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As most of the mitochondrial proteome is encoded in the nucleus, mitochondrial functions critically depend on nuclear gene expression and bidirectional mito-nuclear communication. However, mitochondria-to-nucleus communication pathways in mammals are incompletely understood. Here, we identify G-Protein Pathway Suppressor 2 (GPS2) as a mediator of mitochondrial retrograde signaling and a transcriptional activator of nuclear-encoded mitochondrial genes. GPS2-regulated translocation from mitochondria to nucleus is essential for the transcriptional activation of a nuclear stress response to mitochondrial depolarization and for supporting basal mitochondrial biogenesis in differentiating adipocytes and brown adipose tissue (BAT) from mice. In the nucleus, GPS2 recruitment to target gene promoters regulates histone H3K9 demethylation and RNA POL2 activation through inhibition of Ubc13-mediated ubiquitination. These findings, together, reveal an additional layer of regulation of mitochondrial gene transcription, uncover a direct mitochondria-nuclear communication pathway, and indicate that GPS2 retrograde signaling is a key component of the mitochondrial stress response in mammals.
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Núcleo Celular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Mitocondrias/metabolismo , Biogénesis de Organelos , Transducción de Señal/fisiología , Células 3T3-L1 , Transporte Activo de Núcleo Celular/fisiología , Animales , Núcleo Celular/genética , Células HeLa , Histonas/genética , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Metilación , Ratones , Mitocondrias/genética , Regiones Promotoras Genéticas/fisiología , Activación Transcripcional/fisiologíaRESUMEN
Drug-target binding affinity prediction is a fundamental task for drug discovery and has been studied for decades. Most methods follow the canonical paradigm that processes the inputs of the protein (target) and the ligand (drug) separately and then combines them together. In this study we demonstrate, surprisingly, that a model is able to achieve even superior performance without access to any protein-sequence-related information. Instead, a protein is characterized completely by the ligands that it interacts. Specifically, we treat different proteins separately, which are jointly trained in a multi-head manner, so as to learn a robust and universal representation of ligands that is generalizable across proteins. Empirical evidences show that the novel paradigm outperforms its competitive sequence-based counterpart, with the Mean Squared Error (MSE) of 0.4261 versus 0.7612 and the R-Square of 0.7984 versus 0.6570 compared with DeepAffinity. We also investigate the transfer learning scenario where unseen proteins are encountered after the initial training, and the cross-dataset evaluation for prospective studies. The results reveals the robustness of the proposed model in generalizing to unseen proteins as well as in predicting future data. Source codes and data are available at https://github.com/huzqatpku/SAM-DTA.
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Proteínas , Programas Informáticos , Ligandos , Estudios Prospectivos , Proteínas/química , Secuencia de Aminoácidos , Unión ProteicaRESUMEN
Excessive gluconeogenesis can lead to hyperglycemia and diabetes through as yet incompletely understood mechanisms. Herein, we show that hepatic ZBTB22 expression is increased in both diabetic clinical samples and mice, being affected by nutritional status and hormones. Hepatic ZBTB22 overexpression increases the expression of gluconeogenic and lipogenic genes, heightening glucose output and lipids accumulation in mouse primary hepatocytes (MPHs), while ZBTB22 knockdown elicits opposite effects. Hepatic ZBTB22 overexpression induces glucose intolerance and insulin resistance, accompanied by moderate hepatosteatosis, while ZBTB22-deficient mice display improved energy expenditure, glucose tolerance, and insulin sensitivity, and reduced hepatic steatosis. Moreover, hepatic ZBTB22 knockout beneficially regulates gluconeogenic and lipogenic genes, thereby alleviating glucose intolerance, insulin resistance, and liver steatosis in db/db mice. ZBTB22 directly binds to the promoter region of PCK1 to enhance its expression and increase gluconeogenesis. PCK1 silencing markedly abolishes the effects of ZBTB22 overexpression on glucose and lipid metabolism in both MPHs and mice, along with the corresponding changes in gene expression. In conclusion, targeting hepatic ZBTB22/PEPCK1 provides a potential therapeutic approach for diabetes.
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Hígado Graso , Intolerancia a la Glucosa , Hiperglucemia , Resistencia a la Insulina , Ratones , Animales , Gluconeogénesis/genética , Resistencia a la Insulina/genética , Hígado/metabolismo , Hiperglucemia/genética , Hiperglucemia/metabolismo , Glucosa/metabolismo , Hígado Graso/metabolismo , Ratones Endogámicos C57BL , Hepatocitos/metabolismoRESUMEN
O3-type layered oxides have been extensively studied as cathode materials for sodium-ion batteries due to their high reversible capacity and high initial sodium content, but they suffer from complex phase transitions and an unstable structure during sodium intercalation/deintercalation. Herein, we synthesize a high-entropy O3-type layered transition metal oxide, NaNi0.3Cu0.05Fe0.1Mn0.3Mg0.05Ti0.2O2 (NCFMMT), by simultaneously doping Cu, Mg, and Ti into its transition metal layers, which greatly increase structural entropy, thereby reducing formation energy and enhancing structural stability. The high-entropy NCFMMT cathode exhibits significantly improved cycling stability (capacity retention of 81.4% at 1C after 250 cycles and 86.8% at 5C after 500 cycles) compared to pristine NaNi0.3Fe0.4Mn0.3O2 (71% after 100 cycles at 1C), as well as remarkable air stability. Finally, the NCFMMT//hard carbon full-cell batteries deliver a high initial capacity of 103 mAh g-1 at 1C, with 83.8 mAh g-1 maintained after 300 cycles (capacity retention of 81.4%).
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A major challenge in prevention and early treatment of organ fibrosis is the lack of valuable tools to assess the evolving profibrotic maladaptive repair after injury in vivo in a non-invasive way. Here, using acute kidney injury (AKI) as an example, we tested the utility of fibroblast activation protein (FAP) imaging for dynamic assessment of maladaptive repair after injury. The temporospatial pattern of kidney FAP expression after injury was first characterized. Single-cell RNA sequencing and immunostaining analysis of patient biopsies were combined to show that FAP was specifically upregulated in kidney fibroblasts after AKI and was associated with fibroblast activation and chronic kidney disease (CKD) progression. This was corroborated in AKI mouse models, where a sustained and exaggerated kidney FAP upregulation was coupled to persistent fibroblast activation and a fibrotic outcome, linking kidney FAP level to post-insult maladaptive repair. Furthermore, using positron emission tomography (PET)/CT scanning with FAP-inhibitor tracers ([18F]FAPI-42, [18F]FAPT) targeting FAP, demonstrated the feasibility of non-invasively tracking of maladaptive repair evolution toward kidney fibrosis. Importantly, a sustained increase in kidney [18F]FAPT (less hepatobiliary metabolized than [18F]FAPI-42) uptake reflected persistent kidney upregulation of FAP and characterized maladaptive repair after AKI. Kidney [18F]FAPT uptake at hour 2-day 7 correlated with kidney fibrosis 14 days after AKI. Similar changes in [18F]FAPI-42 PET/CT imaging were observed in patients with AKI and CKD progression. Thus, persistent kidney FAP upregulation after AKI was associated with maladaptive repair and a fibrotic outcome. Hence, FAP-specific PET/CT imaging enables dynamic visualization of maladaptive repair after AKI and prediction of kidney fibrosis within a clinically actionable window.
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GRP78, a member of the HSP70 superfamily, is an endoplasmic reticulum chaperone protein overexpressed in various cancers, making it a promising target for cancer imaging and therapy. Positron emission tomography (PET) imaging offers unique advantages in real time, noninvasive tumor imaging, rendering it a suitable tool for targeting GRP78 in tumor imaging to guide targeted therapy. Several studies have reported successful tumor imaging using PET probes targeting GRP78. However, existing PET probes face challenges such as low tumor uptake, inadequate in vivo distribution, and high abdominal background signal. Therefore, this study introduces a novel peptide PET probe, [18F]AlF-NOTA-c-DVAP, for targeted tumor imaging of GRP78. [18F]AlF-NOTA-c-DVAP was radiolabeled with fluoride-18 using the aluminum-[18F]fluoride ([18F]AlF) method. The study assessed the partition coefficients, stability in vitro, and metabolic stability of [18F]AlF-NOTA-c-DVAP. Micro-PET imaging, pharmacokinetic analysis, and biodistribution studies were carried out in tumor-bearing mice to evaluate the probe's performance. Docking studies and pharmacokinetic analyses of [18F]AlF-NOTA-c-DVAP were also performed. Immunohistochemical and immunofluorescence analyses were conducted to confirm GRP78 expression in tumor tissues. The probe's binding affinity to GRP78 was analyzed by molecular docking simulation. [18F]AlF-NOTA-c-DVAP was radiolabeled in just 25 min with a high yield of 51 ± 16%, a radiochemical purity of 99%, and molar activity within the range of 20-50 GBq/µmol. [18F]AlF-NOTA-c-DVAP demonstrated high stability in vitro and in vivo, with a logD value of -3.41 ± 0.03. Dynamic PET imaging of [18F]AlF-NOTA-c-DVAP in tumors showed rapid uptake and sustained retention, with minimal background uptake. Biodistribution studies revealed rapid blood clearance and excretion through the kidneys following a single-compartment reversible metabolic model. In PET imaging, the T/M ratios for A549 tumors (high GRP78 expression), MDA-MB-231 tumors (medium expression), and HepG2 tumors (low expression) at 60 min postintravenous injection were 10.48 ± 1.39, 6.25 ± 0.47, and 3.15 ± 1.15% ID/g, respectively, indicating a positive correlation with GRP78 expression. This study demonstrates the feasibility of using [18F]AlF-NOTA-c-DVAP as a PET tracer for imaging GRP78 in tumors. The probe shows promising results in terms of stability, specificity, and tumor targeting. Further research may explore the clinical utility and potential therapeutic applications of this PET tracer for cancer diagnosis.
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Chaperón BiP del Retículo Endoplásmico , Radioisótopos de Flúor , Proteínas de Choque Térmico , Tomografía de Emisión de Positrones , Radiofármacos , Animales , Ratones , Humanos , Tomografía de Emisión de Positrones/métodos , Radioisótopos de Flúor/farmacocinética , Distribución Tisular , Proteínas de Choque Térmico/metabolismo , Radiofármacos/farmacocinética , Radiofármacos/administración & dosificación , Línea Celular Tumoral , Ratones Desnudos , Femenino , Ratones Endogámicos BALB C , Compuestos Heterocíclicos con 1 Anillo/química , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacocinéticaRESUMEN
Early diagnosis and precise surgical intervention are crucial for cancer patients. We aimed to develop a novel positron emission tomography (PET)/fluorescence dual-modality probe for preoperative diagnosis, intraoperative guidance, and postoperative monitoring of fibroblast activation protein (FAP)-positive tumors. FAPI-FAM was synthesized and labeled with gallium-68. [68Ga]Ga-FAPI-FAM showed favorable in vivo and in vitro characteristics, specific binding affinity, and excellent tumor accumulation in FAP-positive cells and mice xenografts. Excellent tumor-to-background contrast was found owing to high tumor uptake, prolonged retention, and rapid renal clearance of [68Ga]Ga-FAPI-FAM. Moreover, a specific fluorescence signal was detected in FAP-positive tumors during ex vivo fluorescence imaging, demonstrating the feasibility of whole-body tumor detection and intraoperative tumor delineation.
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Neoplasias , Quinolinas , Humanos , Ratones , Animales , Radioisótopos de Galio , Fluorescencia , Tomografía de Emisión de Positrones/métodos , Neoplasias/metabolismo , Fibroblastos/metabolismoRESUMEN
Solid-state electrolytes (SEs) have attracted overwhelming attention as a promising alternative to traditional organic liquid electrolytes (OLEs) for high-energy-density sodium-metal batteries (SMBs), owing to their intrinsic incombustibility, wider electrochemical stability window (ESW), and better thermal stability. Among various kinds of SEs, inorganic solid-state electrolytes (ISEs) stand out because of their high ionic conductivity, excellent oxidative stability, and good mechanical strength, rendering potential utilization in safe and dendrite-free SMBs at room temperature. However, the development of Na-ion ISEs still remains challenging, that a perfect solution has yet to be achieved. Herein, we provide a comprehensive and in-depth inspection of the state-of-the-art ISEs, aiming at revealing the underlying Na+ conduction mechanisms at different length scales, and interpreting their compatibility with the Na metal anode from multiple aspects. A thorough material screening will include nearly all ISEs developed to date, i.e., oxides, chalcogenides, halides, antiperovskites, and borohydrides, followed by an overview of the modification strategies for enhancing their ionic conductivity and interfacial compatibility with Na metal, including synthesis, doping and interfacial engineering. By discussing the remaining challenges in ISE research, we propose rational and strategic perspectives that can serve as guidelines for future development of desirable ISEs and practical implementation of high-performance SMBs.
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BACKGROUND: Microglia play a pivotal role in neuroinflammation, while obesity triggers hypothalamic microglia activation and inflammation. Sirt6 is an important regulator of energy metabolism in many peripheral tissues and hypothalamic anorexic neurons. However, the exact mechanism for microglia Sirt6 in controlling high-fat diet-induced obesity remain unknown. METHODS: Microglia Sirt6 expression levels under various nutritional conditions were measured in the hypothalamus of mice. Also, microglia Sirt6-deficient mice were provided various diets to monitor metabolic changes and hypothalamic inflammatory response. Besides, RNA-seq and Co-IP of microglia with Sirt6 alterations were conducted to further investigate the detailed mechanism by which Sirt6 modulated microglia activity. RESULTS: We found that Sirt6 was downregulated in hypothalamic microglia in mice given a high-fat diet (HFD). Additionally, knockout of microglia Sirt6 exacerbated high-fat diet-induced hypothalamic microglial activation and inflammation. As a result, mice were more prone to obesity, exhibiting a decrease in energy expenditure, impaired glucose tolerance, insulin and leptin resistance, and increased food intake. In vitro, Sirt6 overexpression in BV2 cells displayed protective effects against oleic acid and palmitic acid treatment-derived inflammatory response. Mechanically, Sirt6 deacetylated and stabilised NRF2 to increase the expression of anti-oxidative genes and defend against reactive oxygen species overload. Pharmacological inhibition of NRF2 eliminated the beneficial modulating effects of Sirt6 on microglial activity. CONCLUSION: Collectively, our results revealed that microglial Sirt6 was a primary contributor of microglial activation in the central regulation of obesity. Thus, microglial Sirt6 may be an important therapeutic target for obesity.
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Microglía , Sirtuinas , Ratones , Animales , Microglía/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Dieta Alta en Grasa/efectos adversos , Obesidad/genética , Obesidad/metabolismo , Hipotálamo , Inflamación/metabolismo , Ratones Endogámicos C57BL , Sirtuinas/genética , Sirtuinas/metabolismoRESUMEN
PURPOSE: Research on fibroblast activating protein (FAP)-targeting inhibitor (FAPI) has become an important focus for cancer imaging and radiotherapy. Quinoline-based tracers [68 Ga]FAPI-04 and [18F]FAPI-42 have been widely used for positron emission tomography (PET) imaging of most tumors. However, there exist some limitations of these tracers with high uptake in biliary duct system and unstable uptake in pancreas, unsuitable for abdominal tumors PET imaging. Here we developed a [18F]-labeled glycopeptide-containing FAPI tracer (named [18F]FAPT) for PET imaging of FAP in cancers. METHODS: [18F]FAPT was synthesized manually and automatically. The competitive binding to FAP, cellular internalization, and efflux characteristics were examined in vitro using A549-FAP cells. Dynamic MicroPET and biodistribution studies of [18F]FAPT were then conducted in A549-FAP and U87MG xenograft tumor mouse models compared with [18F]FAPI-42. Five healthy volunteers and three patients with cancer underwent [18F]FAPT PET/CT. RESULTS: Preclinical and clinical studies showed specific binding of [18F]FAPT to FAP and favorable pharmacokinetic properties with better hydrophilicity, lower uptake in biliary duct system, higher tumor uptake and longer tumor retention compared with [18F]FAPI-42. The biodistribution of [18F]FAPT in healthy volunteers and patients with cancer displayed low uptake in most normal tissues except for pancreas, thyroid and salivary gland, which could contribute to high tumor-to-background ratios in most cancers. CONCLUSION: [18F]FAPT is better PET tracer than [18F]FAPI-42 for imaging of biliary duct system cancer, potentially providing a tool to examine FAP expression in most cancers with high tumor-to-background ratios.
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Neoplasias Abdominales , Quinolinas , Humanos , Animales , Ratones , Tomografía Computarizada por Tomografía de Emisión de Positrones , Distribución Tisular , Tomografía de Emisión de Positrones , Fibroblastos , Modelos Animales de Enfermedad , Radioisótopos de GalioRESUMEN
The ability of neural stem cells (NSCs) to switch between quiescence and proliferation is crucial for brain development and homeostasis. Increasing evidence suggests that variants of histone lysine methyltransferases including KMT5A are associated with neurodevelopmental disorders. However, the function of KMT5A/Pr-set7/SETD8 in the central nervous system is not well established. Here, we show that Drosophila Pr-Set7 is a novel regulator of NSC reactivation. Loss of function of pr-set7 causes a delay in NSC reactivation and loss of H4K20 monomethylation in the brain. Through NSC-specific in vivo profiling, we demonstrate that Pr-set7 binds to the promoter region of cyclin-dependent kinase 1 (cdk1) and Wnt pathway transcriptional co-activator earthbound1/jerky (ebd1). Further validation indicates that Pr-set7 is required for the expression of cdk1 and ebd1 in the brain. Similar to Pr-set7, Cdk1 and Ebd1 promote NSC reactivation. Finally, overexpression of Cdk1 and Ebd1 significantly suppressed NSC reactivation defects observed in pr-set7-depleted brains. Therefore, Pr-set7 promotes NSC reactivation by regulating Wnt signaling and cell cycle progression. Our findings may contribute to the understanding of mammalian KMT5A/PR-SET7/SETD8 during brain development.
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Histonas , Células-Madre Neurales , Animales , Proteína Quinasa CDC2 , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Células-Madre Neurales/metabolismoRESUMEN
6-O-[18F]Fluoroethylerlotinib (6-O-[18F]FEE), with a suitable half-life for commercial distribution, may be a good replacement for [11C]erlotinib to identify epidermal growth factor receptor (EGFR) positive tumors with activating mutations to tyrosine kinase inhibitors therapy. In this study, we explored the fully automated synthesis of 6-O-[18F]FEE and investigated its pharmacokinetics in tumor-bearing mice. 6-O-[18F]FEE with high specific activity (28-100 GBq/µmol) and radiochemistry purity (over 99 %) was obtained by two-step reaction and Radio-HPLC separation in PET-MF-2 V-IT-1 automated synthesizer. PET imaging of 6-O-[18F]FEE in HCC827, A431, and U87 tumor-bearing mice with different EGFR expression and mutation was performed. Uptake and blocking of PET imaging indicated that the probe specifically targeted exon 19 deleted EGFR (the quantitative analysis of tumor-to-mouse ratio for HCC827, HCC827 blocking, U87, A431 was 2.58 ± 0.24, 1.20 ± 0.15, 1.18 ± 0.19, and 1.05 ± 0.13 respectively). Dynamic imaging was used to study the pharmacokinetics of the probe in tumor-bearing mice. Logan plot graphical analysis demonstrated late linearity and a high fitting correlation coefficient (0.998), supporting reversible kinetics. According to the Akaike Information Criterion (AIC) rule, the 2-compartment reversible model was more consistent with the metabolic properties of 6-O-[18F]FEE. The automated radiosynthesis and pharmacokinetic analysis will promote clinically transformation of 6-O-[18F]FEE.
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Neoplasias Pulmonares , Tomografía de Emisión de Positrones , Animales , Ratones , Clorhidrato de Erlotinib , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/genética , Receptores ErbB , Mutación , Línea Celular TumoralRESUMEN
Fibroblast activation protein (FAP) is a promising molecular target for imaging in various types of cancers. Several 18F-labeled FAP inhibitor (FAPI) tracers have been evaluated in clinical study. However, these tracers display high physiological uptake in gallbladder and bile duct system. To overcome the limitation, we herein designed a novel radiotracer named 18F-FAPTG. 18F-FAPTG was produced with a non-decay-corrected radiochemical yield of 24.0 ± 6.0% and 22.0 ± 7.0% for manual and automatic synthesis, respectively. 18F-FAPTG exhibited high hydrophilicity and stability in vitro. The studies of cellular uptake, internalization, efflux properties and competitive binding to FAP of 18F-FAPTG indicated that the tracer showed high specificity, rapid internalization and low cellular efflux in FAP-positive cells. Biodistribution studies and microPET in mice bearing FAP-positive xenografts demonstrated extremely low uptake in the majority of other organs and main excretion of 18F-FAPTG through the urinary system. Furthermore, compared to 18F-FAPI-42, 18F-FAPTG showed significantly lower uptake in gallbladder, higher tumor uptake and longer tumor retention. In the pilot clinical study, 18F-FAPTG PET/CT demonstrated favorable tumor-to-background ratios in most organs and clearly displayed the malignant lesions. Our findings indicated that 18F-FAPTG had an advantage over 18F-FAPI-42 in PET imaging for cancers located in gallbladder the bile duct system. Thus, 18F-FAPTG could be an alternative to the currently available FAPI tracers.
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Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Ratones , Animales , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Distribución Tisular , Tomografía de Emisión de Positrones , Neoplasias/metabolismo , Fibroblastos/metabolismoRESUMEN
OBJECTIVE: To assess the feasibility and safety of three-dimensional (3D) laparoscopic nephrectomy in combination with bench surgery and autotransplantation for treating highly complex renal tumors. MATERIALS AND METHODS: The clinical data of six patients with highly complex renal cell carcinoma were collected. All patients underwent 3D laparoscopic nephrectomy in combination with bench surgery and autotransplantation by the same surgeons, two of them had previously undergone laparoscopic partial nephrectomy for contralateral renal cancer. RESULTS: The total operative time was 366 ± 65 min, the warm ischemia time (WIT) was 1.3 ± 0.4 min, and the cold ischemia time was 121 ± 26 min. While one patient received a diluted autologous blood transfusion, the intraoperative blood loss was 217 ± 194 ml. No increase in the serum creatinine (SCr) level was observed at postoperative day 30 compared with the preoperative time, and none of the patients received dialysis either during the hospital stay or to date. Although one patient underwent nephrectomy due to tumor recurrence in the transplanted kidney, the others reported no tumor recurrence or distant metastases on imaging to date. CONCLUSION: 3D laparoscopic nephrectomy, when combined with bench surgery and autotransplantation, can become a feasible option for treating highly complex renal cell carcinoma cases when expecting to preserve renal function maximally.
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Carcinoma de Células Renales , Neoplasias Renales , Laparoscopía , Humanos , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , Trasplante Autólogo , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Nefrectomía/métodos , Riñón/fisiología , Riñón/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Neural stem cells (NSCs) are crucial for development, regeneration, and repair of the nervous system. Most NSCs in mammalian adult brains are quiescent, but in response to extrinsic stimuli, they can exit from quiescence and become reactivated to give rise to new neurons. The delicate balance between NSC quiescence and activation is important for adult neurogenesis and NSC maintenance. However, how NSCs transit between quiescence and activation remains largely elusive. Here, we discuss our current understanding of the molecular mechanisms underlying the reactivation of quiescent NSCs. We review recent advances on signaling pathways originated from the NSC niche and their crosstalk in regulating NSC reactivation. We also highlight new intrinsic paradigms that control NSC reactivation in Drosophila and mammalian systems. We also discuss emerging evidence on modeling human neurodevelopmental disorders using NSCs.
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Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Trastornos del Neurodesarrollo/patología , Transducción de Señal , Animales , Drosophila melanogaster/citología , Drosophila melanogaster/metabolismo , Humanos , Insulina/metabolismo , Trastornos del Neurodesarrollo/terapia , Nicho de Células MadreRESUMEN
Muscle atrophy is a common complication in chronic kidney disease (CKD). Inflammation and myostatin play important roles in CKD muscle atrophy. Formononetin (FMN), which is a major bioactive isoflavone compound in Astragalus membranaceus, exerts anti-inflammatory effects and the promotion of myogenic differentiation. Our study is based on myostatin to explore the effects and mechanisms of FMN in relation to CKD muscle atrophy. In this study, CKD rats and tumour necrosis factor α (TNF-α)-induced C2C12 myotubes were used for in vivo and in vitro models of muscle atrophy. The results showed that FMN significantly improved the renal function, nutritional status and inflammatory markers in CKD rats. Values for bodyweight, weight of tibialis anterior and gastrocnemius muscles, and cross-sectional area (CSA) of skeletal muscles were significantly larger in the FMN treatment rats. Furthermore, FMN significantly suppressed the expressions of MuRF-1, MAFbx and myostatin in the muscles of CKD rats and the TNF-α-induced C2C12 myotubes. Importantly, FMN significantly increased the phosphorylation of PI3K, Akt, and FoxO3a and the expressions of the myogenic proliferation and differentiation markers, myogenic differentiation factor D (MyoD) and myogenin in muscles of CKD rats and the C2C12 myotubes. Similar results were observed in TNF-α-induced C2C12 myotubes transfected with myostatin-small interfering RNA (si-myostatin). Notably, myostatin overexpression plasmid (myostatin OE) abolished the effect of FMN on the phosphorylation of the PI3K/Akt/FoxO3a pathway and the expressions of MyoD and myogenin. Our findings suggest that FMN ameliorates muscle atrophy related to myostatin-mediated PI3K/Akt/FoxO3a pathway and satellite cell function.
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Proteína Forkhead Box O3/metabolismo , Isoflavonas/farmacología , Miostatina/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células Satélite del Músculo Esquelético/efectos de los fármacos , Células Satélite del Músculo Esquelético/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Masculino , Ratones , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/etiología , Atrofia Muscular/patología , Miostatina/genética , Fosforilación , Ratas , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patologíaRESUMEN
Elevated autophagy is highly associated with cancer development and progression. Fruit extracts of several plants inhibit activity of autophagy-related protease ATG4B and autophagy activity in colorectal cancer cells. However, the effects of these plant extracts in oral cancer cells remain unclear. In this study, we found that the extracted Tribulus terrestris fruit (TT-(fr)) and Xanthium strumarium fruit had inhibitory effects on autophagy inhibition in both SAS and TW2.6 oral cancer cells. Moreover, the fruit extracts had differential effects on cell proliferation of oral cancer cells. In addition, the fruit extracts hampered cell migration and invasion of oral cancer cells, particularly in TT-(fr) extracts. Our results indicated that TT-(fr) extracts consistently inhibited autophagic flux, cell growth and metastatic characteristics of oral cancer cells, suggesting TT-(fr) might contain function ingredient to suppress oral cancer cells.
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Neoplasias de la Boca , Tribulus , Autofagia , Proliferación Celular , Frutas , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Extractos Vegetales/farmacologíaRESUMEN
Acute rhinosinusitis is a common infectious disease, which, in more than 90% of cases, is caused by viruses rather than by bacteria. Even so, antibiotics are often unnecessarily prescribed, and in the long run this contributes to the alarming level of antibiotics resistance. The reason is that there are no good guiding tools for defining the background reason of the infection. One main factor for the clearance of the infection is if there is non-obstructed ventilation from the sinus to the nasal cavity. Gas in Scattering Media Absorption Spectroscopy (GASMAS) has potential for diagnosing this. We have performed a study of frontal sinuses of volunteers with a focus on signal stability and reproducibility over time, accurate oxygen concentration determination, and assessment of gas transport through passages, naturally and after decongestant spray administration. Different from earlier studies on frontal sinuses, water vapor, serving the purpose of oxygen signal normalization, was measured at 818 nm rather than earlier at 937 nm, now closer to the 760 nm oxygen absorption band and thus resulting in more reliable results. In addition, the action of decongestants was objectively demonstrated for the first time. Evaluated oxygen concentration values for left- and right-hand side sinus cavities were found to agree within 0.3%, and a left-right geometrical asymmetry parameter related to anatomical differences was stable within 10%.
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Senos Paranasales , Sinusitis , Humanos , Reproducibilidad de los Resultados , Análisis Espectral , VaporRESUMEN
G protein pathway suppressor 2 (GPS2) is a multifunctional protein involved in the regulation of a number of metabolic organs. First identified as part of the NCoR-SMRT corepressor complex, GPS2 is known to play an important role in the nucleus in the regulation of gene transcription and meiotic recombination. In addition, we recently reported a non-transcriptional role of GPS2 as an inhibitor of the proinflammatory TNFα pathway in the cytosol. Although this suggests that the control of GPS2 localization may be an important determinant of its molecular functions, a clear understanding of GPS2 differential targeting to specific cellular locations is still lacking. Here we show that a fine balance between protein stabilization and degradation tightly regulates GPS2 nuclear function. Our findings indicate that GPS2 is degraded upon polyubiquitination by the E3 ubiquitin ligase Siah2. Unexpectedly, interaction with the exchange factor TBL1 is required to protect GPS2 from degradation, with methylation of GPS2 by arginine methyltransferase PRMT6 regulating the interaction with TBL1 and inhibiting proteasome-dependent degradation. Overall, our findings indicate that regulation of GPS2 by posttranslational modifications provides an effective strategy for modulating its molecular function within the nuclear compartment.