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A key organismal response to overnutrition involves the development of new adipocytes through the process of adipogenesis. Preadipocytes sense changes in the systemic nutrient status and metabolites can directly modulate adipogenesis. We previously identified a role of de novo nucleotide biosynthesis in adipogenesis induction, whereby inhibition of nucleotide biosynthesis suppresses the expression of the transcriptional regulators PPARγ and C/EBPα. Here, we set out to identify the global transcriptomic changes associated with the inhibition of nucleotide biosynthesis. Through RNA sequencing (RNAseq), we discovered that mitochondrial signatures were the most altered in response to inhibition of nucleotide biosynthesis. Blocking nucleotide biosynthesis induced rounded mitochondrial morphology, and altered mitochondrial function, and metabolism, reducing levels of tricarboxylic acid cycle intermediates, and increasing fatty acid oxidation (FAO). The loss of mitochondrial function induced by suppression of nucleotide biosynthesis was rescued by exogenous expression of PPARγ. Moreover, inhibition of FAO restored PPARγ expression, mitochondrial protein expression, and adipogenesis in the presence of nucleotide biosynthesis inhibition, suggesting a regulatory role of nutrient oxidation in differentiation. Collectively, our studies shed light on the link between substrate oxidation and transcription in cell fate determination.
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Low response rate, treatment relapse, and resistance remain key challenges for cancer treatment with immune checkpoint blockade (ICB). Here we report that loss of specific tumor suppressors (TS) induces an inflammatory response and promotes an immune suppressive tumor microenvironment. Importantly, low expression of these TSs is associated with a higher expression of immune checkpoint inhibitory mediators. Here we identify, by using in vivo CRISPR/Cas9 based loss-of-function screening, that NF1, TSC1, and TGF-ß RII as TSs regulating immune composition. Loss of each of these three TSs leads to alterations in chromatin accessibility and enhances IL6-JAK3-STAT3/6 inflammatory pathways. This results in an immune suppressive landscape, characterized by increased numbers of LAG3+ CD8 and CD4 T cells. ICB targeting LAG3 and PD-L1 simultaneously inhibits metastatic progression in preclinical triple negative breast cancer (TNBC) mouse models of NF1-, TSC1- or TGF-ß RII- deficient tumors. Our study thus reveals a role of TSs in regulating metastasis via non-cell-autonomous modulation of the immune compartment and provides proof-of-principle for ICB targeting LAG3 for patients with NF1-, TSC1- or TGF-ß RII-inactivated cancers.
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Antígeno B7-H1 , Inhibidores de Puntos de Control Inmunológico , Proteína del Gen 3 de Activación de Linfocitos , Neoplasias de la Mama Triple Negativas , Proteína 1 del Complejo de la Esclerosis Tuberosa , Microambiente Tumoral , Microambiente Tumoral/inmunología , Animales , Ratones , Femenino , Humanos , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/genética , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 1 del Complejo de la Esclerosis Tuberosa/metabolismo , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Línea Celular Tumoral , Linfocitos T CD8-positivos/inmunología , Inflamación/inmunología , Linfocitos T CD4-Positivos/inmunología , Regulación Neoplásica de la Expresión Génica , Sistemas CRISPR-CasRESUMEN
AIMS: Epidemiological evidence indicates that there is a substantial association between body mass index (BMI) and at least ten forms of cancer, including melanoma, and BMI imbalance contributes to the poor survival rate of cancer patients before and after therapy. Nevertheless, few pharmacological studies on models of obesity and cancer have been reported. In this study, we administered epigallocatechin gallate (EGCG) to B16BL6 tumor-bearing mice that received a high-fat diet (HFD) to examine its impact. METHODS: B16BL6 tumor-bearing mice were fed a HFD. Body weight and food intake were documented every week. We conducted a Western blot analysis to examine the protein levels in the tumor, gastrocnemius (GAS), and tibialis anterior (TA) muscles, as well as the inguinal and epididymal white adipose tissues (iWAT and eWAT). KEY FINDINGS: EGCG has been shown to have anti-cancer effects equivalent to those of cisplatin, a chemotherapy drug. Furthermore, EGCG protected against the loss of epidydimal white adipose tissue by regulating protein levels of lipolysis factors of adipose triglyceride lipase and hormone-sensitive lipase as well as WAT browning factors of uncoupling protein 1, as opposed to cisplatin. EGCG was shown to reduce the protein levels of muscular atrophy factors of muscle RING-finger protein-1, whereas cisplatin did not contribute to rescuing the atrophy of TA and GAS muscles. CONCLUSION: Taken together, our findings indicate that EGCG has a preventive effect against cachexia symptoms and has anti-cancer effects similar to those of cisplatin in tumor-bearing mice fed a high-fat diet.
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Catequina , Dieta Alta en Grasa , Melanoma Experimental , Ratones Endogámicos C57BL , Atrofia Muscular , Animales , Catequina/análogos & derivados , Catequina/farmacología , Catequina/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Ratones , Masculino , Atrofia Muscular/prevención & control , Atrofia Muscular/metabolismo , Atrofia Muscular/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patologíaRESUMEN
Capsicum annuum var. abbreviatum (CAAE), which is in the genus Capsicum L. (Solanaceae), was found to be richer in polyphenols and flavonoids than other prevalent peppers of Capsicum annuum var. angulosum and Capsicum annuum. L. Yet, it is still unclear how CAAE reduces inflammation. In this study, we used the lipopolysaccharide-stimulated RAW264.7 macrophage cell line and bone marrow-derived macrophages to assess its anti-inflammatory activities. Initially, we discovered that CAAE decreased the levels of nitric oxide and inducible nitric oxide synthase. In addition, CAAE decreased the intracellular reactive oxygen species levels and increased the nuclear factor-erythroid 2-related factor 2 and heme oxygenase-1 compared with the phenotype of M2 macrophages. CAAE inhibited the activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases, c-Jun N-terminal kinases, and p38 MAPKs. CAAE also inhibited the translocation of nuclear factor kappa B into nuclear, hence preventing the production of proinflammatory cytokines. Therefore, we suggest that CAAE might have potential as a candidate therapeutic agent for inflammatory diseases.
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Capsicum , Lipopolisacáridos/farmacología , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Macrófagos/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , FN-kappa B/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fenotipo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico/metabolismoRESUMEN
Cancer cachexia is a type of energy-wasting syndrome characterized by fatigue, anorexia, muscle weakness, fat loss, and systemic inflammation. Baicalein, a flavonoid with bioactive properties, has demonstrated the ability to mitigate cardiac and skeletal muscle atrophy in different experimental settings. This effect is achieved through the inhibition of muscle proteolysis, suggesting its potential in preserving skeletal muscle homeostasis. In this study, we investigated the anti-cancer cachexia effects of baicalein in the regulation of muscle and fat wasting, both in vivo and in vitro. Baicalein attenuated body weight loss, including skeletal muscle and white adipose tissue (WAT), in CT26-induced cachectic mice. Moreover, baicalein increased muscle fiber thickness and suppressed the muscle-specific ubiquitin-protease system, including F-box only protein 32 and muscle RING-finger protein-1, by activating AKT phosphorylation both in vivo and in vitro. The use of LY294002, a particular inhibitor of AKT, eliminated the observed impact of baicalein on the improvement of muscle atrophy. In conclusion, baicalein inhibits muscle proteolysis and enhances AKT phosphorylation, indicating its potential role in cancer cachexia-associated muscle atrophy.
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Caquexia , Neoplasias del Colon , Flavanonas , Animales , Ratones , Caquexia/etiología , Caquexia/prevención & control , Caquexia/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Atrofia Muscular/etiología , Atrofia Muscular/prevención & control , Neoplasias del Colon/complicacionesRESUMEN
Most tumor cells undergo apoptosis in circulation and at the metastatic organ sites due to host immune surveillance and a hostile microenvironment. It remains to be elucidated whether dying tumor cells have a direct effect on live tumor cells during the metastatic process and what the underlying mechanisms are. Here we report that apoptotic cancer cells enhance the metastatic outgrowth of surviving cells through Padi4-mediated nuclear expulsion. Tumor cell nuclear expulsion results in an extracellular DNA-protein complex that is enriched with receptor for advanced glycation endproducts (RAGE) ligands. The chromatin-bound RAGE ligand S100a4 activates RAGE receptors in neighboring surviving tumor cells, leading to Erk activation. In addition, we identified nuclear expulsion products in human patients with breast, bladder and lung cancer and a nuclear expulsion signature correlated with poor prognosis. Collectively, our study demonstrates how apoptotic cell death can enhance the metastatic outgrowth of neighboring live tumor cells.
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Neoplasias Pulmonares , Proteína de Unión al Calcio S100A4 , Humanos , Apoptosis , Neoplasias Pulmonares/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Proteína de Unión al Calcio S100A4/genética , Proteína de Unión al Calcio S100A4/metabolismo , Microambiente TumoralRESUMEN
Panax ginseng C.A. Meyer, a widely used traditional medicine in East Asia, shows many beneficial effects on immune function, male erectile dysfunction, cancer, excessive oxidants, and aging issues. However, its effect on benign prostatic hyperplasia (BPH) and its potential in the treatment of side effects related to finasteride (Fi), an FDA-approved drug for BPH, are less known. This study aimed to verify the therapeutic effects of a water extract of P. ginseng (PGWE) on BPH in testosterone propionate (TP)-induced BPH rats and TP-treated RWPE-1 human epithelial cells, and the inhibitory potential on the Fi-induced side effects is also explored. In the TP-induced BPH rat model, PGWE alleviated the pathological markers of BPH such as weight and epithelial thickness of the prostate, and the serum level of dihydrotestosterone. PGWE downregulated androgen-related BPH factors such as 5α-reductase 2 and androgen receptor. PGWE also showed prostatic cell apoptosis accompanied by increased expression of Bax and decreased expression of Bcl-xL and cleaved-caspase 3, respectively, in addition to increasing mitochondrial dynamics in both in vivo and in vitro BPH models. Notably, reduced sperm count, one of the serious side effects of Fi, in the epididymis of BPH rats was recovered with PGWE treatment, suggesting less toxicity to sperm development by PGWE. PGWE also protected against Fi-induced sperm loss when PGWE was administered in combination with Fi without compromising the therapeutic effects of Fi on BPH. Based on these findings, we propose that PGWE could be an alternative therapeutic agent for BPH.
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Cisplatin is a prominent chemotherapeutic agent that can induce significant damage to normal cells. Therefore, it is important to develop agents that protect normal cells without influencing the chemotherapeutic effect of cisplatin. The present study was conducted to explore the protective effects of Annona muricata leaf polysaccharides (ALPS) against cisplatininduced toxicity in macrophages. Apoptosis was assessed in macrophages and lung cancer cells to investigate the cytoprotective effect of ALPS, their effect on the production of cisplatininduced reactive oxygen species (ROS) and the loss of the mitochondrial transmembrane potential (MTP). Cisplatin, when used alone or in combination with ALPS, showed significant toxicity against A549 and H460 lung cancer cells. However, cisplatininduced cytotoxicity was suppressed by cotreatment of RAW 264.7 macrophages with ALPS. ALPS significantly inhibited the upregulation of Bax, cytosolic cytochrome c and caspases3, 8 and 9. Moreover, ALPS resulted in the cleavage of PARP and downregulation of Bcl2 levels in a concentrationdependent manner, which ultimately led to a reduction in the apoptotic and necrotic populations of cisplatintreated RAW 264.7 macrophages. The suppression of the apoptotic signaling pathways was mediated through the reduction of ROS and MTP loss in cisplatintreated RAW 264.7 macrophages. In addition, ALPS alleviated cell damage by suppressing the mitochondrial apoptotic pathways in cisplatintreated bone marrowderived macrophages. Together, these findings suggested that ALPS may alleviate the toxic side effects of chemotherapeutic agents and act as a potential candidate for use as an effective adjuvant therapy.
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Annona , Neoplasias Pulmonares , Cisplatino/farmacología , Especies Reactivas de Oxígeno , Polisacáridos/farmacología , Macrófagos , Hojas de la Planta , MitocondriasRESUMEN
BACKGROUND: Benign prostatic hyperplasia (BPH) is an age-related disease in adult men. There are two pharmacological treatments for BPH. However, these synthetic materials have various risks, many studies are being conducted to develop new drugs from natural sources. PURPOSE: In this study, we proposed a beneficial effect of Glycyrrhiza uralensis Fischer on the development and progression of BPH, focusing on the androgen receptor (AR) and 5α-reductase 2 (5AR2) signaling axis. METHODS: To explain the therapeutic efficacy of a water extract of G. uralensis (GUWE) for BPH, we used testosterone propionate (TP)-induced BPH rat models and TP-treated RWPE-1 human prostate epithelial cells. RESULTS: In the TP-induced BPH rat models, GUWE reduced the enlarged prostate weight, prostate index, prostate epithelial thickness, and serum DHT levels. In addition, the protein levels of AR and 5AR2 in prostate tissues were significantly decreased by GUWE treatment. Furthermore, GUWE induced apoptosis signaling through an increase of Bcl-2 associated X protein (Bax), caspase 3, and Poly (ADP-ribose) polymerase (PARP) and a decrease of B-cell lymphoma-extra-large (Bcl-xL) in prostate tissues of TP-induced BPH rats. These findings were also confirmed in TP-treated RWPE-1 cells. Fi treatment markedly decreased the sperm count in the epididymis of BPH rats, but GUWE treatment did not affect the sperm count, suggesting less toxicity. CONCLUSION: These findings suggested that GUWE reduces the development of BPH by inhibiting AR-5AR2 and activating the apoptosis signaling pathway. Furthermore, unlike finasteride, GUWE did not affect sperm count. Therefore, we suggest that GUWE has a potential as a safer alternative option for BPH treatment.
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Glycyrrhiza uralensis , Hiperplasia Prostática , Propionato de Testosterona , Animales , Apoptosis , Colestenona 5 alfa-Reductasa , Humanos , Masculino , Extractos Vegetales , Ratas , Ratas Sprague-Dawley , Semillas , TestosteronaRESUMEN
The mechanisms of how cancer cells are selected and evolve to establish distant metastatic colonies remain unclear. Tumor heterogeneity and lack of biomarkers are some of the most difficult challenges in cancer biology and treatment. Here using mouse models for triple-negative breast cancer (TNBC) metastasis, we report heterogeneous expression of DNA methyltransferase 3B (DNMT3B) in both mouse and human primary tumors. High levels of DNMT3B were correlated with poor clinical outcomes in multiple human breast cancer datasets. Mechanistically, clonal cells with high DNMT3B (DNMT3BH) showed higher vimentin (VIM) expression and displayed enhanced epithelial-to-mesenchymal transition capacity. Deletion of VIM diminished the metastatic phenotype of DNMT3BH cells. Importantly, in preclinical mouse models in which the primary tumors were surgically removed, perioperative targeting of DNMT3B in combination with chemotherapy markedly suppressed tumor recurrence and metastasis. Our studies identify DNMT3B-mediated transcription regulation as an important mediator of tumor heterogeneity and show that DNMT3B is critical for tumor invasion and metastasis, reinforcing its potential as a target for treating metastatic disease. IMPLICATIONS: Our findings of transcriptome changes mediated by DNMT3B provide new mechanistic insight for intratumor heterogeneity and chemoresistance, and therapeutic targeting of DNMT3B in combination with chemotherapy offer additional treatment options for metastatic disease especially for patients with TNBC.
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ADN (Citosina-5-)-Metiltransferasas , Neoplasias de la Mama Triple Negativas , Animales , Humanos , Ratones , Línea Celular Tumoral , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Recurrencia Local de Neoplasia/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , ADN Metiltransferasa 3BRESUMEN
Deinococcus radiodurans is an extremophilic bacterium that can thrive in harsh environments. This property can be attributed to its unique metabolites that possess strong antioxidants and other pharmacological properties. To determine the potential of D. radiodurans R1 lysate (DeinoLys) as a pharmacological candidate for inflammatory bowel disease (IBD), we investigated the anti-inflammatory activity of DeinoLys in bone marrow-derived dendritic cells (BMDCs) and a colitis mice model. Lipopolysaccharide (LPS)-stimulated BMDCs treated with DeinoLys exhibited alterations in their phenotypic and functional properties by changing into tolerogenic DCs, including strongly inhibited proinflammatory cytokines (TNF-α and IL-12p70) and surface molecule expression and activated DC-induced T cell proliferation/activation with high IL-10 production. These phenotypic and functional changes in BMDCs induced by DeinoLys in the presence of LPS were abrogated by IL-10 neutralization. Furthermore, oral administration of DeinoLys significantly reduced clinical symptoms against dextran sulfate sodium-induced colitis, including body weight loss, disease activity index, histological severity in colon tissue, and lower myeloperoxidase level in mice. Our results establish DeinoLys as a potential anti-inflammatory candidate for IBD therapy.
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Colitis , Deinococcus , Enfermedades Inflamatorias del Intestino , Animales , Antiinflamatorios/farmacología , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Citocinas/metabolismo , Deinococcus/metabolismo , Células Dendríticas/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Interleucina-10/metabolismo , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BLRESUMEN
Benign prostate hyperplasia (BPH) is an age-related disease in men characterized by the growth of prostate cells and hyperproliferation of prostate tissue. This condition is closely related to chronic inflammation. In this study, we highlight the therapeutic efficacy of ellagic acid (EA) for BPH by focusing on the AR signaling axis and STAT3. To investigate the effect of EA on BPH, we used EA, a phytochemical abundant in fruits and vegetables, to treat testosterone propionate (TP)-induced BPH rats and RWPE-1 human prostate epithelial cells. The EA treatment reduced prostate weight, prostate epithelial thickness, and serum DHT levels in the TP-induced BPH rat model. In addition, EA improved testicular injury by increasing antioxidant enzymes in testis of the BPH rats. EA reduced the protein levels of AR, 5AR2, and PSA. It also induced apoptosis by regulating Bax, Bcl_xL, cytochrome c, caspase 9, and caspase 3 with increasing mitochondrial dynamics. Furthermore, EA reduced the expression of IL-6, TNF-α, and NF-κB, as well as phosphorylation of STAT3 and IκBα. These findings were also confirmed in TP-treated RWPE-1 cells. Overall, our data provide evidence of the role of EA in improving BPH through inhibition of AR and the STAT3 pathway.
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Hiperplasia Prostática , Propionato de Testosterona , Andrógenos/farmacología , Animales , Ácido Elágico/efectos adversos , Humanos , Hiperplasia/patología , Masculino , Extractos Vegetales/farmacología , Próstata/metabolismo , Hiperplasia Prostática/inducido químicamente , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/metabolismo , Propionato de Testosterona/efectos adversosRESUMEN
Obesity is a burden to global health. Non-shivering thermogenesis of brown adipose tissue (BAT) and white adipose tissue (WAT) is a novel strategy for obesity treatment. Anmyungambi (AMGB) decoction is a multi-herb decoction with clinical anti-obesity effects. Here, we show the effects of AMGB decoction using high-fat diet (HFD)-fed C57BL6/J mice. All four versions of AMGB decoction (100 mg/kg/day, oral gavage for 28 days) suppressed body weight gain and obesity-related blood parameters in the HFD-fed obese mice. They also inhibited adipogenesis and induced lipolysis in inguinal WAT (iWAT). Especially, the AMGB-4 with 2:1:3:3 composition was the most effective; thus, further studies were performed with the AMGB-4 decoction. The AMGB-4 decoction displayed a dose-dependent body weight gain suppression. Serum triglyceride, total cholesterol, and blood glucose decreased as well. In epididymal WAT, iWAT, and BAT, the AMGB-4 decoction increased lipolysis markers. Additionally, the AMGB-4 decoction-fed mice showed an increased non-shivering thermogenic program in BAT and iWAT. Excessive reactive oxygen species (ROS) and suppressed antioxidative factors induced by the HFD feeding were also altered to normal levels by the AMGB-4 decoction treatment. Overall, our study supports the clinical use of AMGB decoction for obesity treatment by studying its mechanisms. AMGB decoction alleviates obesity through the activation of the lipolysis-thermogenesis program and the elimination of pathological ROS in thermogenic adipose tissues.
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Non-shivering thermogenesis (NST) is a heat generating process controlled by the mitochondria of brown adipose tissue (BAT). In the recent decade, 'functionally' acting brown adipocytes in white adipose tissue (WAT) has been identified as well: the so-called process of the 'browning' of WAT. While the importance of uncoupling protein 1 (UCP1)-oriented mitochondrial activation has been intensely studied, the role of peroxisomes during the browning of white adipocytes is poorly understood. Here, we assess the change in peroxisomal membrane proteins, or peroxins (PEXs), during cold stimulation and importantly, the role of PEX13 in the cold-induced remodeling of white adipocytes. PEX13, a protein that originally functions as a docking factor and is involved in protein import into peroxisome matrix, was highly increased during cold-induced recruitment of beige adipocytes within the inguinal WAT of C57BL/6 mice. Moreover, beige-induced 3 T3-L1 adipocytes and stromal vascular fraction (SVF) cells by exposure to the peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone showed a significant increase in mitochondrial thermogenic factors along with peroxisomal proteins including PEX13, and these were confirmed in SVF cells with the beta 3 adrenergic receptor (ß3AR)-selective agonist CL316,243. To verify the relevance of PEX13, we used the RNA silencing method targeting the Pex13 gene and evaluated the subsequent beige development in SVF cells. Interestingly, siPex13 treatment suppressed expression of thermogenic proteins such as UCP1 and PPARγ coactivator 1 alpha (PGC1α). Overall, our data provide evidence supporting the role of peroxisomal proteins, in particular PEX13, during beige remodeling of white adipocytes.
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Tejido Adiposo Blanco/metabolismo , Proteínas de la Membrana/genética , PPAR gamma/genética , Termogénesis/genética , Proteína Desacopladora 1/genética , Células 3T3-L1 , Tejido Adiposo Pardo/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Animales , Dioxoles/farmacología , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Peroxisomas/genética , Interferencia de ARN , Receptores Adrenérgicos beta 3/genética , Fracción Vascular Estromal/genética , Fracción Vascular Estromal/metabolismoRESUMEN
In this study, we investigated the pharmacological effect of a water extract of Raphani Semen (RSWE) on alcoholic fatty liver disease (AFLD) using ethanol-induced AFLD mice (the NIAAA model) and palmitic acid (PA)-induced steatosis HepG2 cells. An RSWE supplement improved serum and hepatic triglyceride (TG) levels of AFLD mice, as well as their liver histological structure. To explore the molecular action of RSWE in the improvement of AFLD, we investigated the effect of RSWE on four major pathways for lipid homeostasis in the liver: free fatty acid transport, lipogenesis, lipolysis, and ß-oxidation. Importantly, RSWE decreased the mRNA expression of de novo lipogenesis-related genes, such as Srebf1, Cebpa, Pparg, and Lpin1, as well as the protein levels of these factors, in the liver of AFLD mice. That these actions of RSWE affect lipogenesis was confirmed using PA-induced steatosis HepG2 cells. Overall, our findings suggest that RSWE has the potential for improvement of AFLD by inhibiting de novo lipogenesis.
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Hígado Graso Alcohólico/tratamiento farmacológico , Lipogénesis/efectos de los fármacos , Extractos Vegetales/farmacología , Raphanus/química , Semillas/química , Animales , Etanol/efectos adversos , Ácidos Grasos no Esterificados/metabolismo , Hígado Graso Alcohólico/metabolismo , Células Hep G2 , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Lipólisis/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidación-Reducción/efectos de los fármacos , Ácido Palmítico/efectos adversos , Fosfatidato Fosfatasa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/sangreRESUMEN
The extract of the Gardenia jasminoides fruit (GJFE) can been consumed as an herbal tea or used as a yellow dye. Recently, studies report that GFJE exerts inhibitory effects on lipid accumulation and adipogenesis in white adipocytes. We evaluated the thermogenic actions of GJFE by focusing on mitochondrial activation and studying the underlying mechanisms. To investigate the role of GJFE on thermogenesis in mice, we used an acute cold exposure model. After 2 weeks of feeding, the cold tolerance of GJFE-fed mice was notably increased compared to PBS-fed mice. This was due to an increase in thermogenic proteins in the inguinal white adipose tissue of the cold-exposed mice. Moreover, GJFE significantly increased thermogenic factors such as peroxisome proliferator-activated receptor gamma (PPARγ), uncoupling protein 1 (UCP1), and PPARγ coactivator 1 alpha (PGC1α) in vitro as well. Factors related to mitochondrial abundance and functions were also induced by GJFE in white and beige adipocytes. However, the treatment of PPARγ inhibitor abolished the GJFE-induced changes, indicating that activation of PPARγ is critical for the thermogenic effect of GJFE. In conclusion, GJFE induces thermogenic action by activating mitochondrial function via PPARγ activation. Through these findings, we suggest GJFE as a potential anti-obesity agent with a novel mechanism involving thermogenic action in white adipocytes.
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To determine whether ellagic acid (EA) induces the "beige remodeling" of white adipose tissue (WAT), we treated cold-exposed mice and mouse stromal vascular fraction (SVF) cells with EA, a phytochemical abundant in fruits and vegetables, in particular berries. We then investigated the mechanism of EA in beige remodeling with a particular focus on DRP1-mediated mitochondrial fission and SIRT3. EA induced the trans-differentiation of white adipocytes to beige adipocytes by promoting the expression of UCP1 and other brown and beige adipocytes/fat factors (PRDM16, UCP1, PGC1α, CD137, and TBX1) and mitochondrial dynamics-related factors (SIRT3, NRF1, CPT1ß, DRP1, and FIS1) in 3T3-L1/SVF cells, and these were confirmed in the inguinal WAT of a cold-exposed mouse model. The browning effect of EA was abolished by a potent DRP1 inhibitor Mdivi-1 or SIRT3 knockdown, suggesting that EA induces beige remodeling of WAT by regulating the mitochondrial dynamics and SIRT3.
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Adipocitos Beige/fisiología , Tejido Adiposo Blanco/fisiología , Ácido Elágico/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Dinámicas Mitocondriales , Sirtuina 3/metabolismo , Adipocitos Beige/citología , Adipocitos Beige/efectos de los fármacos , Tejido Adiposo Blanco/citología , Tejido Adiposo Blanco/efectos de los fármacos , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Sirtuina 3/genética , TermogénesisRESUMEN
Although our previous study revealed that gamma-irradiated chrysin enhanced anti-inflammatory activity compared to intact chrysin, it remains unclear whether the chrysin derivative, CM1, produced by gamma irradiation, negatively regulates toll-like receptor (TLR) signaling. In this study, we investigated the molecular basis for the downregulation of TLR4 signal transduction by CM1 in macrophages. We initially determined the appropriate concentration of CM1 and found no cellular toxicity below 2 µg/mL. Upon stimulation with lipopolysaccharide (LPS), CM1 modulated LPS-stimulated inflammatory action by suppressing the release of proinflammatory mediators (cytokines TNF-α and IL-6) and nitric oxide (NO) and downregulated the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Furthermore, CM1 markedly elevated the expression of the TLR negative regulator toll-interacting protein (Tollip) in dose- and time-dependent manners. LPS-induced expression of cell surface molecules (CD80, CD86, and MHC class I/II), proinflammatory cytokines (TNF-α and IL-6), COX-2, and iNOS-mediated NO were inhibited by CM1; these effects were prevented by the knockdown of Tollip expression. Additionally, CM1 did not affect the downregulation of LPS-induced expression of MAPKs and NF-κB signaling in Tollip-downregulated cells. These findings provide insight into effective therapeutic intervention of inflammatory disease by increasing the understanding of the negative regulation of TLR signaling induced by CM1.
Asunto(s)
Flavonoides/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macrófagos/metabolismo , Animales , Antiinflamatorios/farmacología , Flavonoides/metabolismo , Flavonoides/efectos de la radiación , Inflamación/tratamiento farmacológico , Interleucina-6 , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Receptores Toll-Like/metabolismo , Factor de Necrosis Tumoral alfaRESUMEN
Obesity is known to be associated with risk and aggressiveness of cancer. Melanoma, the most lethal type of skin cancer, is also closely related to the prevalence of obesity. In this study, we established a cancer-obesity comorbidity (COC) model to investigate the effects of vanillic acid (VA). After a five-week administration with a high-fat diet (HFD) to induce obesity, subcutaneous allograft of B16BL6 cells were followed, and VA was orally administrated for an additional two weeks. VA-fed mice showed significantly decreased body weight and white adipose tissue (WAT) weight, which were due to increased thermogenesis and AMPK activation in WATs. Growth of cancer was also suppressed. Mechanistic studies revealed increased apoptosis and autophagy markers by VA; however, caspase 3 was not involved. Since signal transducer and activator of transcription 3 (STAT3) is suggested as an important pathway linking obesity and cancer, we further investigated to find out if STAT3 phosphorylation was repressed by VA treatment, and this was again confirmed in a COC cell model of adipocyte conditioned medium-treated B16BL6 melanoma cells. Overall, our results show VA induces STAT3-mediated autophagy to inhibit cancer growth and thermogenesis to ameliorate obesity in COC. Based on these findings, we suggest VA as a candidate therapeutic agent for COC treatment.
Asunto(s)
Melanoma Experimental/prevención & control , Obesidad/prevención & control , Factor de Transcripción STAT3/metabolismo , Ácido Vanílico/farmacología , Células 3T3-L1 , Adipocitos/citología , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Animales , Autofagia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Dieta Alta en Grasa/efectos adversos , Lipólisis/efectos de los fármacos , Masculino , Melanoma Experimental/complicaciones , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL , Obesidad/complicaciones , Obesidad/etiología , Tamaño de los Órganos/efectos de los fármacos , Fosforilación/efectos de los fármacos , Termogénesis/efectos de los fármacosRESUMEN
Secoisolariciresinol diglucoside (SDG) is the main phytoestrogen component of flaxseed known as an antioxidant. Current study focused on the effect of SDG in white adipose tissue (WAT) browning. Browning of WAT is considered as a promising treatment strategy for metabolic diseases. To demonstrate the effect of SDG as an inducer of browning, brown adipocyte markers were investigated in inguinal WAT (iWAT) of high fat diet-fed obese mice and genetically obese db/db mice after SDG administration. SDG increased thermogenic factors such as uncoupling protein 1, peroxisome proliferator-activated receptor gamma coactivator 1 alpha and PR domain containing 16 in iWAT and brown adipose tissue (BAT) of mice. Similar results were shown in beige-induced 3T3-L1 adipocytes and primary cultured brown adipocytes. Furthermore, SDG increased factors of mitochondrial biogenesis and activation. We also observed SDG-induced alteration of AMP-activated protein kinase α (AMPKα). As AMPKα is closely related in the regulation of adipogenesis and thermogenesis, we then evaluated the effect of SDG in AMPKα-inhibited conditions. Genetic or chemical inhibition of AMPKα demonstrated that the role of SDG on browning and thermogenesis was dependent on AMPKα signaling. In conclusion, our data suggest SDG as a potential candidate for improvement of obesity and other metabolic disorders.