin, which is a junctional protein that preserves the microvascular barrier function, decreased to ~74.05% of the baseline levels in the no-reflow rats and increased to 89.87%(1.08 g·kg-1 SL), 82.23% (2.16 g·kg-1 SL), and 89.69% (4.32 g·kg-1 SL) of the baseline levels by SL treatment. SL administration repressed the neutrophil migration into the myocardium. The oxygen-glucose deprivation/reoxygenation (OGD/R) model was induced in vitro to mimic microvascular ischemia-reperfusion injury. The impaired mitochondrial function after OGD/R injury led to decreased ATP production, calcium overload, the excessive opening of the Mitochondrial Permeability Transition Pore, decreased mitochondrial membrane potential, and reduced ROS scavenging ability (p < 0.05 or p < 0.01). The normal autophagosomes (double-membrane vacuoles with autophagic content) in the sham group were rarely found. The large morphology and autophagosomes were frequently observed in the model group. By contrast, SL inhibited the excessive activation of mitochondrial autophagy. The mitochondrial autophagy regulated by the PINK/Parkin pathway was excessively activated. However, administration of SL prevented the activation of the PINK/Parkin pathway and inhibited excessive mitochondrial autophagy to regulate mitochondrial dysfunction. Results also demonstrated that mitochondrial dysfunction stimulated endothelial cell barrier dysfunction, but Evans blue transmission was significantly decreased and transmembrane resistance was increased significantly by SL treatment (p < 0.05 or p < 0.01). Carbonylcyanide-3-chlorophenylhydrazone (CCCP) could activate the PINK/Parkin pathway. CCCP reversed the regulation of SL on mitochondrial autophagy and mitochondrial function. SL could alleviate coronary artery no-reflow by protecting the microvasculature by regulating mitochondrial function. The underlying mechanism was related to decreased mitochondrial autophagy by the PINK/Parkin pathway.


Asunto(s)
Vasos Coronarios , Daño por Reperfusión Miocárdica , Ratas , Animales , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Vasos Coronarios/metabolismo , Células Endoteliales/metabolismo , Carbonil Cianuro m-Clorofenil Hidrazona/metabolismo , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Volumen Sistólico , Función Ventricular Izquierda , Autofagia , Mitocondrias , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/farmacología , Oxígeno/metabolismo , Adenosina Trifosfato/metabolismo , Glucosa/metabolismo
7.
Comput Math Methods Med ; 2021: 6009602, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34899967

RESUMEN

How to choose the right plan is the key to treatment, and this must take into account the local eradication of Helicobacter pylori and the drug resistance of Helicobacter pylori. In order to better eradicate Helicobacter pylori, in the current clinical treatment process, most of the combined treatments of triple drugs are used, but the therapeutic effect is still not ideal. In addition, many studies have focused on changing the types and dosages of drugs, but they have not yet achieved good results. This paper combines experimental research to analyze the drug resistance rate of Helicobacter pylori and obtains gastric mucosal specimens of patients through gastroscopy to cultivate clinical isolates of H. pylori.. Furthermore, this study used the Kirby-Bauer drug susceptibility disc technique to determine the sensitivity of H. pylori clinical isolates to a range of regularly used clinical antibiotics, as well as a set of instances of H. pylori antibiotic resistance. Finally, this research integrates experimental analyses and various successful eradication treatment plans to provide a unique eradication treatment strategy.


Asunto(s)
Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Helicobacter pylori/efectos de los fármacos , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Biología Computacional , Farmacorresistencia Microbiana/genética , Quimioterapia Combinada , Mucosa Gástrica/microbiología , Genes Bacterianos , Helicobacter pylori/genética , Helicobacter pylori/aislamiento & purificación , Humanos , Pruebas de Sensibilidad Microbiana , Desacopladores/farmacología
8.
Appl Environ Microbiol ; 87(18): e0091521, 2021 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-34260305

RESUMEN

Rice is an important source of food for more than half of the world's population. Bacterial panicle blight (BPB) is a disease of rice characterized by grain discoloration or sheath rot caused mainly by Burkholderia glumae. B. glumae synthesizes toxoflavin, an essential virulence factor that is required for symptoms of the disease. The products of the tox operons, ToxABCDE and ToxFGHI, are responsible for the synthesis and the proton motive force (PMF)-dependent secretion of toxoflavin, respectively. The DedA family is a highly conserved membrane protein family found in most bacterial genomes that likely function as membrane transporters. Our previous work has demonstrated that absence of certain DedA family members results in pleiotropic effects, impacting multiple pathways that are energized by PMF. We have demonstrated that a member of the DedA family from Burkholderia thailandensis, named DbcA, is required for the extreme polymyxin resistance observed in this organism. B. glumae encodes a homolog of DbcA with 73% amino acid identity to Burkholderia thailandensis DbcA. Here, we created and characterized a B. glumae ΔdbcA strain. In addition to polymyxin sensitivity, the B. glumae ΔdbcA strain is compromised for virulence in several BPB infection models and secretes only low amounts of toxoflavin (∼15% of wild-type levels). Changes in membrane potential in the B. glumae ΔdbcA strain were reproduced in the wild-type strain by the addition of subinhibitory concentrations of sodium bicarbonate, previously demonstrated to cause disruption of PMF. Sodium bicarbonate inhibited B. glumae virulence in rice, suggesting a possible non-toxic chemical intervention for bacterial panicle blight. IMPORTANCE Bacterial panicle blight (BPB) is a disease of rice characterized by grain discoloration or sheath rot caused mainly by Burkholderia glumae. The DedA family is a highly conserved membrane protein family found in most bacterial genomes that likely function as membrane transporters. Here, we constructed a B. glumae mutant with a deletion in a DedA family member named dbcA and report a loss of virulence in models of BPB. Physiological analysis of the mutant shows that the proton motive force is disrupted, leading to reduction of secretion of the essential virulence factor toxoflavin. The mutant phenotypes are reproduced in the virulent wild-type strain without an effect on growth using sodium bicarbonate, a nontoxic buffer that has been reported to disrupt the PMF. The results presented here suggest that bicarbonate may be an effective antivirulence agent capable of controlling BPB without imposing an undue burden on the environment.


Asunto(s)
Burkholderia , Oryza/microbiología , Enfermedades de las Plantas/microbiología , Fuerza Protón-Motriz , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Burkholderia/efectos de los fármacos , Burkholderia/genética , Burkholderia/metabolismo , Burkholderia/patogenicidad , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Cebollas/microbiología , Pirimidinonas/metabolismo , Bicarbonato de Sodio/farmacología , Triazinas/metabolismo , Virulencia , Factores de Virulencia/metabolismo
9.
Cell Res ; 28(12): 1171-1185, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30287942

RESUMEN

Iron has been shown to trigger oxidative stress by elevating reactive oxygen species (ROS) and to participate in different modes of cell death, such as ferroptosis, apoptosis and necroptosis. However, whether iron-elevated ROS is also linked to pyroptosis has not been reported. Here, we demonstrate that iron-activated ROS can induce pyroptosis via a Tom20-Bax-caspase-GSDME pathway. In melanoma cells, iron enhanced ROS signaling initiated by CCCP, causing the oxidation and oligomerization of the mitochondrial outer membrane protein Tom20. Bax is recruited to mitochondria by oxidized Tom20, which facilitates cytochrome c release to cytosol to activate caspase-3, eventually triggering pyroptotic death by inducing GSDME cleavage. Therefore, ROS acts as a causative factor and Tom20 senses ROS signaling for iron-driven pyroptotic death of melanoma cells. Since iron activates ROS for GSDME-dependent pyroptosis induction and melanoma cells specifically express a high level of GSDME, iron may be a potential candidate for melanoma therapy. Based on the functional mechanism of iron shown above, we further demonstrate that iron supplementation at a dosage used in iron-deficient patients is sufficient to maximize the anti-tumor effect of clinical ROS-inducing drugs to inhibit xenograft tumor growth and metastasis of melanoma cells through GSDME-dependent pyroptosis. Moreover, no obvious side effects are observed in the normal tissues and organs of mice during the combined treatment of clinical drugs and iron. This study not only identifies iron as a sensitizer amplifying ROS signaling to drive pyroptosis, but also implicates a novel iron-based intervention strategy for melanoma therapy.


Asunto(s)
Hierro/farmacología , Melanoma/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Mitocondrias , Piroptosis/efectos de los fármacos , Receptores de Superficie Celular/metabolismo , Animales , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Caspasa 3/metabolismo , Línea Celular Tumoral , Citocromos c/metabolismo , Células HEK293 , Humanos , Melanoma/tratamiento farmacológico , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Especies Reactivas de Oxígeno/metabolismo , Receptores de Estrógenos/metabolismo , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína X Asociada a bcl-2/metabolismo
10.
Biochim Biophys Acta Mol Cell Res ; 1865(9): 1312-1325, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29932990

RESUMEN

Hypothalamic leptin receptor (LR) signaling regulates body weight by balancing food intake and energy expenditure. It is well established that the human LR undergoes ectodomain shedding, but little is known about the fate of the remaining cytosolic domain. This study demonstrates that regulated intramembrane proteolysis (RIP) releases the LR intracellular domain (LR ICD), which translocates to the mitochondria where it binds to SOCS6. This LR ICD-SOCS6 interaction stabilizes both proteins on the mitochondrial outer membrane and requires a functional BC box in SOCS6 for mitochondrial association and a central motif in the LR ICD for SOCS6 binding. The LR ICD prevents CCCP-induced mitochondrial depolarization and mitophagy as shown by lowered Parkin translocation and p62 accumulation. Strict regulation of mitochondrial dynamics in the hypothalamus is known to be essential for body weight homeostasis. This is the first study showing that the LR can directly modulate mitochondrial biology.


Asunto(s)
Mitocondrias/fisiología , Receptores de Leptina/química , Receptores de Leptina/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Línea Celular Tumoral , Polaridad Celular/efectos de los fármacos , Células HEK293 , Células HeLa , Humanos , Hipotálamo/metabolismo , Mitocondrias/efectos de los fármacos , Mitofagia , Dominios Proteicos , Proteolisis
11.
Sci Adv ; 4(3): eaap9302, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29536043

RESUMEN

Monitoring subcellular functional and structural changes associated with metabolism is essential for understanding healthy tissue development and the progression of numerous diseases, including cancer, diabetes, and cardiovascular and neurodegenerative disorders. Unfortunately, established methods for this purpose either are destructive or require the use of exogenous agents. Recent work has highlighted the potential of endogenous two-photon excited fluorescence (TPEF) as a method to monitor subtle metabolic changes; however, mechanistic understanding of the connections between the detected optical signal and the underlying metabolic pathways has been lacking. We present a quantitative approach to detecting both functional and structural metabolic biomarkers noninvasively, relying on endogenous TPEF from two coenzymes, NADH (reduced form of nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide). We perform multiparametric analysis of three optical biomarkers within intact, living cells and three-dimensional tissues: cellular redox state, NADH fluorescence lifetime, and mitochondrial clustering. We monitor the biomarkers in cells and tissues subjected to metabolic perturbations that trigger changes in distinct metabolic processes, including glycolysis and glutaminolysis, extrinsic and intrinsic mitochondrial uncoupling, and fatty acid oxidation and synthesis. We demonstrate that these optical biomarkers provide complementary insights into the underlying biological mechanisms. Thus, when used in combination, these biomarkers can serve as a valuable tool for sensitive, label-free identification of changes in specific metabolic pathways and characterization of the heterogeneity of the elicited responses with single-cell resolution.


Asunto(s)
Imagenología Tridimensional/métodos , Metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Animales , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Línea Celular , Ácidos Grasos/biosíntesis , Flavina-Adenina Dinucleótido/metabolismo , Fluorescencia , Glutamina/metabolismo , Glucólisis , Humanos , Metabolismo/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , NAD/metabolismo , Oxidación-Reducción/efectos de los fármacos
12.
J Orthop Res ; 36(4): 1086-1092, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28885721

RESUMEN

Staphylococcus aureus is often found in orthopaedic infections and may be protected from commonly prescribed antibiotics by forming biofilms or growing intracellularly within osteoblasts. To investigate the effect of non-antibiotic compounds in conjunction with antibiotics to clear intracellular and biofilm forming S. aureus causing osteomyelitis. SAOS-2 osteoblast-like cell lines were infected with S. aureus BB1279. Antibiotics (vancomycin, VAN; and dicloxacillin, DICLOX), bacterial efflux pump inhibitors (piperine, PIP; carbonyl cyanide m-chlorophenyl hydrazone, CCCP), and bone morphogenetic protein (BMP-2) were evaluated individually and in combination to kill intracellular bacteria. We present direct evidence that after gentamicin killed extracellular planktonic bacteria and antibiotics had been stopped, seeding from the infected osteoblasts grew as biofilms. VAN was ineffective in treating the intracellular bacteria even at 10× MIC; however in presence of PIP or CCCP the intracellular S. aureus was significantly reduced. Bacterial efflux pump inhibitors (PIP and CCCP) were effective in enhancing permeability of antibiotics within the osteoblasts and facilitated killing of intracellular S. aureus. Confocal laser scanning microscopy (CLSM) showed increased uptake of propidium iodide within osteoblasts in presence of PIP and CCCP. BMP-2 had no effect on growth of S. aureus either alone or in combination with antibiotics. Combined application of antibiotics and natural agents could help in the treatment of osteoblast infected intracellular bacteria and biofilms associated with osteomyelitis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1086-1092, 2018.


Asunto(s)
Alcaloides/administración & dosificación , Antibacterianos/administración & dosificación , Benzodioxoles/administración & dosificación , Proteína Morfogenética Ósea 2/administración & dosificación , Carbonil Cianuro m-Clorofenil Hidrazona/administración & dosificación , Osteomielitis/tratamiento farmacológico , Piperidinas/administración & dosificación , Alcamidas Poliinsaturadas/administración & dosificación , Infecciones Estafilocócicas/tratamiento farmacológico , Línea Celular Tumoral , Dicloxacilina , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Interacciones Huésped-Patógeno , Humanos , Pruebas de Sensibilidad Microbiana , Osteoblastos/microbiología , Osteomielitis/microbiología , Staphylococcus aureus/fisiología , Vancomicina
13.
J Anim Sci ; 93(11): 5214-21, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26641041

RESUMEN

Sturgeon spermatozoa maturation during their passage through the kidney is a prerequisite for initiation of motility. Samples of sterlet () testicular sperm (TS) were matured in vitro by incubation in seminal fluid (SF) or in SF supplemented with carbonyl cyanide -chlorophenyl hydrazone (CCCP; a respiration uncoupling agent). Sperm was diluted in activation medium (AM) containing 10 m Tris-HCl buffer (pH 8.5) and 0.25% Pluronic, and spermatozoon motility was assessed. Samples were taken and fixed in 3 perchloric acid at 3 points in the incubation process. Quantification of ATP, ADP, and creatine phosphate (CrP) was conducted using liquid chromatography/high-resolution mass spectrometry. We observed a significant decrease in CrP during artificial maturation of TS in SF. In contrast, ATP and ADP were not significantly affected. Addition of CCCP to SF halted maturation and led to significantly lower CrP whereas ADP significantly increased and ATP was unaffected. Dilution of matured and immature TS with AM led to a significant decrease of ATP and CrP and an increase of ADP compared with their levels before dilution, although immature TS were not motile. Energy dependency of TS maturation in sturgeon was confirmed, which suggests that mitochondrial oxidative phosphorylation is needed for maturation of sturgeon TS.


Asunto(s)
Adenosina Difosfato/metabolismo , Adenosina Trifosfato/metabolismo , Peces/fisiología , Fosfocreatina/metabolismo , Maduración Sexual/fisiología , Espermatozoides/metabolismo , Animales , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Masculino , Fosforilación Oxidativa , Motilidad Espermática/fisiología , Espermatozoides/fisiología , Desacopladores/farmacología
14.
Plant Signal Behav ; 10(10): e1071750, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26237427

RESUMEN

A memristor is a nonlinear element because its current-voltage characteristic is similar to that of a Lissajous pattern for nonlinear systems. This element was postulated recently and researchers are looking for it in different biosystems. We investigated electrical circuitry of red Irish potato tubers (Solanum tuberosum L.). The goal was to discover if potato tubers might have a new electrical component - a resistor with memory. The analysis was based on a cyclic current-voltage characteristic where the resistor with memory should manifest itself. We found that the electrostimulation by bipolar sinusoidal or triangle periodic waves induces electrical responses in the potato tubers with fingerprints of memristors. Tetraethylammonium chloride, an inhibitor of voltage gated K(+) channels, transforms a memristor to a resistor in potato tubers. Our results demonstrate that a voltage gated K(+) channel in the excitable tissue of potato tubers has properties of a memristor. Uncoupler carbonylcyanide-4-trifluoromethoxy-phenyl hydrazone decreases the amplitude of electrical responses at low and high frequencies of bipolar periodic sinusoidal or triangle electrostimulating waves. The discovery of memristors in plants creates a new direction in the understanding of electrical phenomena in plants.


Asunto(s)
Electricidad , Proteínas de Plantas/metabolismo , Tubérculos de la Planta/metabolismo , Canales de Potasio con Entrada de Voltaje/metabolismo , Solanum tuberosum/metabolismo , Carbonil Cianuro m-Clorofenil Hidrazona/análogos & derivados , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Memoria , Tubérculos de la Planta/fisiología , Solanum tuberosum/fisiología , Tetraetilamonio/metabolismo
15.
Plant Signal Behav ; 9(10): e982029, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25482796

RESUMEN

The fourth basic circuit element, a memristor, is a resistor with memory that was postulated by Chua in 1971. Here we found that memristors exist in vivo. The electrostimulation of the Mimosa pudica by bipolar sinusoidal or triangle periodic waves induce electrical responses with fingerprints of memristors. Uncouplers carbonylcyanide-3-chlorophenylhydrazone and carbonylcyanide-4-trifluoromethoxy-phenyl hydrazone decrease the amplitude of electrical responses at low and high frequencies of bipolar sinusoidal or triangle periodic electrostimulating waves. Memristive behavior of an electrical network in the Mimosa pudica is linked to the properties of voltage gated ion channels: the channel blocker TEACl reduces the electric response to a conventional resistor. Our results demonstrate that a voltage gated K(+) channel in the excitable tissue of plants has properties of a memristor. The discovery of memristors in plants creates a new direction in the modeling and understanding of electrical phenomena in plants.


Asunto(s)
Electricidad , Fenómenos Electrofisiológicos , Mimosa/fisiología , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Estimulación Eléctrica , Fenómenos Electrofisiológicos/efectos de los fármacos , Mimosa/efectos de los fármacos , Pulvino/efectos de los fármacos , Pulvino/fisiología
16.
J Surg Res ; 188(2): 473-9, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24582214

RESUMEN

BACKGROUND: Mitochondrial dysfunction has been closely related to many pathologic processes, such as cellular apoptosis. Alterations in organelle membrane potential are associated with mitochondrial dysfunction. A fluorine-18 labeled phosphonium compound: (18)F-triphenylphosphonium ((18)F-TPP) was prepared to determine its potential use as a mitochondria-targeting radiopharmaceutical to evaluate cellular apoptosis. METHODS: Studies were conducted in both ex vivo cell lines and in vivo using a burned animal model. Uptake of (18)F-TPP was assessed in PC-3 cells by gamma counting under the following conditions: graded levels of extracellular potassium concentrations, incubation with carbonyl cyanide m-chlorophenylhydrazone and staurosporine. Apoptosis was studied in a burn animal model using terminal deoxynucleotidyl transferase dUTP nick end labeling staining and simultaneous assessment of (18)F-TPP uptake by biodistribution. RESULTS: We found that stepwise membrane depolarization by potassium (K) resulted in a linear decrease in (18)F-TPP uptake, with a slope of 0.62 ± 0.08 and a correlation coefficient of 0.936 ± 0.11. Gradually increased concentrations of m-chlorophenylhydrazone lead to decreased uptake of (18)F-TPP. Staurosporine significantly decreased the uptake of (18)F-TPP in PC-3 cells from 14.2 ± 3.8% to 5.6 ± 1.3% (P < 0.001). Burn-induced significant apoptosis (sham: 4.4 ± 1.8% versus burn: 24.6 ± 6.7 %; P < 0.005) and a reduced uptake of tracer in the spleens of burn-injured animals as compared with sham burn controls (burn: 1.13 ± 0.24% versus sham: 3.28 ± 0.67%; P < 0.005). Biodistribution studies demonstrated that burn-induced significant reduction in (18)F-TPP uptake in spleen, heart, lung, and liver, which were associated with significantly increased apoptosis. CONCLUSIONS: (18)F-TPP is a promising new voltage sensor for detecting mitochondrial dysfunction and apoptosis in various tissues.


Asunto(s)
Apoptosis , Quemaduras/diagnóstico por imagen , Radioisótopos de Flúor , Potencial de la Membrana Mitocondrial , Compuestos Organofosforados/uso terapéutico , Animales , Carbonil Cianuro m-Clorofenil Hidrazona , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Ratones Endogámicos C57BL , Tomografía de Emisión de Positrones , Potasio , Bazo/diagnóstico por imagen , Estaurosporina , Valinomicina
17.
New Phytol ; 201(4): 1183-1191, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24491113

RESUMEN

• Selenite is a predominant form of selenium (Se) available to plants, especially in anaerobic soils, but the molecular mechanism of selenite uptake by plants is not well understood. • ltn1, a rice mutant previously shown to have increased phosphate (Pi) uptake, was found to exhibit higher selenite uptake than the wild-type in both concentration- and time-dependent selenite uptake assays. Respiratory inhibitors significantly inhibited selenite uptake in the wildtype and the ltn1 mutant, indicating that selenite uptake was coupled with H(+) and energy-dependent. Selenite uptake was greatly enhanced under Pi-starvation conditions, suggesting that Pi transporters are involved in selenite uptake. • OsPT2, the most abundantly expressed Pi transporter in the roots, is also significantly up-regulated in ltn1 and dramatically induced by Pi starvation. OsPT2-overexpressing and knockdown plants displayed significantly increased and decreased rates of selenite uptake, respectively, suggesting that OsPT2 plays a crucial role in selenite uptake. Se content in rice grains also increased significantly in OsPT2-overexpressing plants. • These data strongly demonstrate that selenite and Pi share similar uptake mechanisms and that OsPT2 is involved in selenite uptake, which provides a potential strategy for breeding Se-enriched rice varieties.


Asunto(s)
Oryza/metabolismo , Proteínas de Transporte de Fosfato/metabolismo , Proteínas de Plantas/metabolismo , Ácido Selenioso/metabolismo , 2,4-Dinitrofenol/farmacología , Transporte Biológico Activo/efectos de los fármacos , Carbonil Cianuro m-Clorofenil Hidrazona/análogos & derivados , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Genes de Plantas/genética , Hidrógeno/metabolismo , Mutación/genética , Oryza/efectos de los fármacos , Oryza/genética , Proteínas de Transporte de Fosfato/genética , Fosfatos/metabolismo , Epidermis de la Planta/citología , Proteínas de Plantas/genética , Raíces de Plantas/efectos de los fármacos , Raíces de Plantas/metabolismo , Plantas Modificadas Genéticamente , ARN Mensajero/genética , ARN Mensajero/metabolismo , Selenio/metabolismo , Azufre/metabolismo , Simportadores/metabolismo , Factores de Tiempo
18.
Antimicrob Agents Chemother ; 57(8): 3875-82, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23733465

RESUMEN

Many host defense cationic antimicrobial peptides (HDPs) perturb the staphylococcal cell membrane (CM) and alter transmembrane potential (ΔΨ) as key parts of their lethal mechanism. Thus, a sense-response system for detecting and mediating adaptive responses to such stresses could impact organism survival; the Staphylococcus aureus LytSR two-component regulatory system (TCRS) may serve as such a ΔΨ sensor. One well-known target of this system is the lrgAB operon, which, along with the related cidABC operon, has been shown to be a regulator in the control of programmed cell death and lysis. We used an isogenic set of S. aureus strains: (i) UAMS-1, (ii) its isogenic ΔlytS and ΔlrgAB mutants, and (iii) plasmid-complemented ΔlytSR and ΔlrgAB mutants. The ΔlytS strain displayed significantly increased in vitro susceptibilities to all HDPs tested (neutrophil-derived human neutrophil peptide 1 [hNP-1], platelet-derived thrombin-induced platelet microbicidal proteins [tPMPs], and the tPMP-mimetic peptide RP-1), as well as to calcium-daptomycin (DAP), a cationic antimicrobial peptide (CAP). In contrast, the ΔlrgAB strain exhibited no significant changes in susceptibilities to these cationic peptides, indicating that although lytSR positively regulates transcription of lrgAB, increased HDP/CAP susceptibilities in the ΔlytS mutant were lrgAB independent. Further, parental UAMS-1 (but not the ΔlytS mutant) became more resistant to hNP-1 and DAP following pretreatment with carbonyl cyanide m-chlorophenylhydrazone (CCCP) (a CM-depolarizing agent). Of note, lytSR-dependent survival against CAP/HDP killing was not associated with changes in either surface positive charge, expression of mprF and dlt, or CM fluidity. The ΔlytS strain (but not the ΔlrgAB mutant) displayed a significant reduction in target tissue survival in an endocarditis model during DAP treatment. Collectively, these results suggest that the lytSR TCRS plays an important role in adaptive responses of S. aureus to CM-perturbing HDPs/CAPs, likely by functioning as a sense-response system for detecting subtle changes in ΔΨ.


Asunto(s)
Adaptación Biológica , Péptidos Catiónicos Antimicrobianos/farmacología , Proteínas Bacterianas/metabolismo , Staphylococcus aureus/metabolismo , Factores de Transcripción/metabolismo , Aminoaciltransferasas/genética , Aminoaciltransferasas/metabolismo , Animales , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/metabolismo , Proteínas Bacterianas/genética , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Daptomicina/farmacología , Evaluación Preclínica de Medicamentos , Endocarditis Bacteriana/tratamiento farmacológico , Femenino , Técnicas de Inactivación de Genes , Genes Bacterianos , Prueba de Complementación Genética , Potenciales de la Membrana , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Operón , Conejos , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidad , Factores de Transcripción/genética , Transcripción Genética
19.
J Antibiot (Tokyo) ; 65(4): 179-84, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22274703

RESUMEN

The ingestion of antimicrobial residues in foods of animal origin has the potential risk of exposing colonic bacteria to small concentrations of antibiotics and inducing resistance in the colonic bacteria. To investigate whether human intestinal contents would influence resistance development in bacteria, Escherichia coli ATCC 25922 (MIC of enrofloxacin <0.03 µg ml(-1)) was exposed to 0.01 to 1 µg ml(-1) of enrofloxacin in media supplemented with glucose, sucrose, sodium acetate or sterilized human fecal extract. In the first passage, only the medium containing sterilized fecal extract supported the growth of E. coli at an enrofloxacin concentration equal to the MIC. In the second and third passages following exposure to sub-inhibitory concentrations of the drug, the bacteria in media containing sterilized fecal extract grew at 0.1 µg ml(-1) of enrofloxacin. The efflux pump inhibitors, reserpine and carbonyl cyanide-m-chlorophenylhydrazone (CCCP), increased the sensitivity of bacteria to 0.1 µg ml(-1) of enrofloxacin in the medium containing sucrose, but their effect was not observed in the medium supplemented with 2.5% sterilized fecal extract. The proportions of unsaturated and saturated fatty acids in E. coli grown in the medium with 2.5% sterilized fecal extract differed from those grown in the medium alone. Fecal extract may contain unknown factors that augment the ability of E. coli to grow in concentrations of enrofloxacin higher than MIC, both in the presence and absence of efflux pump inhibitors. This is the first study showing that fecal extract affects the level of sensitivity of E. coli to antimicrobial agents.


Asunto(s)
Antiinfecciosos/farmacología , Escherichia coli/efectos de los fármacos , Heces/química , Fluoroquinolonas/farmacología , Carbonil Cianuro m-Clorofenil Hidrazona/análogos & derivados , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , ADN Bacteriano/química , ADN Bacteriano/genética , Enrofloxacina , Escherichia coli/genética , Escherichia coli/metabolismo , Ácidos Grasos/metabolismo , Humanos , Cinética , Pruebas de Sensibilidad Microbiana , Microscopía de Contraste de Fase , Reacción en Cadena de la Polimerasa , Reserpina/farmacología
20.
J Plant Physiol ; 168(14): 1609-16, 2011 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-21511362

RESUMEN

Proline transporters (ProTs) originally described as highly selective transporters for proline, have been shown to also transport glycinebetaine (betaine). Here we examined and compared the transport properties of Bet/ProTs from betaine accumulating (sugar beet, Amaranthus, and Atriplex,) and non-accumulating (Arabidopsis) plants. Using a yeast mutant deficient for uptake of proline and betaine, it was shown that all these transporters exhibited higher affinity for betaine than proline. The uptake of betaine and proline was pH-dependent and inhibited by the proton uncoupler carbonylcyanide m-chlorophenylhydrazone (CCCP). We also investigated choline transport by using a choline transport-deficient yeast mutant. Results revealed that these transporters exhibited a higher affinity for choline uptake rather than betaine. Uptake of choline by sugar beet BvBet/ProT1 was independent of the proton gradient and the inhibition by CCCP was reduced compared with that for uptake of betaine, suggesting different proton binding properties between the transport of choline and betaine. Additionally, in situ hybridization experiments revealed the localization of sugar beet BvBet/ProT1 in phloem and xylem parenchyma cells.


Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Beta vulgaris/metabolismo , Betaína/metabolismo , Proteínas Portadoras/metabolismo , Colina/metabolismo , Prolina/metabolismo , Amaranthus/genética , Amaranthus/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inhibidores , Sistemas de Transporte de Aminoácidos Neutros/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Atriplex/genética , Atriplex/metabolismo , Secuencia de Bases , Beta vulgaris/genética , Transporte Biológico , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/genética , Proteínas Transportadoras de GABA en la Membrana Plasmática , Concentración de Iones de Hidrógeno , Datos de Secuencia Molecular , Mutación , Floema/metabolismo , Hojas de la Planta/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ionóforos de Protónes/farmacología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Especificidad por Sustrato , Xilema/metabolismo
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