RESUMEN
Epithelial-to-mesenchymal transition (EMT) plays a major role in breast cancer progression and the development of drug resistance. We have previously demonstrated a trans-differentiation therapeutic approach targeting invasive dedifferentiated cancer cells. Using a combination of PPARγ agonists and MEK inhibitors, we forced the differentiation of disseminating breast cancer cells into post-mitotic adipocytes. Utilizing murine breast cancer cells, we demonstrated a broad class effect of PPARγ agonists and MEK inhibitors in inducing cancer cell trans-differentiation into adipocytes. Both Rosiglitazone and Pioglitazone effectively induced adipogenesis in cancer cells, marked by PPARγ and C/EBPα upregulation, cytoskeleton rearrangement, and lipid droplet accumulation. All tested MEK inhibitors promoted adipogenesis in the presence of TGFß, with Cobimetinib showing the most prominent effects. A metastasis ex vivo culture from a patient diagnosed with triple-negative breast cancer demonstrated a synergistic upregulation of PPARγ with the combination of Pioglitazone and Cobimetinib. Our results highlight the potential for new therapeutic strategies targeting cancer cell plasticity and the dedifferentiation phenotype in aggressive breast cancer subtypes. Combining differentiation treatments with standard therapeutic approaches may offer a strategy to overcome drug resistance.
Asunto(s)
Diferenciación Celular , PPAR gamma , Pioglitazona , PPAR gamma/metabolismo , PPAR gamma/agonistas , Humanos , Animales , Ratones , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Pioglitazona/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipogénesis/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Rosiglitazona/farmacología , Azetidinas/farmacología , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Piperidinas/farmacologíaRESUMEN
Cultured fat is an important part of cultured meat, and the ability of adipose-derived mesenchymal stem cells (ADSCs) to differentiate into mature adipose tissue affects the quality of cultured fat. Thus, the primary aim of this study was to screen for combinations of differentiation-inducing factors (DIF) using single-factor experiment and orthogonal experimental design under two-dimensional culture conditions for ADSCs. The results showed that a combination of DIF consisting of 1 µmol/L dexamethasone, 0.1 mmol/L 3-isobutyl-1-methylxanthine, 10 µg/mL insulin, 0.1 mmol/L indomethacin, and 2 µmol/L rosiglitazone was a good choice for the differentiation of ADSCs. An combination of DIF was applied to the preparation of cultured fat with collagen as scaffolds. Forty-eight fatty acids were detected in cultured fat by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Among them, the content of twenty-one fatty acids in cultured fat was significantly higher than that of conventional porcine subcutaneous adipose tissue (P < 0.05), and the content of 14 fatty acids was not significantly different (P > 0.05). The ratio of ω-6 polyunsaturated fatty acids content to ω-3 polyunsaturated fatty acids content was 1.23:1, which meant cultured fat was beneficial for human health. This study provides a method to improve the differentiation ability of ADSCs while also providing a reference for indicating the nutritional value of cultured fat.
Asunto(s)
Diferenciación Celular , Ácidos Grasos , Células Madre Mesenquimatosas , Animales , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Porcinos , Ácidos Grasos/análisis , Células Cultivadas , Tejido Adiposo/citología , Dexametasona/farmacología , Espectrometría de Masas en Tándem , Insulina/metabolismo , Rosiglitazona/farmacología , Indometacina/farmacología , 1-Metil-3-Isobutilxantina/farmacología , Cromatografía Líquida de Alta PresiónRESUMEN
Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.
Asunto(s)
Apoptosis , Proliferación Celular , Modelos Animales de Enfermedad , Piridonas , Pirimidinonas , Rosiglitazona , Neoplasias de la Vejiga Urinaria , Animales , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/genética , Piridonas/farmacología , Piridonas/uso terapéutico , Pirimidinonas/farmacología , Pirimidinonas/uso terapéutico , Rosiglitazona/farmacología , Rosiglitazona/uso terapéutico , Ratones , Apoptosis/efectos de los fármacos , Humanos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Invasividad Neoplásica , Femenino , PPAR gamma/metabolismo , PPAR gamma/agonistas , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Retinoides/farmacología , Retinoides/uso terapéuticoRESUMEN
Macrophages are important regulators of bone remodeling, and M1 polarization is observed in the setting of medication-related osteonecrosis of the jaws (MRONJ). Here, we characterize the phenotype of macrophages during early stages of MRONJ development in zoledronate (ZA)-treated mice with periodontal disease and explore the role of rosiglitazone, a drug that has been reported to lower the M1/M2 macrophage ratio, in MRONJ burden. Mice received ZA, and experimental periodontal disease (EPD) was induced around their second left maxillary molar. The mice were euthanized 1, 2, or 4 wk later. Micro-computed tomography and histologic and immunohistochemical analyses were carried out. In a separate experiment, mice were treated with ZA in the absence or presence of rosiglitazone, EPD was induced for 5 wk, and the MRONJ burden was assessed. An M1 predilection was noted in ZA versus vehicle (Veh) mice at 1, 2, or 4 wk after ligature placement. M1 cells were found to be positive for MMP-13, and their presence coincided with disruption of the surrounding collagen network in ZA mice. Rosiglitazone caused a reversal in the M1/M2 polarization in Veh and ZA mice. Rosiglitazone did not cause significant radiographic changes 5 wk after EPD in Veh or ZA animals. Importantly, percentage osteonecrosis and bone exposure were decreased in the rosiglitazone-treated versus nontreated ZA sites 5 wk after EPD. Our data point to an important role of M1 macrophage polarization with an overexpression of MMP-13 in the early phases of MRONJ development and provide insight into the use of interventional approaches promoting an M2 phenotype as a preventative means to alleviate MRONJ burden.
Asunto(s)
Osteonecrosis de los Maxilares Asociada a Difosfonatos , Imidazoles , Macrófagos , Rosiglitazona , Tiazolidinedionas , Microtomografía por Rayos X , Ácido Zoledrónico , Animales , Ratones , Rosiglitazona/farmacología , Rosiglitazona/uso terapéutico , Ácido Zoledrónico/farmacología , Macrófagos/efectos de los fármacos , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Osteonecrosis de los Maxilares Asociada a Difosfonatos/patología , Osteonecrosis de los Maxilares Asociada a Difosfonatos/etiología , Imidazoles/farmacología , Difosfonatos/farmacología , Metaloproteinasa 13 de la Matriz/metabolismo , Conservadores de la Densidad Ósea/farmacología , Modelos Animales de Enfermedad , Fenotipo , Masculino , Remodelación Ósea/efectos de los fármacos , Ratones Endogámicos C57BL , Enfermedades Periodontales , Colágeno/metabolismoRESUMEN
Rosiglitazone is an activator of nuclear peroxisome proliferator-activated (PPAR) receptor gamma used in the treatment of type 2 diabetes mellitus. The elimination of rosiglitazone occurs mainly via metabolism, with major contribution by enzyme cytochrome P450 (CYP) 2C8. Primary routes of rosiglitazone metabolism are N-demethylation and hydroxylation. Modulation of CYP2C8 activity by co-administered drugs lead to prominent changes in the exposure of rosiglitazone and its metabolites. Here, we attempt to develop mechanistic parent-metabolite physiologically based pharmacokinetic (PBPK) model for rosiglitazone. Our goal is to predict potential drug-drug interaction (DDI) and consequent changes in metabolite N-desmethyl rosiglitazone exposure. The PBPK modeling was performed in the PKSim® software using clinical pharmacokinetics data from literature. The contribution to N-desmethyl rosiglitazone formation by CYP2C8 was delineated using vitro metabolite formation rates from recombinant enzyme system. Developed model was verified for prediction of rosiglitazone DDI potential and its metabolite exposure based on observed clinical DDI studies. Developed model exhibited good predictive performance both for rosiglitazone and N-desmethyl rosiglitazone respectively, evaluated based on commonly acceptable criteria. In conclusion, developed model helps with prediction of CYP2C8 DDI using rosiglitazone as a substrate, as well as changes in metabolite exposure. In vitro data for metabolite formation can be successfully utilized to translate to in vivo conditions.
Asunto(s)
Citocromo P-450 CYP2C8 , Interacciones Farmacológicas , Modelos Biológicos , Rosiglitazona , Rosiglitazona/farmacocinética , Rosiglitazona/metabolismo , Rosiglitazona/farmacología , Citocromo P-450 CYP2C8/metabolismo , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/metabolismo , Tiazolidinedionas/farmacocinética , Tiazolidinedionas/metabolismoRESUMEN
Rosiglitazone (RSG), as an insulin-sensitizing drug to treat type 2 diabetes mellitus (T2DM) is reported to decrease bone quality and increase bone fracture risk. The multiple off-target effects of Resveratrol (RSV), a natural specific agonist of Sirtuin1 (Sirt1) with pro-osteoblastogenesis and anti-adipogenesis effects, on bone loss in T2DM are still under discussion. In this study, successfully ovariectomized rats were fed with high-fat diet and STZ (HFD/STZ) to induced T2DM mice. RSV alone, RSG alone or co-administration of RSV and RSG were given orally to T2DM rats for 8 weeks to determine whether RSV administration had any prevention effect on T2DM osteoporosis. Bone mesenchymal stem cells (BMSCs) and bone marrowderived macrophages (BMMs) were cultured under high glucose condition and were induced to osteoblasts or adipocytes and osteoclasts, respectively. µCT and HE staining showed that in T2DM osteoporotic rats, RSV co-administration prevents RSG induced-bone loss. ELISA results confirmed that RSV suppressed osteoclast activity and promoted osteoblast activity in diabetic osteoporosis rats and RSG-administrated diabetic osteoporosis rats. In vitro study showed that RSV significantly reversed RSG induced inhibition on osteogenesis and promotion on adiopogenesis of BMSC under high glucose (HG). Moreover, RSV significantly reverse RSG induced osteoclast formation and mature under HG. Taken together, these findings uncover a previously unappreciated anti-osteoporosis effect of concomitant treatment with RSV in RSG-administrated diabetic rats, suggesting the clinical use of RSV as an adjuvant in the treatment of T2DM for preventing or reversing RSG administration-associated bone loss.
Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Osteogénesis , Osteoporosis , Ratas Sprague-Dawley , Resveratrol , Rosiglitazona , Animales , Resveratrol/farmacología , Rosiglitazona/farmacología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Osteoporosis/tratamiento farmacológico , Osteoporosis/inducido químicamente , Osteoporosis/patología , Osteoporosis/prevención & control , Ratas , Osteogénesis/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/inducido químicamente , Células Madre Mesenquimatosas/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Hipoglucemiantes/farmacología , Dieta Alta en Grasa/efectos adversos , Osteoclastos/efectos de los fármacos , Osteoclastos/patología , Adipocitos/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate the effects of resveratrol (RSV) on ovarian morphology, plasma anti-Müllerian hormone (AMH) and insulin-like growth factor 1 levels (IGF-1), and oxidative stress parameters in rats with polycystic ovary syndrome (PCOS). METHODS: Forty-six rats were randomly divided into a normal control (n = 12), a PCOS model control (n = 12), a rosiglitazone (RSG, n = 11), and an RSV group (n = 11). The PCOS model was established in the latter three groups by rejection of epidehydroandrosterone. The rats in the normal control and PCOS model control groups were treated by gavage of normal saline and those in the RSG and RSV groups by intragastric administration of RSG at 10 mg/(kg·d) and RSV at 3.0 mg/(kg·d), respectively. After 4 weeks of treatment, the ovarian histology was observed under the light microscope, the levels of plasma AMH and IGF-1 measured by ELISA, and the activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) in the ovarian tissue detected using the Ellman, Sun and AEBI methods, respectively. RESULTS: After a 4-week treatment, statistically significant differences were observed in the above indicators between the normal control and PCOS model control groups (P<0.05). The rats treated with RSG and RSV also showed significant differences in these parameters from the model controls (P<0.05). CONCLUSION: RSV can enhance the local antioxidant capacity of the ovary, reduce the levels of AMH and IGF-1, and improve the morphology of the ovarian tissue in rats with PCOS, indicating its potential value in the treatment of PCOS.
Asunto(s)
Antioxidantes , Factor I del Crecimiento Similar a la Insulina , Ovario , Estrés Oxidativo , Síndrome del Ovario Poliquístico , Resveratrol , Estilbenos , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Femenino , Resveratrol/farmacología , Ratas , Ovario/efectos de los fármacos , Ovario/metabolismo , Estrés Oxidativo/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estilbenos/farmacología , Estilbenos/uso terapéutico , Hormona Antimülleriana/sangre , Superóxido Dismutasa/metabolismo , Glutatión Peroxidasa/metabolismo , Catalasa/metabolismo , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Rosiglitazona/farmacologíaRESUMEN
The aim of the present study was to evaluate the effect of rosiglitazone (RSG) or pioglitazone (POG) on the synaptic plasticity, neuronal apoptosis, brain-derived neurotrophic factor (BDNF), and nitric oxide (NO) metabolites in the hippocampus of juvenile hypothyroid rats. The animals were divided into four groups: control; propylthiouracil (PTU), 0.05% dose in drinking water for 42 days; PTU-POG; and PTU-RSG. The POG (20 mg/kg) and the RSG (4 mg/kg) were administered by IP injection. We conducted longterm potentiation (LTP) in the cornu ammonis 1 area of the hippocampus using highfrequency stimulation of the Schaffer collateral pathway. Then, the hippocampal tissues were collected to determine BDNF and NO levels and the degree of apoptosis. PTU administration decreased the slope (10-90%) and amplitude of the fEPSPs compared to control. Injection of RSG or POG increased the slope, slope (10-90%), and amplitude of the fEPSP in the PTUPOG or PTURSG groups compared to the PTU group. TUNELpositive neurons and NO metabolites in the hippocampus of the PTU group were higher than those of the control group. RSG or POG increased BDNF content in PTU-POG or PTU-RSG groups. Treatment of the rats with POG or RSG decreased apoptotic neurons and NO metabolites in the hippocampus of PTU-POG or PTU-RSG groups, respectively, compared to the PTU group. This study's results revealed that POG or RSG normalized LTP impairment, neuronal apoptosis, and improved BDNF content in the hippocampal tissue of juvenile hypothyroid rats.
Asunto(s)
Apoptosis , Factor Neurotrófico Derivado del Encéfalo , Hipocampo , Hipotiroidismo , Potenciación a Largo Plazo , PPAR gamma , Ratas Wistar , Rosiglitazona , Animales , Apoptosis/efectos de los fármacos , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/inducido químicamente , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Rosiglitazona/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , PPAR gamma/agonistas , PPAR gamma/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Tiazolidinedionas/farmacología , Pioglitazona/farmacología , Ratas , Propiltiouracilo/farmacología , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Óxido Nítrico/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
AIM: This study explores the efficacy of electroacupuncture (EA) in treating cerebral palsy (CP) in Sprague-Dawley (SD) pups, specifically CP animal models, and its molecular mechanisms. METHODS: Gait analysis and Y-maze were used to detect the improvement of motor ability and cognitive function of CP rats after EA treatment. Transcription sequencing was used to determine the key pathway for EA to improve the symptoms of CP. PPAR agonists were used to verify the causal relationship between the pathway and the improvement of CP phenotype. RESULTS: The motor ability and cognitive function of CP pups were improved after EA treatment. The results of transcriptome sequencing suggest that the improvement of CP phenotype may be caused by the activation of PPAR pathway. PPAR pathway is widely activated in the epithelium of CP pups treated with EA, which is verified by qPCR. Rosiglitazone (Ros), a PPAR agonist, can improve CP phenotype while activating PPAR pathway, which proves the causal relationship between PPAR pathway activation and CP phenotype improvement. CONCLUSION: Our study demonstrated behavioral improvements and enhanced cognitive functions in CP models after EA treatment by activating PPAR pathway, suggesting new perspectives for CP rehabilitation, and providing theoretical support for acupuncture treatment of CP.
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Parálisis Cerebral , Electroacupuntura , Receptores Activados del Proliferador del Peroxisoma , Fenotipo , Ratas Sprague-Dawley , Electroacupuntura/métodos , Parálisis Cerebral/terapia , Parálisis Cerebral/metabolismo , Animales , Ratas , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/genética , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Masculino , Femenino , Aprendizaje por Laberinto/fisiología , Aprendizaje por Laberinto/efectos de los fármacos , Modelos Animales de Enfermedad , Rosiglitazona/farmacología , Animales Recién NacidosRESUMEN
Triclosan (TCS) is a widely used antimicrobial, antifungal, and antiviral agent. To date, it has been reported that TCS can enter the human body and disrupt hormonal homeostasis. Therefore, the aim of our paper was to evaluate the impact of TCS on astrocytes, i.e. a crucial population of cells responsible for steroid hormone production. Our data showed that, in mouse primary astrocyte cultures, TCS can act as an endocrine disrupting chemical through destabilization of the production or secretion of progesterone (P4), testosterone (T), and estradiol (E2). TCS affects the mRNA expression of enzymes involved in neurosteroidogenesis, such as Cyp17a1, 17ß-Hsd, and Cyp19a1. Our data showed that a partial PPARγ agonist (honokiol) prevented changes in Cyp17a1 mRNA expression caused by TCS. Similarly, honokiol inhibited TCS-stimulated P4 release. However, rosiglitazone (classic PPARγ agonist) or GW9662 (PPARγ antagonist) had a much stronger effect. Therefore, we believe that the changes observed in the P4, T, and E2 levels are a result of dysregulation of the activity of the aforementioned enzymes, whose expression can be affected by TCS through a Pparγ-dependent pathway. TCS was found to decrease the aryl hydrocarbon receptor (AhR) and Sirtuin 3 protein levels, which may be the result of the activation of the these proteins. Since our study showed dysregulation of the production or secretion of neurosteroids in astrocytes, it can be concluded that TCS reaching the brain may contribute to the development of neurodegenerative diseases in which an abnormal amount of neurosteroids is observed.
Asunto(s)
Astrocitos , Progesterona , Sirtuina 1 , Sirtuina 3 , Triclosán , Animales , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Triclosán/farmacología , Ratones , Células Cultivadas , Progesterona/metabolismo , Sirtuina 1/metabolismo , Sirtuina 1/genética , Sirtuina 3/metabolismo , Sirtuina 3/genética , PPAR gamma/metabolismo , PPAR gamma/genética , Estradiol/farmacología , Estradiol/metabolismo , Testosterona/metabolismo , Esteroide 17-alfa-Hidroxilasa/metabolismo , Esteroide 17-alfa-Hidroxilasa/genética , Disruptores Endocrinos/farmacología , Compuestos de Bifenilo/farmacología , Rosiglitazona/farmacologíaRESUMEN
Periodontitis, a common chronic inflammatory disease, epitomizes a significant impairment in the host immune system and an imbalance of bone metabolism. Macrophage polarization, a dynamic process dictated by the microenvironment, intricately contributes to the interplay between the immune system and bone remodeling, namely the osteoimmune system. Forkhead box protein O1 (FoxO1) has been shown to play a dramatic role in mediating oxidative stress, bone mass, as well as cellular metabolism. Nevertheless, the function and underlying mechanisms of FoxO1 in regulating macrophage polarization-mediated osteogenesis in periodontitis remain to be further elucidated. Here, we found that FoxO1 expression was closely linked to periodontitis, accompanied by aggravated inflammation. Notably, FoxO1 knockdown skewed macrophage polarization from M1 to the antiinflammatory M2 phenotype under inflammatory conditions, which rescued the impaired osteogenic potential. Mechanistically, we revealed that the enhancement of the transcription of peroxisome proliferator-activated receptor (PPAR) signaling in FoxO1-knockdown macrophages. In agreement with this contention, GW9662, a specific inhibitor of PPAR-γ signaling, greatly aggravated macrophage polarization from M2 to the M1 phenotype and attenuated osteogenic potential under inflammatory conditions. Additionally, PPAR-γ signaling agonist rosiglitazone (RSG) was applied to address ligature-induced periodontitis with attenuated inflammation. Our data lend conceptual credence to the function of FoxO1 in mediating macrophage polarization-regulated osteogenesis which serves as a novel therapeutic target for periodontitis.
Asunto(s)
Proteína Forkhead Box O1 , Macrófagos , Osteogénesis , PPAR gamma , Periodontitis , Transducción de Señal , PPAR gamma/metabolismo , PPAR gamma/genética , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Animales , Ratones , Macrófagos/metabolismo , Periodontitis/metabolismo , Periodontitis/patología , Periodontitis/genética , Masculino , Ratones Endogámicos C57BL , Células RAW 264.7 , Rosiglitazona/farmacología , Activación de MacrófagosRESUMEN
The study evaluated the effects of Arthrospira maxima phycobiliproteins (PBPs), rosiglitazone (RSG), and 17ß-estradiol (E) on the differentiation process of 3T3-L1 cells and on their regulation of lipogenic and inflammatory gene expression at different stages of the process. The results showed that phycobiliproteins promoted cell proliferation after 24 h of treatment. Furthermore, for all three treatments, the regulation of the highest number of markers occurred on days 6 and 12 of differentiation, regardless of when the treatment was applied. Phycobiliproteins reduced lipid droplet accumulation on days 3, 6, 10, and 13 of the adipogenic process, while rosiglitazone showed no differences compared to the control. On day 6, both phycobiliproteins and rosiglitazone positively regulated Acc1 mRNA. Meanwhile, all three treatments negatively regulated Pparγ and C/ebpα. Phycobiliproteins and estradiol also negatively regulated Ucp1 and Glut4 mRNAs. Rosiglitazone and estradiol, on the other hand, negatively regulated Ppara and Il-6 mRNAs. By day 12, phycobiliproteins and rosiglitazone upregulated Pparγ mRNA and negatively regulated Tnfα and Il-1ß. Additionally, phycobiliproteins and estradiol positively regulated Il-6 and negatively regulated Ppara, Ucp2, Acc1, and Glut4. Rosiglitazone and estradiol upregulate C/ebpα and Ucp1 mRNAs. The regulation exerted by phycobiliproteins on the mRNA expression of the studied markers was dependent on the phase of cell differentiation. The results of this study highlight that phycobiliproteins have an anti-adipogenic and anti-inflammatory effect by reducing the expression of adipogenic, lipogenic, and inflammatory genes in 3T3-L1 cells at different stages of the differentiation process.
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Células 3T3-L1 , Adipocitos , Adipogénesis , Diferenciación Celular , Estradiol , Ficobiliproteínas , Rosiglitazona , Animales , Ratones , Estradiol/farmacología , Rosiglitazona/farmacología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/citología , Diferenciación Celular/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Adipogénesis/genética , Ficobiliproteínas/farmacología , Ficobiliproteínas/metabolismo , Ficobiliproteínas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Lipogénesis/genética , PPAR gamma/metabolismo , PPAR gamma/genética , Proliferación Celular/efectos de los fármacos , Inflamación/metabolismo , Inflamación/genética , SpirulinaRESUMEN
OBJECTIVE: We aimed to identify metabolites associated with loss of glycemic control in youth-onset type 2 diabetes. RESEARCH DESIGN AND METHODS: We measured 480 metabolites in fasting plasma samples from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study. Participants (N = 393; age 10-17 years) were randomly assigned to metformin, metformin plus rosiglitazone, or metformin plus lifestyle intervention. Additional metabolomic measurements after 36 months were obtained in 304 participants. Cox models were used to assess baseline metabolites, interaction of metabolites and treatment group, and change in metabolites (0-36 months), with loss of glycemic control adjusted for age, sex, race, treatment group, and BMI. Metabolite prediction models of glycemic failure were generated using elastic net regression and compared with clinical risk factors. RESULTS: Loss of glycemic control (HbA1c ≥8% or insulin therapy) occurred in 179 of 393 participants (mean 12.4 months). Baseline levels of 33 metabolites were associated with loss of glycemic control (q < 0.05). Associations of hexose and xanthurenic acid with treatment failure differed by treatment randomization; youths with higher baseline levels of these two compounds had a lower risk of treatment failure with metformin alone. For three metabolites, changes from 0 to 36 months were associated with loss of glycemic control (q < 0.05). Changes in d-gluconic acid and 1,5-AG/1-deoxyglucose, but not baseline levels of measured metabolites, predicted treatment failure better than changes in HbA1c or measures of ß-cell function. CONCLUSIONS: Metabolomics provides insight into circulating small molecules associated with loss of glycemic control and may highlight metabolic pathways contributing to treatment failure in youth-onset diabetes.
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Biomarcadores , Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Metformina , Humanos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Femenino , Adolescente , Metformina/uso terapéutico , Niño , Biomarcadores/sangre , Hipoglucemiantes/uso terapéutico , Control Glucémico , Glucemia/metabolismo , Rosiglitazona/uso terapéutico , Hemoglobina Glucada/metabolismoRESUMEN
A subgroup of endocrine-disrupting chemicals have the ability to disrupt metabolism. These metabolism-disrupting chemicals (MDCs) can end up in aquatic environments and lead to adverse outcomes in fish. Although molecular and physiological effects of MDCs have been studied in adult fish, few studies have investigated the consequences of metabolic disruption in fish during the earliest life stages. To investigate the processes affected by metabolic disruption, zebrafish embryos were exposed to peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone, the PPARγ antagonist T0070907, and the well-known environmentally relevant MDC bisphenol A. Decreased apolipoprotein Ea transcript levels indicated disrupted lipid transport, which was likely related to the observed dose-dependent increases in yolk size across all compounds. Increased yolk size and decreased swimming activity indicate decreased energy usage, which could lead to adverse outcomes because the availability of energy reserves is essential for embryo survival and growth. Exposure to T0070907 resulted in a darkened yolk. This was likely related to reduced transcript levels of genes involved in lipid transport and fatty acid oxidation, a combination of responses that was specific to exposure to this compound, possibly leading to lipid accumulation and cell death in the yolk. Paraoxonase 1 (Pon1) transcript levels were increased by rosiglitazone and T0070907, but this was not reflected in PON1 enzyme activities. The present study shows how exposure to MDCs can influence biochemical and molecular processes involved in early lipid metabolism and may lead to adverse outcomes in the earliest life stages of fish. Environ Toxicol Chem 2024;43:1880-1893. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
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Embrión no Mamífero , Metabolismo de los Lípidos , Contaminantes Químicos del Agua , Pez Cebra , Animales , Metabolismo de los Lípidos/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Contaminantes Químicos del Agua/toxicidad , Yema de Huevo/efectos de los fármacos , Disruptores Endocrinos/toxicidad , Rosiglitazona/farmacología , PPAR gamma/metabolismo , Compuestos de Bencidrilo/toxicidadRESUMEN
Obesity is a major public burden on the working population and induces chronic diseases. Its treatment often requires long-term medication, which makes patient compliance difficult. In this study, we reported the value of HORN-MN, which comprised a fast-soluble hyaluronic acid microneedle matrix and a weak acid-degradable oleanolic acid dimer of rosiglitazone nanoparticles. The results showed that the microneedles easily punctured the stratum corneum and dissolved in the dermis of the abdominal wall within 5 min, followed by the release of rosiglitazone nanoparticles. Thereafter, the nanoparticles were endocytosed by macrophages and white adipocytes, then degraded to oleanolic acid in the lysosomes, thereby, releasing rosiglitazone. Oleanolic acid significantly improved the inflammatory status of obese adipose tissue and promoted white adipocyte browning, and rosiglitazone significantly potentiated WAC browning. Accordingly, the patch demonstrated a remarkable obesity-reducing efficacy in mice. In conclusion, this study developed a quick paster type of soluble rosiglitazone nanoparticle microneedle for the treatment of obesity. This patch can be suitable for working people, with an evident obesity-reducing efficacy but no effect on skin integrity despite multiple administrations.
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Nanopartículas , Agujas , Obesidad , Rosiglitazona , Animales , Obesidad/tratamiento farmacológico , Nanopartículas/química , Ratones , Rosiglitazona/farmacología , Rosiglitazona/administración & dosificación , Masculino , Ratones Endogámicos C57BL , Parche Transdérmico , Solubilidad , Células RAW 264.7 , Ácido Hialurónico/químicaRESUMEN
Molecular Dynamics (MD) is a computational technique widely used to evaluate a molecular system's thermodynamic properties and conformational behavior over time. In particular, the energy analysis of a protein conformation ensemble produced though MD simulations plays a crucial role in explaining the relationship between protein dynamics and its mechanism of action. In this research work, the HINT (Hydropathic INTeractions) LogP-based scoring function was first used to handle MD trajectories and investigate the molecular basis behind the intricate PPARγ mechanism of activation. The Peroxisome Proliferator-Activated Receptor γ (PPARγ) is an emblematic example of a highly flexible protein due to the extended ω-loop delimiting the active site, and it is responsible for the receptor's ability to bind chemically different compounds. In this work, we focused on the PPARγ complex with Rosiglitazone, a common anti-diabetic compound and analyzed the molecular basis of the flexible ω-loop stabilization effect produced by the Oleic Acid co-binding. The HINT-based analysis of the produced MD trajectories allowed us to account for all of the energetic contributions involved in interconverting between conformational states and describe the intramolecular interactions between the flexible ω-loop and the helix H3 triggered by the allosteric binding mechanism.
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Simulación de Dinámica Molecular , PPAR gamma , Humanos , PPAR gamma/química , PPAR gamma/metabolismo , Unión Proteica , Conformación Proteica , Rosiglitazona/química , Rosiglitazona/farmacología , TermodinámicaRESUMEN
Macrophages play pivotal roles in the regulation of inflammatory responses and tissue repair, making them a prime target for inflammation alleviation. However, the accurate and efficient macrophages targeting is still a challenging task. Motivated by the efficient and specific removal of apoptotic cells by macrophages efferocytosis, a novel biomimetic liposomal system called Effero-RLP (Efferocytosis-mediated Red blood cell hybrid Liposomes) is developed which incorporates the membrane of apoptotic red blood cells (RBCs) with liposomes for the purpose of highly efficient macrophages targeting. Rosiglitazone (ROSI), a PPARγ agonist known to attenuate macrophage inflammatory responses, is encapsulated into Effero-RLP as model drug to regulate macrophage functions in DSS-induced colitis mouse model. Intriguingly, the Effero-RLP exhibits selective and efficient uptake by macrophages, which is significantly inhibited by the efferocytosis blocker Annexin V. In animal models, the Effero-RLP demonstrates rapid recognition by macrophages, leading to enhanced accumulation at inflammatory sites. Furthermore, ROSI-loaded Effero-RLP effectively alleviates inflammation and protects colon tissue from injury in the colitis mouse model, which is abolished by deletion of macrophages from mice model. In conclusion, the study highlights the potential of macrophage targeting using efferocytosis biomimetic liposomes. The development of Effero-RLP presents novel and promising strategies for alleviating inflammation.
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Sistemas de Liberación de Medicamentos , Inflamación , Liposomas , Macrófagos , Animales , Ratones , Biomimética/métodos , Colitis/tratamiento farmacológico , Colitis/metabolismo , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos/métodos , Eferocitosis/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Rosiglitazona/farmacologíaRESUMEN
BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) belong to the superfamily of nuclear receptors and represent the targets for the therapeutical treatment of type 2 diabetes, dyslipidemia and hyperglycemia associated with metabolic syndrome. Some medicinal plants have been traditionally used to treat this kind of metabolic diseases. Today only few drugs targeting PPARs have been approved and for this reason, the rapid identification of novel ligands and/or chemical scaffolds starting from natural extracts would benefit of a selective affinity ligand fishing assay. RESULTS: In this paper we describe the development of a new ligand fishing assay based on size exclusion chromatography (SEC) coupled to LC-MS for the analysis of complex samples such as botanical extracts. The known PPARα and PPARγ ligands, WY-14643 and rosiglitazone respectively, were used for system development and evaluation. The system has found application on an Allium lusitanicum methanolic extract, containing saponins, a class of chemical compounds which have attracted interest as PPARs ligands because of their hypolipidemic and insulin-like properties. SIGNIFICANCE: A new SEC-AS-MS method has been developed for the affinity screening of PPARα and PPARγ ligands. The system proved to be highly specific and will be used to improve the throughput for the identification of new selective metabolites from natural souces targeting PPARα and PPARγ.
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Cromatografía en Gel , PPAR alfa , PPAR gamma , Extractos Vegetales , PPAR gamma/metabolismo , PPAR gamma/química , PPAR alfa/metabolismo , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ligandos , Espectrometría de Masas , Rosiglitazona/farmacología , Rosiglitazona/química , Humanos , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/análisis , PirimidinasRESUMEN
Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates nerve transmission and is important for motor coordination and learning. Whether Seipin deficiency-leaded defects in learning and motor coordination is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated. In the present study, we verified the expression of Seipin in oligodendrocytes (OLs) and their precursors, oligodendrocyte precursor cells (OPCs), and demonstrated that Seipin deficiency compromised OPC differentiation, which led to decreased OL numbers, myelin protein, myelinated fiber proportion and thickness of myelin. Deficiency of Seipin resulted in impaired spatial cognition and motor coordination in mice. Mechanistically, Seipin deficiency suppressed sphingolipid metabolism-related genes in OPCs and caused morphological abnormalities in lipid droplets (LDs), which markedly impeded OPC differentiation. Importantly, rosiglitazone, one agonist of PPAR-gamma, substantially restored phenotypes resulting from Seipin deficiency, such as aberrant LDs, reduced sphingolipids, obstructed OPC differentiation, and neurobehavioral defects. Collectively, the present study elucidated how Seipin deficiency-induced lipid dysregulation leads to neurobehavioral deficits via impairing myelination, which may pave the way for developing novel intervention strategy for treating metabolism-involved neurological disorders.
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Diferenciación Celular , Disfunción Cognitiva , Subunidades gamma de la Proteína de Unión al GTP , Vaina de Mielina , Células Precursoras de Oligodendrocitos , Animales , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Subunidades gamma de la Proteína de Unión al GTP/genética , Ratones , Células Precursoras de Oligodendrocitos/metabolismo , Vaina de Mielina/metabolismo , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Disfunción Cognitiva/genética , Metabolismo de los Lípidos , Oligodendroglía/metabolismo , Oligodendroglía/patología , Ratones Endogámicos C57BL , PPAR gamma/metabolismo , PPAR gamma/genética , Ratones Noqueados , Masculino , Rosiglitazona/farmacologíaRESUMEN
Seipin is a key regulator of lipid metabolism, the deficiency of which leads to severe lipodystrophy. Hypothalamus is the pivotal center of brain that modulates appetite and energy homeostasis, where Seipin is abundantly expressed. Whether and how Seipin deficiency leads to systemic metabolic disorders via hypothalamus-involved energy metabolism dysregulation remains to be elucidated. In the present study, we demonstrated that Seipin-deficiency induced hypothalamic inflammation, reduction of anorexigenic pro-opiomelanocortin (POMC), and elevation of orexigenic agonist-related peptide (AgRP). Importantly, administration of rosiglitazone, a thiazolidinedione antidiabetic agent, rescued POMC and AgRP expression, suppressed hypothalamic inflammation, and restored energy homeostasis in Seipin knockout mice. Our findings offer crucial insights into the mechanism of Seipin deficiency-associated energy imbalance and indicates that rosiglitazone could serve as potential intervening agent towards metabolic disorders linked to Seipin.