RESUMEN
Metastasis is a crucial stage in tumour progression, and cancer-associated fibroblasts (CAFs) support metastasis through their participation in extracellular matrix (ECM) stiffness. CD248 is a possible biomarker for non-small cell lung cancer (NSCLC)-derived CAFs, but its role in mediating ECM stiffness to promote NSCLC metastasis is unknown. We investigated the significance of CD248+ CAFs in activating the Hippo axis and promoting connective tissue growth factor (CTGF) expression, which affects the stromal collagen I environment and improves ECM stiffness, thereby facilitating NSCLC metastasis. In this study, we found that higher levels of CD248 in CAFs induced the formation of collagen I, which in turn increased extracellular matrix stiffness, thereby enabling NSCLC cell infiltration and migration. Hippo axis activation by CD248+ CAFs induces CTGF expression, which facilitates the formation of the collagen I milieu in the stromal matrix. In a tumour lung metastasis model utilizing fibroblast-specific CD248 gene knockout mice, CD248 gene knockout mice showed a significantly reduced ability to develop tumour lung metastasis compared to that of WT mice. Our findings demonstrate that CD248+ CAFs activate the Hippo pathway, thereby inducing CTGF expression, which in turn facilitates the collagen I milieu of the stromal matrix, which promotes NSCLC metastasis.
Asunto(s)
Fibroblastos Asociados al Cáncer , Carcinoma de Pulmón de Células no Pequeñas , Factor de Crecimiento del Tejido Conjuntivo , Matriz Extracelular , Vía de Señalización Hippo , Neoplasias Pulmonares , Ratones Noqueados , Proteínas Serina-Treonina Quinasas , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Animales , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Matriz Extracelular/metabolismo , Ratones , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Línea Celular Tumoral , Antígenos CD/metabolismo , Antígenos CD/genética , Metástasis de la Neoplasia , Transducción de Señal , Regulación Neoplásica de la Expresión Génica , Movimiento Celular , Microambiente TumoralRESUMEN
Chemotherapy-resistant non-small cell lung cancer (NSCLC) presents a substantial barrier to effective care. It is still unclear how cancer-associated fibroblasts (CAFs) contribute to NSCLC resistance to chemotherapy. Here, we found that CD248+ CAFs released IL-8 in NSCLC, which, in turn, enhanced the cisplatin (CDDP) IC50 in A549 and NCI-H460 while decreasing the apoptotic percentage of A549 and NCI-H460 in vitro. The CD248+ CAFs-based IL-8 secretion induced NSCLC chemoresistance by stimulating nuclear factor kappa B (NF-κB) and elevating ATP-binding cassette transporter B1 (ABCB1). We also revealed that the CD248+ CAFs-based IL-8 release enhanced cisplatin chemoresistance in NSCLC mouse models in vivo. Relative to wild-type control mice, the CD248 conditional knockout mice exhibited significant reduction of IL-8 secretion, which, in turn, enhanced the therapeutic efficacy of cisplatin in vivo. In summary, our study identified CD248 activates the NF-κB axis, which, consecutively induces the CAFs-based secretion of IL-8, which promotes NSCLC chemoresistance. This report highlights a potential new approach to enhancing the chemotherapeutic potential of NSCLC-treating cisplatin.
Asunto(s)
Antineoplásicos , Fibroblastos Asociados al Cáncer , Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Interleucina-8 , Neoplasias Pulmonares , Animales , Ratones , Antígenos CD , Antígenos de Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Proliferación Celular , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Interleucina-8/genética , Interleucina-8/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , FN-kappa B , HumanosRESUMEN
Cancer associated fibroblasts (CAFs) are one of the main components of tumor microenvironment (TME). In TME, the interaction between tumor cells and non-tumor cells or among non tumor cells can promote the occurrence and development of tumors. CAFs can interact with a variety of immune cells and promote the occurrence and development of tumors by inhibiting the function of adaptive immune cells and reshaping the immune microenvironment in TME. The interaction between CAFs and macrophages and the induction of macrophage polarization towards M2 type play an important role in promoting tumor occurrence and development. This article reviews the research progress of CAF in promoting the polarization of M2 macrophages.
Asunto(s)
Fibroblastos Asociados al Cáncer , Fibroblastos Asociados al Cáncer/patología , Macrófagos/patología , Microambiente TumoralRESUMEN
Knee osteoarthritis (KOA), a common degenerative joint disorder, is characterized by chronic pain and disability, which can progress to irreparable structural damage of the joint. Investigations into the link between articular cartilage, muscles, synovium, and other tissues surrounding the knee joint in KOA are of great importance. Currently, managing KOA includes lifestyle modifications, exercise, medication, and surgical interventions; however, the elucidation of the intricate mechanisms underlying KOA-related pain is still lacking. Consequently, KOA pain remains a key clinical challenge and a therapeutic priority. Tuina has been found to have a regulatory effect on the motor, immune, and endocrine systems, prompting the exploration of whether Tuina could alleviate KOA symptoms, caused by the upregulation of inflammatory factors, and further, if the inflammatory factors in skeletal muscle can augment the progression of KOA. We randomized 32 male Sprague Dawley (SD) rats (180-220 g) into four groups of eight animals each: antiPD-L1+Tuina (group A), model (group B), Tuina (group C), and sham surgery (group D). For groups A, B, and C, we injected 25 µL of sodium monoiodoacetate (MIA) solution (4 mg MIA diluted in 25 µL of sterile saline solution) into the right knee joint cavity, and for group D, the same amount of sterile physiological saline was injected. All the groups were evaluated using the least to most stressful tests (paw mechanical withdrawal threshold, paw withdrawal thermal latency, swelling of the right knee joint, Lequesne MG score, skin temperature) before injection and 2, 9, and 16 days after injection.
Asunto(s)
Osteoartritis de la Rodilla , Ratas , Masculino , Animales , Osteoartritis de la Rodilla/inducido químicamente , Osteoartritis de la Rodilla/terapia , Ratas Sprague-Dawley , Sodio/efectos adversos , Articulación de la Rodilla/cirugía , Dolor/etiología , Inyecciones Intraarticulares/efectos adversosRESUMEN
SCOPE: Propolis has been found to decrease glucose levels and increase insulin sensitivity in type 2 diabetes. However, the active ingredient responsible for these effects and its regulating mechanism are not fully understood. METHODS AND RESULTS: To address this, molecular docking screening is used to screen the effective hypoglycemic ingredient in propolis and found that tectochrysin (TEC) has a high affinity to the insulin receptor (IR), highlighting its potential for glycemic control. In vivo tests show that TEC decreases glucose levels and enhances insulin sensitivity in db/db mice. By hyperinsulinemic euglycemic clamp test, this study further finds that TEC promotes glucose uptake in adipose tissue and skeletal muscle, as well as inhibits hepatic gluconeogenesis. Moreover, it finds that TEC promotes glucose uptake and adipocytes differentiation in 3T3-L1 cells like insulin, suggesting that TEC exerts an insulin mimetic effect. Mechanistically, pharmacology inhibition of IRß abolishes the effects of TEC on glucose uptake and the phosphorylation of IR. The study further demonstrates that TEC binds to and activates IRß by targeting its E1077 and M1079. CONCLUSION: Therefore, this study sheds light on the mechanism underlying propolis' potential for ameliorating type 2 diabetes, offering a natural food-derived compound as a promising therapeutic option.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Própolis , Ratones , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Receptor de Insulina/metabolismo , Própolis/farmacología , Simulación del Acoplamiento Molecular , Insulina/metabolismo , Glucosa/metabolismo , Células 3T3-L1RESUMEN
Skeletal muscle comprises a large, heterogeneous assortment of cell populations that interact to maintain muscle homeostasis, but little is known about the mechanism that controls myogenic development in response to artificial selection. Different pig (Sus scrofa) breeds exhibit distinct muscle phenotypes resulting from domestication and selective breeding. Using unbiased single-cell transcriptomic sequencing analysis (scRNA-seq), the impact of artificial selection on cell profiles is investigated in neonatal skeletal muscle of pigs. This work provides panoramic muscle-resident cell profiles and identifies novel and breed-specific cells, mapping them on pseudotime trajectories. Artificial selection has elicited significant changes in muscle-resident cell profiles, while conserving signs of generational environmental challenges. These results suggest that fibro-adipogenic progenitors serve as a cellular interaction hub and that specific transcription factors identified here may serve as candidate target regulons for the pursuit of a specific muscle phenotype. Furthermore, a cross-species comparison of humans, mice, and pigs illustrates the conservation and divergence of mammalian muscle ontology. The findings of this study reveal shifts in cellular heterogeneity, novel cell subpopulations, and their interactions that may greatly facilitate the understanding of the mechanism underlying divergent muscle phenotypes arising from artificial selection.
Asunto(s)
Adipogénesis , Músculo Esquelético , Humanos , Animales , Ratones , Fenotipo , Desarrollo de Músculos/genética , ARN , MamíferosRESUMEN
Sepsis-induced muscle atrophy often increases morbidity and mortality in intensive care unit (ICU) patients, yet neither therapeutic target nor optimal animal model is available for this disease. Here, by modifying the surgical strategy of cecal ligation and puncture (CLP), a novel sepsis pig model is created that for the first time recapitulates the whole course of sepsis in humans. With this model and sepsis patients, increased levels of the transcription factor zinc finger BED-type containing 6 (ZBED6) in skeletal muscle are shown. Protection against sepsis-induced muscle wasting in ZBED6-deficient pigs is further demonstrated. Mechanistically, integrated analysis of RNA-seq and ChIP-seq reveals dedicator of cytokinesis 3 (DOCK3) as the direct target of ZBED6. In septic ZBED6-deficient pigs, DOCK3 expression is increased in skeletal muscle and myocytes, activating the RAC1/PI3K/AKT pathway and protecting against sepsis-induced muscle wasting. Conversely, opposite gene expression patterns and exacerbated muscle wasting are observed in septic ZBED6-overexpressing myotubes. Notably, sepsis patients show increased ZBED6 expression along with reduced DOCK3 and downregulated RAC1/PI3K/AKT pathway. These findings suggest that ZBED6 is a potential therapeutic target for sepsis-induced muscle atrophy, and the established sepsis pig model is a valuable tool for understanding sepsis pathogenesis and developing its therapeutics.
Asunto(s)
Proteínas Proto-Oncogénicas c-akt , Sepsis , Animales , Humanos , Porcinos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas , Transducción de Señal , Atrofia Muscular/etiología , Atrofia Muscular/prevención & control , Sepsis/complicaciones , Proteína de Unión al GTP rac1/metabolismo , Proteínas del Tejido Nervioso/genética , Factores de Intercambio de Guanina Nucleótido/metabolismoRESUMEN
The mechanism of Sn and Nb influence on the fraction of tetragonal ZrO2 in oxide films on Zr alloys and their influence mechanism on corrosion resistance of Zr alloys, despite decades of research, are ambiguous due to the lack of kinetic knowledge of phase evolution of ZrO2 with doping. Using stochastic surface walking and density functional theory calculations, we investigate the influence of Nb and Sn on the stability of tetragonal (t) and monoclinic (m) ZrO2, and t-m phase transition in oxide films. We found that though Nb and Sn result in similar apparent variation trends in the t-phase fraction in oxide films, their influences on t-m phase transition differ significantly, which is the underlying origin of different influences of the t-phase fraction in oxide films on the corrosion resistance of Zr alloys with Sn and Nb alloying. These results clarify an important aspect of the relationship between the microstructure and corrosion resistance of Zr alloys.
RESUMEN
In this Letter, by cascading several bichromatic photonic crystals we demonstrate that the quality factor can be much larger compared with that in an isolated cavity without increasing the total size of a device. We take a lithium niobate photonic crystal as an example to illustrate that the simulated quality factor of the cascaded cavity can reach 105 with a 70° slant angle, which is an order of magnitude larger than that in an isolated cavity. The device can be fabricated easily by current etching techniques for lithium niobate. We have fabricated the proposed device experimentally including holes with â¼70° slant angle. This work is expected to provide guidance to the design of photonic crystal cavities with high quality factor.
RESUMEN
SCOPE: Insulin resistance is a common feature of obesity and type 2 diabetes and partly results from an imbalance between food intake and energy expenditure. Therefore, efficient and safe insulin resistance treatment therapies are warranted. This work is aim to access the impact of protocatechuic acid (PCA), a catechol-type O-diphenol phenolic acid, in high fat diet (HFD)-induced glucose, and lipid dysregulation. METHODS AND RESULTS: Five-week-old male C57BL/6 mice are fed with HFD for 4 weeks and then are randomly divided into two cohorts: one cohort feed with HFD is free access to sterile water for 4 weeks, another cohort is free access to PCA-containing water (2.7 mM) for 4 weeks with HFD. In this study, using a hyperinsulinemic-euglycemic mouse clamp, it is showed that PCA-treated mice display improved systemic insulin resistance via enhanced fatty acid mobilization and utilization, thereby reducing ectopic lipid accumulation and promoting hepatic and peripheral insulin action. CONCLUSIONS: This study provides insights on the potent pharmacological effects of PCA from food sources on improving high fat diet (HFD)-induced whole-body insulin resistance and type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Ratones , Masculino , Animales , Resistencia a la Insulina/fisiología , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Obesidad/metabolismo , Lípidos/uso terapéutico , InsulinaRESUMEN
Nonsmall cell lung cancer (NSCLC) is among the most prevalent malignant tumours threatening human health. In the tumour microenvironment (TME), cancer-associated fibroblasts (CAFs) induce M2-polarized macrophages, which strongly regulate tumour progression. However, little is known about the association between CAFs and M2 macrophages. CD248 is a transmembrane glycoprotein found in several cancer cells, tumour stromal cells, and pericytes. Here, we isolated CAFs from tumour tissues of NSCLC patients to detect the relationship between CD248 expression and patient prognosis. We knocked down the expression of CD248 on CAFs to detect CXCL12 secretion and macrophage polarization. We then examined the effects of CD248-expressing CAF-induced M2 macrophage polarization to promote NSCLC progression in vitro and in vivo. We found that CD248 is expressed mainly in NSCLC-derived CAFs and that the expression of CD248 correlates with poor patient prognosis. Blocking CXCL12 receptor (CXCR4) drastically decreased M2 macrophage chemotaxis. CD248 promotes CAFs secreting CXCL12 to mediate M2-polarized macrophages to promote NSCLC progression both in vitro and in vivo. Collectively, our data suggest that CD248-positive CAFs induce NSCLC progression by mediating M2-polarized macrophages.
Asunto(s)
Fibroblastos Asociados al Cáncer , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Glicoproteínas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Macrófagos/metabolismo , Microambiente TumoralRESUMEN
Liver development is a complex process that is regulated by a series of signaling pathways. Three-dimensional (3D) chromatin architecture plays an important role in transcriptional regulation; nonetheless, its dynamics and role in the rapid transition of core liver functions during development and obesity-induced metabolic stress remain largely unexplored. To investigate the dynamic chromatin architecture during liver development and under metabolic stress, we generated high-resolution maps of chromatin architecture for porcine livers across six major developmental stages (from embryonic day 38 to the adult stage) and under a high-fat diet-induced obesity. The characteristically loose chromatin architecture supports a highly plastic genome organization during early liver development, which fundamentally contributes to the rapid functional transitions in the liver after birth. We reveal the multi-scale reorganization of chromatin architecture and its influence on transcriptional regulation of critical signaling processes during liver development, and show its close association with transition in hepatic functions (i.e., from hematopoiesis in the fetus to metabolism and immunity after birth). The limited changes in chromatin structure help explain the observed metabolic adaptation to excessive energy intake in pigs. These results provide a global overview of chromatin architecture dynamics associated with the transition of physiological liver functions between prenatal development and postnatal maturation, and a foundational resource that allows for future in-depth functional characterization.
RESUMEN
Increasing evidence has shown that AdipoRon, a synthetic adiponectin receptor agonist, is involved in the regulation of whole-body insulin sensitivity and energy homeostasis. However, the mechanisms underlying these alterations remain unclear. Here, using hyperinsulinemic-euglycemic clamp and isotopic tracing techniques, we show that short-term (10 days) AdipoRon administration indirectly inhibits lipolysis in white adipose tissue via increasing circulating levels of fibroblast growth factor 21 in mice fed a high-fat diet. This led to reduced plasma-free fatty acid concentrations and improved lipid-induced whole-body insulin resistance. In contrast, we found that long-term (20 days) AdipoRon administration directly exacerbated white adipose tissue lipolysis, increased hepatic gluconeogenesis, and impaired the tricarboxylic acid cycle in the skeletal muscle, resulting in aggravated whole-body insulin resistance. Together, these data provide new insights into the comprehensive understanding of multifaceted functional complexity of AdipoRon.
Asunto(s)
Factores de Crecimiento de Fibroblastos , Resistencia a la Insulina , Piperidinas , Animales , Dieta Alta en Grasa , Factores de Crecimiento de Fibroblastos/metabolismo , Técnica de Clampeo de la Glucosa , Insulina/metabolismo , Hígado/metabolismo , Ratones , Piperidinas/farmacologíaRESUMEN
Genetic variants in the asialoglycoprotein receptor 1 (ASGR1) are associated with a reduced risk of cardiovascular disease (CVD) in humans. However, the underlying molecular mechanism remains elusive. Given the cardiovascular similarities between pigs and humans, we generated ASGR1-deficient pigs using the CRISPR/Cas9 system. These pigs show age-dependent low levels of non-HDL-C under standard diet. When received an atherogenic diet for 6 months, ASGR1-deficient pigs show lower levels of non-HDL-C and less atherosclerotic lesions than that of controls. Furthermore, by analysis of hepatic transcriptome and in vivo cholesterol metabolism, we show that ASGR1 deficiency reduces hepatic de novo cholesterol synthesis by downregulating 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and increases cholesterol clearance by upregulating the hepatic low-density lipoprotein receptor (LDLR), which together contribute to the low levels of non-HDL-C. Despite the cardioprotective effect, we unexpectedly observed mild to moderate hepatic injury in ASGR1-deficient pigs, which has not been documented in humans with ASGR1 variants. Thus, targeting ASGR1 might be an effective strategy to reduce hypercholesterolemia and atherosclerosis, whereas further clinical evidence is required to assess its hepatic impact.
Asunto(s)
Receptor de Asialoglicoproteína/genética , Enfermedades Cardiovasculares/prevención & control , Animales , Sistemas CRISPR-Cas , Colesterol/biosíntesis , Modelos Animales de Enfermedad , Humanos , Factores de Riesgo , PorcinosRESUMEN
ZBED6 (zinc finger BED domain containing protein 6) is a transcription factor unique to placental mammals and its interaction with the IGF2 (insulin-like growth factor 2) locus plays a prominent role in the regulation of postnatal skeletal muscle growth. Here, we generated lean Bama miniature pigs by generating ZBED6-knockout (ZBED6-/-) and investigated the mechanism underlying ZBED6 in growth of muscle and internal organs of placental mammals. ZBED6-/- pigs show markedly higher lean mass, lean mass rate, larger muscle fiber area and heavier internal organs (heart and liver) than wild-type (WT) pigs. The striking phenotypic changes of ZBED6-/- pigs coincided with remarkable upregulation of IGF2 mRNA and protein expression across three tissues (gastrocnemius muscle, longissimus dorsi, heart). Despite a significant increase in liver weight, ZBED6-/- pigs show comparable levels of IGF2 expression to those of WT controls. A mechanistic study revealed that elevated methylation in the liver abrogates ZBED6 binding at the IGF2 locus, explaining the unaltered hepatic IGF2 expression in ZBED6-/- pigs. These results indicate that a ZBED6-IGF2-independent regulatory pathway exists in the liver. Transcriptome analysis and ChIP-PCR revealed new ZBED6 target genes other than IGF2, including cyclin dependent kinase inhibitor 1A (CDKN1A) and tsukushi, small leucine rich proteoglycan (TSKU), that regulates growth of muscle and liver, respectively.
Asunto(s)
Músculo Esquelético/metabolismo , Proteínas Represoras/metabolismo , Animales , Femenino , Regulación de la Expresión Génica/fisiología , Factor II del Crecimiento Similar a la Insulina/metabolismo , Hígado/metabolismo , Masculino , Desarrollo de Músculos/fisiología , Fibras Musculares Esqueléticas/metabolismo , Placenta/metabolismo , Embarazo , Porcinos , Factores de Transcripción/metabolismo , Transcriptoma/fisiología , Regulación hacia Arriba/fisiologíaRESUMEN
SCOPE: Obesity is a major public health and economic problem of global significance. Here, we investigate the role of diosmetin, a natural flavonoid presents mainly in citrus fruits, in the regulation of obesity and metabolic dysfunctions in mice. METHODS AND RESULTS: Eight-week-old male C57BL/6 mice fed a high-fat diet (HFD) or 5-week-old male ob/ob mice fed a normal diet are treated with diosmetin (50 mg kg-1 daily) or vehicle for 8 weeks. Diosmetin treatment decreases body weight and fat mass, improves glucose tolerance and insulin resistance in obese mice. These metabolic benefits are mainly attributed to increase energy expenditure via enhancing thermogenesis in brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Mechanistically, diosmetin acts as an agonist for estrogen receptors (ERs), and subsequently elevates adipose expressions of ERs in mice and in cultured adipocytes. When ERs are blocked by their antagonist fulvestrant in mice, diosmetin loses its beneficial effects, suggesting that ERs are indispensable for the metabolic benefits of diosmetin. CONCLUSION: The results indicate that diosmetin may be a potential anti-obesity nutritional supplement and could be explored for low ERs-related obesity populations.
Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Flavonoides/farmacología , Obesidad/prevención & control , Receptores de Estrógenos/metabolismo , Células 3T3-L1 , Adipocitos Blancos/efectos de los fármacos , Adipocitos Blancos/metabolismo , Tejido Adiposo Pardo/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético/efectos de los fármacos , Intolerancia a la Glucosa/prevención & control , Inflamación/prevención & control , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/etiología , Obesidad/genética , Termogénesis/efectos de los fármacosRESUMEN
As the largest tissue in the body, skeletal muscle not only plays key roles in movement and glucose uptake and utilization but also mediates insulin sensitivity in the body by myokines. Insulin resistance in the skeletal muscle is a major feature of type 2 diabetes (T2D). A weakened response to insulin could lead to muscle mass loss and dysfunction. Increasing evidence in skeletal muscle cells, rodents, nonhuman primates, and humans has shown that restriction of caloric or protein intake positively mediates insulin sensitivity. Restriction of essential or nonessential amino acids was reported to facilitate glucose utilization and regulate protein turnover in skeletal muscle under certain conditions. Furthermore, some minerals, such as zinc, chromium, vitamins, and some natural phytochemicals such as curcumin, resveratrol, berberine, astragalus polysaccharide, emodin, and genistein, have been shown recently to protect skeletal muscle cells, mice, or humans with or without diabetes from insulin resistance. In this review, we discuss the roles of nutritional interventions in the regulation of skeletal muscle insulin sensitivity. A comprehensive understanding of the nutritional regulation of insulin signaling would contribute to the development of tools and treatment programs for improving skeletal muscle health and for preventing T2D.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Animales , Diabetes Mellitus Tipo 2/prevención & control , Ingestión de Alimentos , Glucosa , Humanos , Insulina , Ratones , Músculo EsqueléticoRESUMEN
Lithium tantalate (LT) is one of the most attractive optical nonlinear materials, as it possesses a high optical damage threshold and great UV transparency (0.28-5.5 µm). Recently, optical grade LT nanoscale film was developed. Here a high-quality-factor (â¼105) LT microdisk resonator based on LT-on-insulator (LTOI) film is fabricated by utilizing focused ion beam (FIB) milling. 2 µW output second-harmonic waves are achieved in the LTOI microdisk at about 500 mW input power. Cascaded third-harmonic generation is also observed in the fabricated device. This work may pave the way for LTOI in integrated photonic chips.
RESUMEN
Insulin resistance is a major player in the pathogenesis of type II diabetes, the metabolic syndrome, and obesity. SOCS3 plays an important role in the development of insulin resistance. To investigate the role of SOCS3 in porcine adipocyte insulin signaling, we first detected the effect of insulin on SOCS3 mRNA and protein expression in porcine primary adipocytes by real-time RT-PCR and Western blotting. Then, we constructed a recombinant adenovirus encoding SOCS3 gene (Ad-SOCS3) which was used to infect differentiated porcine primary adipocytes for 3 days. The expression and phosphorylation of main insulin signaling components were detected by Western blotting. The results showed that 100 nM insulin could induce SOCS3 mRNA expression but not protein expression, and overexpression of SOCS3 decreased IRS1 protein level, insulin-stimulated IRS1 tyrosine phosphorylation, PI3K activation, and Akt phosphorylation, but increased IRS1 serine phosphorylation in porcine primary adipocytes. These results indicate that SOCS3 is an important negative regulator of insulin signaling in porcine adipocytes. Thus, SOCS3 may be a novel therapeutic target for the prevention or treatment of insulin resistance and type II diabetes.