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1.
Front Endocrinol (Lausanne) ; 15: 1344262, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38559696

RESUMO

Obesity, a multifactorial disease with many complications, has become a global epidemic. Weight management, including dietary supplementation, has been confirmed to provide relevant health benefits. However, experimental evidence and mechanistic elucidation of dietary supplements in this regard are limited. Here, the weight loss efficacy of MHP, a commercial solid beverage consisting of mulberry leaf aqueous extract and Hippophae protein peptides, was evaluated in a high-fat high-fructose (HFF) diet-induced rat model of obesity. Body component analysis and histopathologic examination confirmed that MHP was effective to facilitate weight loss and adiposity decrease. Pathway enrichment analysis with differential metabolites generated by serum metabolomic profiling suggests that PPAR signal pathway was significantly altered when the rats were challenged by HFF diet but it was rectified after MHP intervention. RNA-Seq based transcriptome data also indicates that MHP intervention rectified the alterations of white adipose tissue mRNA expressions in HFF-induced obese rats. Integrated omics reveals that the efficacy of MHP against obesogenic adipogenesis was potentially associated with its regulation of PPARγ and FGFR1 signaling pathway. Collectively, our findings suggest that MHP could improve obesity, providing an insight into the use of MHP in body weight management.


Assuntos
Hippophae , Morus , Ratos , Animais , PPAR gama/genética , PPAR gama/metabolismo , Hippophae/metabolismo , Morus/metabolismo , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Tecido Adiposo Branco/metabolismo , Transdução de Sinais , Redução de Peso
2.
Commun Biol ; 7(1): 429, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38594496

RESUMO

The study aims to explore the effect of PPARγ signaling on ferroptosis and preeclampsia (PE) development. Serum and placental tissue are collected from healthy subjects and PE patients. The PPARγ and Nrf2 decreases in the PE. Rosiglitazone intervention reverses hypoxia-induced trophoblast ferroptosis and decreases lipid synthesis by regulating Nfr2 and SREBP1. Compared to the Hypoxia group, the migratory and invasive abilities enhance after rosiglitazone and ferr1 treatment. Rosiglitazone reduces the effect of hypoxia and erastin. The si-Nrf2 treatment attenuats the effects of rosiglitazone on proliferation, migration, and invasion. The si-Nrf2 does not affect SREBP1 expression. PPARγ agonists alleviates ferroptosis in the placenta of the PE rats. The study confirms that PPARγ signaling and ferroptosis-related indicators were dysregulated in PE. PPARγ/Nrf2 signaling affects ferroptosis by regulating lipid oxidation rather than SREBP1-mediated lipid synthesis. In conclusion, our study find that PPARγ can alleviate PE development by regulating lipid oxidation and ferroptosis.


Assuntos
Ferroptose , Pré-Eclâmpsia , Humanos , Feminino , Gravidez , Ratos , Animais , Rosiglitazona/farmacologia , Rosiglitazona/metabolismo , PPAR gama/metabolismo , Metabolismo dos Lipídeos , Placenta/metabolismo , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/prevenção & controle , Pré-Eclâmpsia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Hipóxia/metabolismo , Lipídeos
3.
Sci Rep ; 14(1): 6656, 2024 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509237

RESUMO

The feed-forward loop between the transcription factors Ppar-gamma and C/ebp-alpha is critical for lineage commitment during adipocytic differentiation. Ppar-gamma interacts with epigenetic cofactors to activate C/ebp-alpha and the downstream adipocytic gene expression program. Therefore, knowledge of the epigenetic cofactors associated with Ppar-gamma, is central to understanding adipocyte differentiation in normal differentiation and disease. We found that Prmt6 is present with Ppar-gamma on the Ppar-gamma and C/ebp-alpha promoter. It contributes to the repression of C/ebp-alpha expression, in part through its ability to induce H3R2me2a. During adipocyte differentiation, Prmt6 expression is reduced and the methyltransferase leaves the promoters. As a result, the expression of Ppar-gamma and C/ebp-alpha is upregulated and the adipocytic gene expression program is established. Inhibition of Prmt6 by a small molecule enhances adipogenesis, opening up the possibility of epigenetic manipulation of differentiation. Our data provide detailed information on the molecular mechanism controlling the Ppar-gamma-C/ebp-alpha feed-forward loop. Thus, they advance our understanding of adipogenesis in normal and aberrant adipogenesis.


Assuntos
Adipogenia , Fatores de Transcrição , Camundongos , Animais , Fatores de Transcrição/metabolismo , Adipogenia/genética , PPAR alfa/metabolismo , Regulação da Expressão Gênica , Adipócitos/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Diferenciação Celular/genética , PPAR gama/genética , PPAR gama/metabolismo , Células 3T3-L1
4.
Eur J Med Chem ; 269: 116325, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38527378

RESUMO

By virtue of the drug repurposing strategy, the anti-osteoporosis drug raloxifene was identified as a novel PPARγ ligand through structure-based virtual high throughput screening (SB-VHTS) of FDA-approved drugs and TR-FRET competitive binding assay. Subsequent structural refinement of raloxifene led to the synthesis of a benzothiophene derivative, YGL-12. This compound exhibited potent PPARγ modulation with partial agonism, uniquely promoting adiponectin expression and inhibiting PPARγ Ser273 phosphorylation by CDK5 without inducing the expression of adipongenesis associated genes, including PPARγ, aP2, CD36, FASN and C/EBPα. This specific activity profile resulted in effective hypoglycemic properties, avoiding major TZD-related adverse effects like weight gain and hepatomegaly, which were demonstrated in db/db mice. Molecular docking studies showed that YGL-12 established additional hydrogen bonds with Ile281 and enhanced hydrogen-bond interaction with Ser289 as well as PPARγ Ser273 phosphorylation-related residues Ser342 and Glu343. These findings suggested YGL-12 as a promising T2DM therapeutic candidate, thereby providing a molecular framework for the development of novel PPARγ modulators with an enhanced therapeutic index.


Assuntos
PPAR gama , Cloridrato de Raloxifeno , Tiofenos , Camundongos , Animais , PPAR gama/metabolismo , Simulação de Acoplamento Molecular , Reposicionamento de Medicamentos
5.
Eur J Med Chem ; 269: 116279, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38460271

RESUMO

In the current study, two series of novel thiazolidin-4-one benzenesulfonamide arylidene hybrids 9a-l and 10a-f were designed, synthesized and tested in vitro for their PPARÉ£ agonistic activity. The phenethyl thiazolidin-4-one sulphonamide 9l showed the highest PPARÉ£ activation % by 41.7%. Whereas, the 3-methoxy- and 4-methyl-4-benzyloxy thiazolidin-4-one sulphonamides 9i, and 9k revealed moderate PPARÉ£ activation % of 31.7, and 32.8%, respectively, in addition, the 3-methoxy-3-benzyloxy thiazolidin-4-one sulphonamide 10d showed PPARÉ£ activation % of 33.7% compared to pioglitazone. Compounds 9b, 9i, 9k, 9l, and 10d revealed higher selectivity to PPARÉ£ over the PPARδ, and PPARα isoforms. An immunohistochemical study was performed in HepG-2 cells to confirm the PPARÉ£ protein expression for the most active compounds. Compounds 9i, 9k, and 10d showed higher PPARÉ£ expression than that of pioglitazone. Pharmacological studies were also performed to determine the anti-diabetic activity in rats at a dose of 36 mg/kg, and it was revealed that compounds 9i and 10d improved insulin secretion as well as anti-diabetic effects. The 3-methoxy-4-benzyloxy thiazolidin-4-one sulphonamide 9i showed a better anti-diabetic activity than pioglitazone. Moreover, it showed a rise in blood insulin by 4-folds and C-peptide levels by 48.8%, as well as improved insulin sensitivity. Moreover, compound 9i improved diabetic complications as evidenced by decreasing liver serum enzymes, restoration of total protein and kidney functions. Besides, it combated oxidative stress status and exerted anti-hyperlipidemic effect. Compound 9i showed a superior activity by normalizing some parameters and amelioration of pancreatic, hepatic, and renal histopathological alterations caused by STZ-induction of diabetes. Molecular docking studies, molecular dynamic simulations, and protein ligand interaction analysis were also performed for the newly synthesized compounds to investigate their predicted binding pattern and energies in PPARÉ£ binding site.


Assuntos
Diabetes Mellitus Tipo 2 , Ratos , Animais , Pioglitazona/farmacologia , PPAR gama/metabolismo , Simulação de Acoplamento Molecular , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/farmacologia
6.
Cell Mol Biol Lett ; 29(1): 45, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38553665

RESUMO

BACKGROUND: Both glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ) play a critical role in adipocyte differentiation. Mifepristone is not only an antagonist of the glucocorticoid receptor but also an agonist of PPARγ. Therefore, the present study investigated the effect of mifepristone on adipocyte differentiation. METHODS: Mouse 3T3-L1 cells were used as a model for adipocyte differentiation. The lipid droplet formation was evaluated with Bodipy493/503 staining and the expression of adipocyte markers [adiponectin and adipocyte fatty acid binding protein-4 (Fabp4)] was evaluated with quantitative PCR and immunoblot analyses for indication of adipocyte differentiation. siRNA and neutralizing antibodies were used to elucidate the molecular mechanism of mifepristone-induced adipocyte differentiation. Luciferase reporter assay was used to examine the effect of mifepristone on the promoter activity of PPAR-response element (PPRE). The DNA microarray analysis was used to characterize the transcriptome of the mifepristone-induced adipocytes. In vivo adipogenic effect of mifepristone was examined in mice. RESULTS: Mifepristone not only enhanced adipocyte differentiation induced by the conventional protocol consisting of insulin, dexamethasone and 3-isobutyl-1-methylxanthine but also induced adipocyte differentiation alone, as evidenced by lipid droplets formation and induction of the expression of adiponectin and Fabp4. These effects were inhibited by an adiponectin-neutralizing antibody and a PPARγ antagonist. Mifepristone activated the promoter activity of PPRE in a manner sensitive to PPARγ antagonist. A principal component analysis (PCA) of DNA microarray data revealed that the mifepristone-induced adipocytes represent some characteristics of the in situ adipocytes in normal adipose tissues to a greater extent than those induced by the conventional protocol. Mifepristone administration induced an increase in the weight of epididymal, perirenal and gluteofemoral adipose tissues. CONCLUSIONS: Mifepristone alone is capable of inducing adipocyte differentiation in 3T3-L1 cells and adipogenesis in vivo. PPARγ plays a critical role in the mifepristone-induced adipocyte differentiation. Mifepristone-induced adipocytes are closer to the in situ adipocytes than those induced by the conventional protocol. The present study proposes a single treatment with mifepristone as a novel protocol to induce more physiologically relevant adipocytes in 3T3-L1 cells than the conventional protocol.


Assuntos
Adiponectina , Mifepristona , Camundongos , Animais , Adiponectina/metabolismo , Adiponectina/farmacologia , Mifepristona/farmacologia , Mifepristona/metabolismo , PPAR gama/metabolismo , Células 3T3-L1 , Receptores de Glucocorticoides/metabolismo , Diferenciação Celular , Adipogenia/genética , Adipócitos/metabolismo
7.
J Therm Biol ; 120: 103824, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38428104

RESUMO

This research endeavored to elucidate the transcriptional modulation of heat shock proteins and adipogenic regulators in bovine subcutaneous adipocytes following thermal exposure. Post-differentiation, mature adipocytes were subjected to three treatments of control (CON), moderate (MHS), and extreme (EHS) heat stress. These treatments consist of thermal conditions at temperatures of 38 °C (CON), 39.5 °C (MHS), or 41 °C (EHS) along with of 3 or 12 h. There was no statistically significant variations observed in the gene expressions of HSP27 and HSP70 when comparing CON with MHS across both exposures. Contrastingly, when comparing CON with EHS, an upregulation (P < 0.01) in HSP27 gene expression was evident for both 3 and 12 h of incubation, while HSP70 gene expression exhibited elevation (P < 0.01) at the 3-h mark, with no change observed at 12 h. Protein quantification, however, revealed an elevation (P < 0.01) in HSP27 and HSP70 for both CON vs. MHS and CON vs. EHS at the 12-h exposure. This trend in protein level mirrored (P < 0.05) that of proliferator-activated receptor-gamma (PPARγ). Elevated (P < 0.05) protein levels of fatty acid synthase (FAS) were exclusively discernible in the CON vs. MHS. Increased (P < 0.01) transcriptional activity of PPARγ, CCAAT/enhancer-binding protein alpha (C/EBPα), stearoyl-CoA desaturase (SCD), and FAS was evident in the CON vs. EHS comparison. Complementary to these molecular findings, an augmented lipid droplet accumulation was observed (P < 0.01) in EHS-exposed adipocytes progressively from day 6 through day 9. Our current study highlights how different levels and lengths of heat stress can impact the activity of important heat-related proteins and factors that play a role in fat development in beef cattle. These findings can help guide strategies to manage how beef cattle are exposed to heat, which can affect fat storage and ultimately the quality of the meat's marbling.


Assuntos
Proteínas de Choque Térmico HSP27 , PPAR gama , Bovinos , Animais , PPAR gama/genética , PPAR gama/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Adipócitos/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Proteínas de Transporte , Proteínas de Choque Térmico HSP70/metabolismo
8.
PLoS One ; 19(3): e0300520, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38512891

RESUMO

Stellera chamaejasme L. (SCL) is a perennial herb with demonstrated bioactivities against inflammation and metabolic dysfunction. Adipocyte differentiation is a critical regulator of metabolic homeostasis and a promising target for the treatment of metabolic diseases, so we examined the effects of SCL on adipogenesis. A methanol extract of SCL dose-dependently suppressed intracellular lipid accumulation in adipocyte precursors cultured under differentiation induction conditions and reduced expression of the adipogenic transcription factors PPARγ and C/EBPα as well as the downstream lipogenic genes fatty acid binding protein 4, adiponectin, fatty acid synthase, and stearoyl-CoA desaturase. The extract also promoted precursor cell proliferation and altered expression of the cell cycle regulators cyclin-dependent kinase 4, cyclin E, and cyclin D1. In addition, SCL extract stimulated extracellular signal-regulated kinase (ERK) phosphorylation, while pharmacological inhibition of ERK effectively blocked the inhibitory effects of SCL extract on preadipocyte differentiation. These results suggest that SCL extract contains bioactive compounds that can suppress adipogenesis through modulation of the ERK pathway.


Assuntos
Adipogenia , MAP Quinases Reguladas por Sinal Extracelular , Camundongos , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Diferenciação Celular , Metabolismo dos Lipídeos , Adipócitos/metabolismo , Células 3T3-L1 , PPAR gama/metabolismo
9.
Biochem Pharmacol ; 222: 116097, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428827

RESUMO

OBJECTIVES: Chemoprevention, consisting of the administration of natural and/or synthetic compounds, appears to be an alternative way to common therapeutical approaches to preventing the occurrence of various cancers. Cladosporols, secondary metabolites from Cladosporium tenuissimum, showed a powerful ability in controlling human colon cancer cell proliferation through a peroxisome proliferator-activated receptor gamma (PPARγ)-mediated modulation of gene expression. Hence, we carried out experiments to verify the anticancer properties of cladosporols in human prostate cancer cells. Prostate cancer represents one of the most widespread tumors in which several risk factors play a role in determining its high mortality rate in men. MATERIALS AND METHODS: We assessed, by viability assays, PPARγ silencing and overexpression experiments and western blotting analysis, the anticancer properties of cladosporols in cancer prostate cell lines. RESULTS: Cladosporols A and B selectively inhibited the proliferation of human prostate PNT-1A, LNCaP and PC-3 cells and their most impactful antiproliferative ability towards PC-3 prostate cancer cells, was mediated by PPARγ modulation. Moreover, the anticancer ability of cladosporols implied a sustained apoptosis. Finally, cladosporols negatively regulated the expression of enzymes involved in the biosynthesis of fatty acids and cholesterol, thus enforcing the relationship between prostate cancer development and lipid metabolism dysregulation. CONCLUSION: This is the first work, to our knowledge, in which the role of cladosporols A and B was disclosed in prostate cancer cells. Importantly, the present study highlighted the potential of cladosporols as new therapeutical tools, which, interfering with cell proliferation and lipid pathway dysregulation, may control prostate cancer initiation and progression.


Assuntos
Naftalenos , PPAR gama , Neoplasias da Próstata , Masculino , Humanos , PPAR gama/metabolismo , Células PC-3 , Neoplasias da Próstata/metabolismo , Apoptose , Proliferação de Células , Lipídeos , Linhagem Celular Tumoral
10.
Int J Mol Med ; 53(4)2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38426604

RESUMO

The effects of adipocyte­rich microenvironment (ARM) on chemoresistance have garnered increasing interest. Ovarian cancer (OVCA) is a representative adipocyte­rich associated cancer. In the present study, epithelial OVCA (EOC) was used to investigate the influence of ARM on chemoresistance with the aim of identifying novel targets and developing novel strategies to reduce chemoresistance. Bioinformatics analysis was used to explore the effects of ARM­associated mechanisms contributing to chemoresistance and treated EOC cells, primarily OVCAR3 cells, with human adipose tissue extracts (HATES) from the peritumoral adipose tissue of patients were used to mimic ARM in vitro. Specifically, the peroxisome proliferator­activated receptor Î³ (PPARγ) antagonist GW9662 and the ABC transporter G family member 2 (ABCG2) inhibitor KO143, were used to determine the underlying mechanisms. Next, the effect of HATES on the expression of PPARγ and ABCG2 in OVCAR3 cells treated with cisplatin (DDP) and paclitaxel (PTX) was determined. Additionally, the association between PPARγ, ABCG2 and chemoresistance in EOC specimens was assessed. To evaluate the effect of inhibiting PPARγ, using DDP, a nude mouse model injected with OVCAR3­shPPARγ cells and a C57BL/6 model injected with ID8 cells treated with GW9662 were established. Finally, the factors within ARM that contributed to the mechanism were determined. It was found that HATES promoted chemoresistance by increasing ABCG2 expression via PPARγ. Expression of PPARγ/ABCG2 was related to chemoresistance in EOC clinical specimens. GW9662 or knockdown of PPARγ improved the efficacy of chemotherapy in mice. Finally, angiogenin and oleic acid played key roles in HATES in the upregulation of PPARγ. The present study showed that the introduction of ARM­educated PPARγ attenuated chemoresistance in EOC, highlighting a potentially novel therapeutic adjuvant to chemotherapy and shedding light on a means of improving the efficacy of chemotherapy from the perspective of ARM.


Assuntos
Anilidas , Neoplasias Ovarianas , Animais , Feminino , Humanos , Camundongos , Adipócitos/metabolismo , Apoptose , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Microambiente Tumoral , Regulação para Cima
11.
Brain Res Bull ; 209: 110918, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38432497

RESUMO

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of high mortality and disability worldwide. Overactivation of astrocytes and overexpression of inflammatory responses in the injured brain are characteristic pathological features of TBI. Rosiglitazone (ROS) is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist known for its anti-inflammatory activity. However, the relationship between the inflammatory response involved in ROS treatment and astrocyte A1 polarization remains unclear. OBJECTIVE: This study aimed to investigate whether ROS treatment improves dysfunction and astrocyte A1 polarization induced after TBI and to elucidate the underlying mechanisms of these functions. METHODS: SD rats were randomly divided into sham operation group, TBI group, TBI+ROS group, and TBI+ PPAR-γ antagonist group (GW9662 + TBI). The rat TBI injury model was prepared by the CCI method; brain water content test and wire grip test scores suggested the prognosis; FJB staining showed the changes of ROS on the morphology and number of neurons in the peripheral area of cortical injury; ELISA, immunofluorescence staining, and western blotting analysis revealed the effects of ROS on inflammatory response and astrocyte activation with the degree of A1 polarization after TBI. RESULTS: Brain water content, inflammatory factor expression, and astrocyte activation in the TBI group were higher than those in the sham-operated group (P < 0.05); compared with the TBI group, the expression of the above indexes in the ROS group was significantly lower (P < 0.05). Compared with the TBI group, PPAR-γ content was significantly higher and C3 content was considerably lower in the ROS group (P < 0.05); compared with the TBI group, PPAR-γ content was significantly lower and C3 content was substantially higher in the inhibitor group (P < 0.05). CONCLUSION: ROS can exert neuroprotective effects by inhibiting astrocyte A1 polarization through the PPAR-γ pathway based on the reduction of inflammatory factors and astrocyte activation in the brain after TBI.


Assuntos
Astrócitos , Lesões Encefálicas Traumáticas , Hipoglicemiantes , Doenças Neuroinflamatórias , Rosiglitazona , Animais , Ratos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Doenças Neuroinflamatórias/tratamento farmacológico , PPAR gama/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masculino
12.
Pharmacol Res ; 202: 107136, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38460778

RESUMO

CREB-regulated transcription coactivator 1 (CRTC1), a pivotal synaptonuclear messenger, regulates synaptic plasticity and transmission to prevent depression. Despite exhaustive investigations into CRTC1 mRNA reductions in the depressed mice, the regulatory mechanisms governing its transcription remain elusive. Consequently, exploring rapid but non-toxic CRTC1 inducers at the transcriptional level is important for resisting depression. Here, we demonstrate the potential of D-arabinose, a unique monosaccharide prevalent in edible-medicinal plants, to rapidly enter the brain and induce CRTC1 expression, thereby eliciting rapid-acting and persistent antidepressant responses in chronic restrain stress (CRS)-induced depressed mice. Mechanistically, D-arabinose induces the expressions of peroxisome proliferator-activated receptor gamma (PPARγ) and transcription factor EB (TFEB), thereby activating CRTC1 transcription. Notably, we elucidate the pivotal role of the acetyl-CoA synthetase short-chain family member 2 (ACSS2) as an obligatory mediator for PPARγ and TFEB to potentiate CRTC1 transcription. Furthermore, D-arabinose augments ACSS2-dependent CRTC1 transcription by activating AMPK through lysosomal AXIN-LKB1 pathway. Correspondingly, the hippocampal down-regulations of ACSS2, PPARγ or TFEB alone failed to reverse CRTC1 reductions in CRS-exposure mice, ultimately abolishing the anti-depressant efficacy of D-arabinose. In summary, our study unveils a previously unexplored role of D-arabinose in activating the ACSS2-PPARγ/TFEB-CRTC1 axis, presenting it as a promising avenue for the prevention and treatment of depression.


Assuntos
Arabinose , PPAR gama , Camundongos , Animais , PPAR gama/genética , PPAR gama/metabolismo , Arabinose/farmacologia , Arabinose/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Encéfalo/metabolismo
13.
Aquat Toxicol ; 269: 106884, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38458066

RESUMO

Triclosan (TCS), recognized as an endocrine disruptor, has raised significant concerns due to its widespread use and potential health risks. To explore the impact of TCS on lipid metabolism, both larval and adult zebrafish were subjected to acute and chronic exposure to TCS. Through analyzes of biochemical and physiological markers, as well as Oil Red O (ORO) and hematoxylin and eosin (H&E) staining, our investigation revealed that TCS exposure induced hepatic and intestinal lipid accumulation in larval and adult zebrafish, leading to structural damage and inflammatory responses in these tissues. The strong affinity of TCS with PPARγ and subsequent pathway activation indicate that PPARγ pathway plays a crucial role in TCS-induced lipid buildup. Furthermore, we observed a decrease in m6A-RNA methylation levels in the TCS-treated group, which attributed to the increased activity of the demethylase FTO and concurrent suppression of the methyltransferase METTL3 gene expression by TCS. The alteration in methylation dynamics is identified as a potential underlying mechanism behind TCS-induced lipid accumulation. To address this concern, we explored the impact of folic acid-a methyl donor for m6A-RNA methylation-on lipid accumulation in zebrafish. Remarkably, folic acid administration partially alleviated lipid accumulation by restoring m6A-RNA methylation. This restoration, in turn, contributed to a reduction in inflammatory damage observed in both the liver and intestines. Additionally, folic acid partially mitigates the up-regulation of PPARγ and related genes induced by TCS. These findings carry substantial implications for understanding the adverse effects of environmental pollutants such as TCS. They also emphasize the promising potential of folic acid as a therapeutic intervention to alleviate disturbances in lipid metabolism induced by environmental pollutants.


Assuntos
Adenina/análogos & derivados , Triclosan , Poluentes Químicos da Água , Animais , Triclosan/toxicidade , Triclosan/metabolismo , Peixe-Zebra/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Poluentes Químicos da Água/toxicidade , Fígado , Lipídeos , Intestinos , Ácido Fólico/metabolismo , Ácido Fólico/farmacologia
14.
Pestic Biochem Physiol ; 199: 105757, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38458660

RESUMO

Fenhexamid are fungicides that act against plant pathogens by inhibiting sterol biosynthesis. Nonetheless, it can trigger endocrine disruption and promote breast cancer cell growth. In a recent study, we investigated the mechanism underlying the lipid accumulation induced by fenhexamid hydroxyanilide fungicides in 3 T3-L1 adipocytes. To examine the estrogen receptor alpha (ERα)-agonistic effect, ER transactivation assay using the ERα-HeLa-9903 cell line was applied, and fenhexamid-induced ERα agonist effect was confirmed. Further confirmation that ERα-dependent lipid accumulation occurred was provided by treating 3 T3-L1 adipocytes with Methyl-piperidino-pyrazole hydrate (MPP), an ERα-selective antagonist. Fenhexamid mimicked the actions of ERα agonists and impacted lipid metabolism, and its mechanism involves upregulation of the expression of transcription factors that facilitate adipogenesis and lipogenesis. Additionally, it stimulated the expression of peroxisome proliferator-activated receptor (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), fatty acid synthase (FAS), and sterol regulatory element-binding protein 1 (SREBP1) and significantly elevated the expression of fatty acid-binding protein 4 (FABP4). In contrast, in combination with an ERα-selective antagonist, fenhexamid suppressed the expression of adipogenic/lipogenic transcription factors. These results suggest that fenhexamid affects the endocrine system and leads to lipid accumulation by interfering with processes influenced by ERα activation.


Assuntos
Amidas , Receptor alfa de Estrogênio , Fungicidas Industriais , Camundongos , Animais , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Fungicidas Industriais/toxicidade , Fungicidas Industriais/metabolismo , Adipócitos/metabolismo , Adipogenia , Metabolismo dos Lipídeos , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/farmacologia , Lipídeos , Células 3T3-L1 , PPAR gama/metabolismo
15.
Int Immunopharmacol ; 131: 111834, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38493696

RESUMO

Pulmonary fibrosis is a chronic and progressively deteriorating lung condition that can be replicated in laboratory animals by administering bleomycin, a chemotherapeutic antibiotic known for its lung fibrosis-inducing side effects. L-arginine, a semi-essential amino acid, is recognized for its diverse biological functions, including its potential to counteract fibrosis. This study aimed to evaluate the antifibrotic properties of L-arginine on bleomycin-induced pulmonary fibrosis in rats. The administration of a single intratracheal dose of bleomycin resulted in visible and microscopic damage to lung tissues, an uptick in oxidative stress markers, and an elevation in inflammatory, apoptotic, and fibrotic indicators. A seven-day treatment with L-arginine post-bleomycin exposure markedly improved the gross and histological architecture of the lungs, prevented the rise of malondialdehyde and carbonyl content, and enhanced total antioxidant capacity alongside the activities of antioxidant enzymes. Also, L-arginine attenuated the expression of the pro-fibrotic factors, transforming growth factor-ß and lactate dehydrogenase in bronchoalveolar lavage fluid. In the lung tissue, L-arginine reduced collagen deposition, hydroxyproline concentration, and mucus production, along with decreasing expression of α-smooth muscle actin, tumor necrosis factor-α, caspase-3, matrix metalloproteinase-9, and ß-catenin. Moreover, it boosted levels of nitric oxide and upregulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), heme oxygenase-1 (HO-1), and E-cadherin and downregulating the expression of ß-catenin. These findings suggest that L-arginine has preventive activities against bleomycin-induced pulmonary fibrosis. This effect can be attributed to the increased production of nitric oxide, which modulates the HO-1/PPAR-γ/ß-catenin axis.


Assuntos
Fibrose Pulmonar , Ratos , Animais , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Bleomicina/efeitos adversos , Heme Oxigenase-1/metabolismo , Antioxidantes/farmacologia , beta Catenina/metabolismo , PPAR gama/metabolismo , Óxido Nítrico/metabolismo , Pulmão/patologia , Fibrose , Arginina/uso terapêutico
16.
Int Immunopharmacol ; 131: 111898, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38513573

RESUMO

Vancomycin (VCM) is the first-line antibiotic for severe infections, but nephrotoxicity limits its use. Leonurine (Leo) has shown protective effects against kidney damage. However, the effect and mechanism of Leo on VCM nephrotoxicity remain unclear. In this study, mice and HK-2 cells exposed to VCM were treated with Leo. Biochemical and pathological analysis and fluorescence probe methods were performed to examine the role of Leo in VCM nephrotoxicity. Immunohistochemistry, q-PCR, western blot, FACS, and Autodock software were used to verify the mechanism. The present results indicate that Leo significantly alleviates VCM-induced renal injury, morphological damage, and oxidative stress. Increased intracellular and mitochondrial ROS in HK-2 cells and decreased mitochondrial numbers in mouse renal tubular epithelial cells were reversed in Leo-administrated groups. In addition, molecular docking analysis using Autodock software revealed that Leo binds to the PPARγ protein with high affinity. Mechanistic exploration indicated that Leo inhibited VCM nephrotoxicity via activating PPARγ and inhibiting the TLR4/NF-κB/TNF-α inflammation pathway. Taken together, our results indicate that the PPARγ inhibition and inflammation reactions were implicated in the VCM nephrotoxicity and provide a promising therapeutic strategy for renal injury.


Assuntos
Ácido Gálico/análogos & derivados , Insuficiência Renal , Vancomicina , Camundongos , Animais , Vancomicina/metabolismo , Vancomicina/farmacologia , Vancomicina/uso terapêutico , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , PPAR gama/metabolismo , Receptor 4 Toll-Like/metabolismo , Simulação de Acoplamento Molecular , Rim/patologia , Insuficiência Renal/metabolismo , Inflamação/tratamento farmacológico
17.
Biochem Biophys Res Commun ; 707: 149617, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38520942

RESUMO

Preeclampsia (PE) is characterized by hypertension, proteinuria, and fetal growth restriction during pregnancy, suggesting that the preeclamptic intrauterine environment may affect the growth and health of the offspring. This study aimed to how maternal hypertension affects male offspring growth, focusing on lipid metabolism and blood pressure in mice. Female mice were infused with angiotensin II (Ang II) on gestational day 12. Dysregulation and accumulation of lipid were observed in the placenta of Ang II-induced maternal hypertensive dams, associating with fetal growth restriction. Ang II-offspring showed lower birth weight than in the control-offspring. Isolated and differentiated adipocyte from neonatal mice of Ang II-dams showed higher Pparγ mRNA expression compared with the control group. Lower body weight tendency had continued in Ang II-offspring during long period, body weight of Ang II-offspring caught up the control-offspring at 16 weeks of age. The adipose tissue of Ang II-offspring in adult also showed higher Pparγ mRNA expression with the accumulation of neutrophils and inflammatory monocytes than in those control. In addition, Ang II-offspring had higher basal blood pressure and higher sensitivity to hypertensive stimuli than in the control-offspring. Taken together, maternal hypertension induced by Ang II changes placental function, causing a lower birth weight. These changes in the intrauterine environment may affect adipocyte function and blood pressure of offspring after growth.


Assuntos
Hipertensão , Pré-Eclâmpsia , Humanos , Feminino , Gravidez , Masculino , Animais , Camundongos , Pressão Sanguínea/fisiologia , Retardo do Crescimento Fetal/etiologia , Peso ao Nascer , PPAR gama/genética , PPAR gama/metabolismo , Placenta/metabolismo , Sistema Renina-Angiotensina/fisiologia , Hipertensão/metabolismo , Angiotensina II/metabolismo , Pré-Eclâmpsia/metabolismo , Tecido Adiposo/metabolismo , RNA Mensageiro/metabolismo
18.
Lipids Health Dis ; 23(1): 76, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468335

RESUMO

BACKGROUND: Atherosclerosis (AS) is a persistent inflammatory condition triggered and exacerbated by several factors including lipid accumulation, endothelial dysfunction and macrophages infiltration. Nobiletin (NOB) has been reported to alleviate atherosclerosis; however, the underlying mechanism remains incompletely understood. METHODS: This study involved comprehensive bioinformatic analysis, including multidatabase target prediction; GO and KEGG enrichment analyses for function and pathway exploration; DeepSite and AutoDock for drug binding site prediction; and CIBERSORT for immune cell involvement. In addition, target intervention was verified via cell scratch assays, oil red O staining, ELISA, flow cytometry, qRT‒PCR and Western blotting. In addition, by establishing a mouse model of AS, it was demonstrated that NOB attenuated lipid accumulation and the extent of atherosclerotic lesions. RESULTS: (1) Altogether, 141 potentially targetable genes were identified through which NOB could intervene in atherosclerosis. (2) Lipid and atherosclerosis, fluid shear stress and atherosclerosis may be the dominant pathways and potential mechanisms. (3) ALB, AKT1, CASP3 and 7 other genes were identified as the top 10 target genes. (4) Six genes, including PPARG, MMP9, SRC and 3 other genes, were related to the M0 fraction. (5) CD36 and PPARG were upregulated in atherosclerosis samples compared to the normal control. (6) By inhibiting lipid uptake in RAW264.7 cells, NOB prevents the formation of foam cell. (7) In RAW264.7 cells, the inhibitory effect of oxidized low-density lipoprotein on foam cells formation and lipid accumulation was closely associated with the PPARG signaling pathway. (8) In vivo validation showed that NOB significantly attenuated intra-arterial lipid accumulation and macrophage infiltration and reduced CD36 expression. CONCLUSIONS: Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway.


Assuntos
Aterosclerose , Flavonas , PPAR gama , Animais , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Macrófagos , Células Espumosas , Lipoproteínas LDL/farmacologia , Antígenos CD36/genética , Antígenos CD36/metabolismo
19.
J Agric Food Chem ; 72(10): 5452-5462, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38428036

RESUMO

Deoxynivalenol (DON) is a common mycotoxin that induces intestinal inflammation and oxidative damage in humans and animals. Given that lithocholic acid (LCA) has been suggested to inhibit intestinal inflammation, we aimed to investigate the protective effects of LCA on DON-exposed porcine intestinal epithelial IPI-2I cells and the underlying mechanisms. Indeed, LCA rescued DON-induced cell death in IPI-2I cells and reduced DON-stimulated inflammatory cytokine levels and oxidative stress. Importantly, the nuclear receptor PPARγ was identified as a key transcriptional factor involved in the DON-induced inflammation and oxidative stress processes in IPI-2I cells. The PPARγ function was found compromised, likely due to the hyperphosphorylation of the p38 and ERK signaling pathways. In contrast, the DON-induced inflammatory responses and oxidative stress were restrained by LCA via PPARγ-mediated reprogramming of the core inflammatory and antioxidant genes. Notably, the PPARγ-modulated transcriptional regulations could be attributed to the altered recruitments of coactivator SRC-1/3 and corepressor NCOR1/2, along with the modified histone marks H3K27ac and H3K18la. This study emphasizes the protective actions of LCA on DON-induced inflammatory damage and oxidative stress in intestinal epithelial cells via PPARγ-mediated epigenetically transcriptional reprogramming, including histone acetylation and lactylation.


Assuntos
Ácido Litocólico , PPAR gama , Tricotecenos , Humanos , Animais , Suínos , PPAR gama/metabolismo , Ácido Litocólico/efeitos adversos , Ácido Litocólico/metabolismo , Células Epiteliais/metabolismo , Estresse Oxidativo , Inflamação/metabolismo
20.
Exp Cell Res ; 437(1): 113992, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38492634

RESUMO

BACKGROUND: Hepatic fibrosis, a common pathological process that occurs in end-stage liver diseases, is a serious public health problem and lacks effective therapy. Notoginsenoside R1 (NR1) is a small molecule derived from the traditional Chinese medicine Sanqi, exhibiting great potential in treating diverse metabolie disorders. Here we aimed to enquired the role of NR1 in liver fibrosis and its underlying mechanism in hepatoprotective effects. METHODS: We investigated the anti-fibrosis effect of NR1 using CCl4-induced mouse mode of liver fibrosis as well as TGF-ß1-activated JS-1, LX-2 cells and primary hepatic stellate cell. Cell samples treated by NR1 were collected for transcriptomic profiling analysis. PPAR-γ mediated TGF-ß1/Smads signaling was examined using PPAR-γ selective inhibitors and agonists intervention, immunofluorescence staining and western blot analysis. Additionally, we designed and studied the binding of NR1 to PPAR-γ using molecular docking. RESULTS: NR1 obviously attenuated liver histological damage, reduced serum ALT, AST levels, and decreased liver fibrogenesis markers in mouse mode. Mechanistically, NR1 elevated PPAR-γ and decreased TGF-ß1, p-Smad2/3 expression. The TGF-ß1/Smads signaling pathway and fibrotic phenotype were altered in JS-1 cells after using PPAR-γ selective inhibitors and agonists respectively, confirming PPAR-γ played a pivotal protection role inNR1 treating liver fibrosis. Further molecular docking indicated NR1 had a strong binding tendency to PPAR-γ with minimum free energy. CONCLUSIONS: NR1 attenuates hepatic stellate cell activation and hepatic fibrosis by elevating PPAR-γ to inhibit TGF-ß1/Smads signalling. NR1 may be a potential candidate compound for reliving liver fibrosis.


Assuntos
Ginsenosídeos , Células Estreladas do Fígado , Fator de Crescimento Transformador beta1 , Animais , Camundongos , Fibrose , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Simulação de Acoplamento Molecular , PPAR gama/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
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