RESUMO
Macrophages have crucial roles in immune responses and tumor progression, exhibiting diverse phenotypes based on environmental cues. In the present study, the impact of cinobufagin (CB) on macrophage polarization and the consequences on tumorassociated behaviors were investigated. Morphological transformations of THP1 cells into M0, M1 and M2 macrophages were observed, including distinct changes in the size, shape and adherence properties of these cells. CB treatment inhibited the viability of A549 and LLC cells in a concentrationdependent manner, with an IC50 of 28.8 and 30.12 ng/ml, respectively. CB at concentrations of <30 ng/ml had no impact on the viability of M0 macrophages and lung epithelial (BEAS2B) cells. CB influenced the expression of macrophage surface markers, reducing CD206 positivity in M2 macrophages without affecting CD86 expression in M1 macrophages. CB also altered certain expression profiles at the mRNA level, notably downregulating macrophage receptor with collagenous structure (MARCO) expression in M2 macrophages and upregulating tumor necrosis factorα and interleukin1ß in both M0 and M1 macrophages. Furthermore, ELISA analyses revealed that CB increased the levels of proinflammatory cytokines in M1 macrophages and reduced the levels of antiinflammatory factors in M2 macrophages. CB treatment also attenuated the migration and invasion capacities of A549 and LLC cells stimulated by M2 macrophageconditioned medium. Additionally, CB modulated peroxisome proliferatoractivated receptor γ (PPARγ) and MARCO expression in M2 macrophages and epithelialmesenchymal transition in A549 cells, which was partially reversed by rosiglitazone, a PPARγ agonist. Finally, CB and cisplatin treatments hindered tumor growth in vivo, with distinct impacts on animal body weight and macrophage marker expression in tumor tissues. In conclusion, the results of the present study demonstrated that CB exerted complex regulatory effects on macrophage polarization and tumor progression, suggesting its potential as a modulator of the tumor microenvironment and a therapeutic for cancer treatment.
Assuntos
Bufanolídeos , Movimento Celular , Neoplasias Pulmonares , Invasividade Neoplásica , Macrófagos Associados a Tumor , Bufanolídeos/farmacologia , Bufanolídeos/uso terapêutico , Humanos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/imunologia , Animais , Camundongos , Movimento Celular/efeitos dos fármacos , Células A549 , Ensaios Antitumorais Modelo de Xenoenxerto , Células THP-1 , PPAR gama/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
Cyclophosphamide (CP) is an anticancer drug that causes infertility disorders. This study was designed to evaluate a nanoformulation of chitosan with an ethanolic extract from Spirulina platensis in terms of its protection against cyclophosphamide-induced ovarian toxicity. Nine groups of female Wistar rats were randomly assigned as follows: 1: control vehicle, 2: chitosan polymer, 3: telmisartan, 4: Spirulina platensis extract, 5: nanoformulation of the Spirulina platensis, and 6: single injection of CP; groups 7, 8, and 9 received the same treatments as those used in groups 3, 4, and 5, respectively, with a single dose of CP (200 mg/kg, I.P). The results displayed that the CP treatment decreased estradiol, progesterone, anti-mullerian hormone, and GSH content, and it downregulated PPAR-γ, Nrf-2, and HO-1 gene expression. In addition, the CP treatment caused an increase in the FSH, LH, and MDA levels. In the same manner, the protein expression of caspase-3, NF-kB, and TNF-α was upregulated in response to the CP treatment, while PPAR-γ was downregulated in comparison with the control. The rats treated with SPNPs exhibited a substantial reduction in the detrimental effects of oxidative stress and inflammation of the ovarian tissue. This study's conclusions showed that SPNPs counteracted the effects of CP, preventing the death of ovarian follicles and restoring the gonadotropin hormone balance and normal ovarian histological appearance.
Assuntos
Quitosana , Ciclofosfamida , Fator 2 Relacionado a NF-E2 , NF-kappa B , Ovário , PPAR gama , Fator de Necrose Tumoral alfa , Animais , Feminino , Ratos , Quitosana/química , Quitosana/farmacologia , Ciclofosfamida/toxicidade , Etanol/química , Heme Oxigenase (Desciclizante)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ovário/efeitos dos fármacos , Ovário/patologia , Ovário/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Spirulina , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Sepsis, a multifaceted syndrome driven by an imbalanced host response to infection, remains a significant medical challenge. At its core lies the pivotal role of glycolysis, orchestrating immune responses especially in severe sepsis. The intertwined dynamics between glycolysis, sepsis, and immunity, however, have gaps in knowledge with several Crucial genes still shrouded in ambiguity. We harvested transcriptomic profiles from the peripheral blood of 107 septic patients juxtaposed against 29 healthy controls. Delving into this dataset, differential expression analysis shed light on genes distinctly linked to glycolysis in both cohorts. Harnessing the prowess of LASSO regression and SVM-RFE, we isolated Crucial genes, paving the way for a sepsis risk prediction model, subsequently vetted via Calibration and decision curve analysis. Using the CIBERSORT algorithm, we further mapped 22 immune cell subtypes within the septic samples, establishing potential interactions with the delineated Crucial genes. Our efforts unveiled 21 genes intricately tied to glycolysis that exhibited differential expression patterns. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses offered insights, spotlighting pathways predominantly associated with oxidative phosphorylation, PPAR signaling pathway, Glycolysis/Gluconeogenesis and HIF-1 signaling pathway. Among the myriad genes, IER3, DSC2, and PPARG emerged as linchpins, their prominence in sepsis further validated through ROC analytics. These sentinel genes demonstrated profound affiliations with various immune cell facets, bridging the complex terrain of glycolysis, sepsis, and immune responses. In line with our endeavor to "unveil the glycolysis in sepsis," the discovery of IER3, DSC2, and PPARG reinforces their cardinal roles in sepsis pathogenesis. These revelations accentuate the intricate dance between glycolysis and immunological shifts in septic conditions, offering novel avenues for therapeutic interventions.
Assuntos
Biologia Computacional , Glicólise , Aprendizado de Máquina , PPAR gama , Sepse , Humanos , Sepse/genética , Sepse/imunologia , Sepse/metabolismo , Glicólise/genética , PPAR gama/genética , PPAR gama/metabolismo , Biologia Computacional/métodos , Masculino , Feminino , Pessoa de Meia-Idade , TranscriptomaRESUMO
This study investigated the effects of ascochlorin (ASC), a natural compound derived from the fungus Ascochyta viciae, on adipogenesis and obesity. We determined the effects of ASC on 3T3-L1 preadipocytes and whether it ameliorated to mitigate high-fat diet (HFD)-induced obesity in C57BL/6J mice. We found that ASC significantly inhibited the differentiation of preadipocytes by modulating the Wnt/ß-catenin signaling pathway, a key regulator of adipogenic processes. Treatment with ASC not only reduced the mRNA and protein expression of key adipogenic transcription factors such as C/EBPα and PPARγ, but also reduced lipid accumulation both in vitro and in vivo. In addition, treatment HFD-fed mice with ASC significantly reduced their weight gain and adiposity vs. control mice. These results suggest that ASC has considerable potential as a therapeutic agent for obesity, owing to its dual action of inhibiting adipocyte differentiation and reducing lipid accumulation. Thus, ASC represents a promising candidate as a natural anti-obesity agent.
Assuntos
Adipócitos , Adipogenia , Dieta Hiperlipídica , Obesidade , Via de Sinalização Wnt , Animais , Masculino , Camundongos , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Alcenos , Fármacos Antiobesidade/farmacologia , beta Catenina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/etiologia , Fenóis/farmacologia , PPAR gama/metabolismo , PPAR gama/genética , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
BACKGROUND: Capsaicin, a bioactive compound found in peppers, is recognized for its anti-inflammatory, antioxidant, and anti-lipidemic properties. This study aimed to evaluate the effects of capsaicin on atherosclerosis progression. METHODS: Apolipoprotein E knockout mice and their C57BL/6 controls were utilized to assess blood lipid profile, inflammatory status, and atherosclerotic lesions. We also examined the influence of capsaicin on cholesterol influx and efflux, and the role of TRPV1 and PPARγ signaling pathways in bone marrow-derived macrophages. RESULTS: Capsaicin treatment reduced weight gain, visceral adiposity, blood triglycerides, and total and non-HDL cholesterol. These improvements were associated with a reduction in atherosclerotic lesions in the aorta and carotid. Capsaicin also improved hepatic oxidative and inflammatory status. Systemic inflammation was also reduced, as indicated by reduced leukocyte rolling and adhesion on the mesenteric plexus. Capsaicin decreased foam cell formation by reducing cholesterol influx through scavenger receptor A and increasing cholesterol efflux via ATP-binding cassette transporter A1, an effect primarily linked to TRPV1 activation. CONCLUSIONS: These findings underscore the potential of capsaicin as a promising agent for atherosclerosis prevention, highlighting its comprehensive role in modulating lipid metabolism, foam cell formation, and inflammatory responses.
Assuntos
Aterosclerose , Capsaicina , Células Espumosas , Inflamação , PPAR gama , Canais de Cátion TRPV , Animais , Masculino , Camundongos , Anti-Inflamatórios/farmacologia , Aterosclerose/prevenção & controle , Aterosclerose/tratamento farmacológico , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Capsaicina/farmacologia , Colesterol/sangue , Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Inflamação/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , PPAR gama/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/metabolismoRESUMO
Ischaemic stroke is a common condition that can lead to cerebral ischaemia-reperfusion injury. Phillygenin (PHI), a natural bioactive compound derived from Forsythia suspensa, has been shown to play a crucial role in regulating inflammation across various diseases. However, its specific regulatory effects in ischaemic stroke progression remain unclear. In this study, we established a middle cerebral artery occlusion (MCAO) rat model. Treatment with PHI (50 or 100 mg/kg) significantly reduced cerebral infarction in MCAO rats. PHI treatment also mitigated the increased inflammatory response observed in these rats. Additionally, PHI suppressed microglial activation by reducing iNOS expression, a marker of M1-type polarization of microglia, and attenuated increased brain tissue apoptosis in MCAO rats. Furthermore, PHI's anti-inflammatory effects in MCAO rats were abrogated upon co-administration with GW9662, a peroxisome proliferator-activated receptor γ (PPARγ) inhibitor. In summary, PHI attenuated microglial activation and apoptosis in cerebral ischaemia-reperfusion injury through PPARγ activation, suggesting its potential as a therapeutic agent for mitigating cerebral ischaemia-reperfusion injury.
Assuntos
Apoptose , Infarto da Artéria Cerebral Média , Microglia , PPAR gama , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Animais , PPAR gama/metabolismo , Apoptose/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Ratos , Masculino , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , LignanasRESUMO
OBJECTIVE: To elucidate the therapeutic mechanism of Qingxin Jieyu Granule (QXJYG) against atherosclerosis (AS) based on network pharmacology. METHODS: The major targets and pathways of QXJYG against AS were analyzed using network pharmacology. Rat models of AS established by high-fat feeding combined with intraperitoneal vitamin D3 injection were treated daily with normal saline, atorvastatin (13.15 mg/kg), or QXJYG at 0.99, 1.98, and 3.96 g/kg for 8 weeks (n=6). Ultrasound and HE staining were used to assess the function and pathologies of the abdominal aorta. Blood lipids and serum levels of Ang â ¡, ET-1, TXA2, PGI2, and ox-LDL of the rats were detected using an automatic biochemical analyzer or ELISA. The expressions of LOX-1, PPARγ, RXRα, p-P65, VCAM-1 and ICAM-1 in the abdominal aorta were detected with immunohistochemistry. RESULTS: The rat models of AS showed obvious abdominal aorta wall thickening, increased pulse wave velocity and pulse index, decreased inner diameter of the abdominal aorta, elevated levels of TC, LDL-C, Ang â ¡, ET-1 and TXA2, and lowered levels of HDL-C and PGI2. QXJYG and atorvastatin treatment of the rat models significantly alleviated histopathological changes of the abdominal aorta, decreased serum levels of TC, LDL-C, Ang â ¡, ET-1 and TXA2, and increased the levels of HDL-C and PGI2. Network pharmacology study suggested the therapeutic effect of QXJYG against AS was mediated by regulating lipid metabolism, PPAR and NF-κB pathways. Consistently, treatments with QXJYG were found to significantly decrease ox-LDL level and LOX-1, P-P65, VCAM-1 and ICAM-1 protein expressions while increasing PPARγ and RXRα expressions in the aorta of AS rats. CONCLUSION: QXJYG alleviates lipid metabolism disorder and improves histopathological changes of the abdominal aorta of AS rats possibly by lowering ox-LDL level, reducing LOX-1 expression, activating PPARγ and RXRα, and inhibiting P65 phosphorylation to reduce VCAM-1 and ICAM-1 expression in the aorta.
Assuntos
Aterosclerose , Medicamentos de Ervas Chinesas , Metabolismo dos Lipídeos , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Ratos , Metabolismo dos Lipídeos/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aorta Abdominal/metabolismo , Aorta Abdominal/efeitos dos fármacos , Farmacologia em Rede , Lipoproteínas LDL/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , PPAR gama/metabolismo , Masculino , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Molécula 1 de Adesão de Célula Vascular/metabolismo , Ratos Sprague-Dawley , Modelos Animais de Doenças , Lipídeos/sangue , Tromboxano A2/metabolismo , Epoprostenol/análogos & derivados , Receptores Depuradores Classe ERESUMO
This study examines the therapeutic effects of Shengmai Powder (SMP) on both in vitro and in vivo models of chronic obstructive pulmonary disease (COPD) and the underlying mechanisms. Cigarette smoke and cigarette extracts were used to create in vitro and in vivo models of COPD. ELISA was used to measure the levels of pro-inflammatory factors (IL-6, TNF-α, and IL-1ß) in mouse lung tissue and alveolar macrophages. Flow cytometry assessed the phagocytic capacity of alveolar macrophage. Western blotting was used to analyze the expression of RhoA, PPARγ, IκBα, p-IκBα, P65, and p-P65 in alveolar. The results show that SMP reversed the increased levels of pro-inflammatory factors (IL-6, TNF-α, and IL-1ß) in mouse lung tissue and alveolar macrophages induced by cigarette smoke and cigarette extract. SMP also restored the decreased fluorescence intensity and RhoA levels in alveolar macrophages caused by cigarette extract. Additionally, SMP increased PPARγ expression and decreased IκBα and P65 phosphorylation in alveolar macrophages exposed to cigarette extract. Also, the effects of SMP were reversed by PPARγ inhibitors. The study concluded that SMP regulates alveolar macrophage phagocytic function through the PPAR-γ/NF-κB pathway, thereby improving the chronic inflammatory state of COPD.
Assuntos
Combinação de Medicamentos , Medicamentos de Ervas Chinesas , Macrófagos Alveolares , PPAR gama , Doença Pulmonar Obstrutiva Crônica , Animais , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/imunologia , PPAR gama/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Camundongos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Modelos Animais de Doenças , Fagocitose/efeitos dos fármacos , Humanos , Masculino , Citocinas/metabolismo , Pós , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismoRESUMO
ZLY06 is a dual agonist of peroxisome proliferator-activated receptor (PPAR) δ/γ, showing potential therapeutic effects on metabolic syndrome. However, our research has revealed that ZLY06 exhibits hepatotoxicity in normal C57BL/6J mice, though the precise mechanism remains unclear. This study aims to investigate the manifestations and mechanisms of ZLY06-induced hepatotoxicity. We administered ZLY06 via oral gavage to C57BL/6J mice (once daily for six weeks) and monitored various indicators to preliminarily explore its hepatotoxicity. Additionally, we further investigate the specific mechanisms of ZLY06-induced hepatotoxicity using PPAR inhibitors (GW9662 and GSK0660) and the Protein kinase B (AKT) activator (SC79). Results showed that ZLY06 led to increased serum ALP, ALT and AST, as well as elevated liver index and hepatic lipid levels. There was upregulation in the gene and protein expression of lipid metabolism-related molecules Acc, Scd1, Cd36, Fabp1 and Fabp2 in hepatocytes, with Cd36 showing the most significant change. Furthermore, cotreatment with SC79 significantly reduced ZLY06-induced hepatotoxicity in AML12 cells, evidenced by decreased intracellular TG levels and downregulation of CD36 expression. Specific knockdown of CD36 also mitigated ZLY06-induced hepatotoxicity. The study found that ZLY06 may bind to AKT1, inhibiting its phosphorylation activation, with the downregulation of p-AKT1 preceding the upregulation of CD36. In summary, ZLY06 mediates the upregulation of CD36 by potentially binding to and inhibiting the phosphorylation of AKT1, leading to hepatic lipid metabolism disorder and inducing liver toxicity.
Assuntos
Antígenos CD36 , Metabolismo dos Lipídeos , Fígado , Camundongos Endogâmicos C57BL , PPAR gama , Proteínas Proto-Oncogênicas c-akt , Regulação para Cima , Animais , Antígenos CD36/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosforilação/efeitos dos fármacos , Camundongos , Regulação para Cima/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , PPAR gama/agonistas , PPAR gama/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR delta/metabolismo , PPAR delta/agonistas , PPAR delta/antagonistas & inibidoresRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung epithelial phenotypes, fibroblast activation, and increased extracellular matrix deposition. Transforming growth factor-beta (TGF-ß)1-induced Smad signaling and downregulation of peroxisomal genes are involved in the pathogenesis and can be inhibited by peroxisome proliferator-activated receptor (PPAR)-α activation. However, the three PPARs, that is PPAR-α, PPAR-ß/δ, and PPAR-γ, are known to interact in a complex crosstalk. METHODS: To mimic the pathogenesis of lung fibrosis, primary lung fibroblasts from control and IPF patients with comparable levels of all three PPARs were treated with TGF-ß1 for 24 h, followed by the addition of PPAR ligands either alone or in combination for another 24 h. Fibrosis markers (intra- and extracellular collagen levels, expression and activity of matrix metalloproteinases) and peroxisomal biogenesis and metabolism (gene expression of peroxisomal biogenesis and matrix proteins, protein levels of PEX13 and catalase, targeted and untargeted lipidomic profiles) were analyzed after TGF-ß1 treatment and the effects of the PPAR ligands were investigated. RESULTS: TGF-ß1 induced the expected phenotype; e.g. it increased the intra- and extracellular collagen levels and decreased peroxisomal biogenesis and metabolism. Agonists of different PPARs reversed TGF-ß1-induced fibrosis even when given 24 h after TGF-ß1. The effects included the reversals of (1) the increase in collagen production by repressing COL1A2 promoter activity (through PPAR-ß/δ activation); (2) the reduced activity of matrix metalloproteinases (through PPAR-ß/δ activation); (3) the decrease in peroxisomal biogenesis and lipid metabolism (through PPAR-γ activation); and (4) the decrease in catalase protein levels in control (through PPAR-γ activation) and IPF (through a combined activation of PPAR-ß/δ and PPAR-γ) fibroblasts. Further experiments to explore the role of catalase showed that an overexpression of catalase protein reduced collagen production. Additionally, the beneficial effect of PPAR-γ but not of PPAR-ß/δ activation on collagen synthesis depended on catalase activity and was thus redox-sensitive. CONCLUSION: Our data provide evidence that IPF patients may benefit from a combined activation of PPAR-ß/δ and PPAR-γ.
Assuntos
Fibrose Pulmonar Idiopática , PPAR delta , PPAR gama , PPAR beta , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/genética , PPAR gama/metabolismo , PPAR gama/genética , PPAR beta/metabolismo , PPAR beta/genética , PPAR beta/agonistas , Células Cultivadas , PPAR delta/metabolismo , PPAR delta/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/efeitos dos fármacos , Peroxissomos/metabolismo , Peroxissomos/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Masculino , Fator de Crescimento Transformador beta1/metabolismo , FemininoRESUMO
With aging populations in many countries, including Japan, efforts to mitigate the aging-related decline in physical function have gained importance not only for improving individual quality of life but also for mitigating the effects of this loss of function on society. Impaired glucose tolerance, muscle weakness, and cognitive decline are well-known effects of aging. These interrelated factors can create a vicious cycle because impaired glucose tolerance can accelerate muscle weakness and cognitive decline. Unmodulated 40 Hz (u40Hz) stimulation is imperceptible to the human ear and has been reported to improve cognitive function in humans and mice. However, research on the effects of u40Hz stimulation is still limited. This study aimed to report the effects of u40Hz stimulation on glucose tolerance and muscle strength in senescence-accelerated prone (SAMP)-10 mice, a model of accelerated aging. SAMP-10 mice underwent five weeks of u40Hz stimulation followed by glucose-tolerance tests, cognitive and behavioral assessments, and frailty evaluations. In comparison with the control group, the u40Hz-stimulation group showed mitigation of age-related decline in glucose tolerance, a better frailty index (FI), and notably preserved muscle strength. Microarray analysis of stimulated muscle tissue revealed significant upregulation of ß-oxidation genes and genes functioning downstream of peroxisome proliferator-activated receptor gamma, and significant downregulation of clock genes. These findings indicate the beneficial effects of u40Hz stimulation on glucose tolerance, muscle strength, and cognitive function, warranting further research in this area.
Assuntos
Envelhecimento , Cognição , Fragilidade , Animais , Camundongos , Envelhecimento/fisiologia , Fragilidade/metabolismo , Fragilidade/terapia , Masculino , Força Muscular , PPAR gama/metabolismo , PPAR gama/genética , Teste de Tolerância a Glucose , Disfunção Cognitiva/terapia , Disfunção Cognitiva/metabolismoRESUMO
Obesity and type 2 diabetes mellitus are global public health issues. Although males show higher obesity and insulin resistance prevalence, current treatments often neglect sex-specific differences. White adipose tissue (WAT) is crucial in preventing lipotoxicity and inflammation and has become a key therapeutic target. Rosiglitazone (RSG), a potent PPARγ agonist, promotes healthy WAT growth and mitochondrial function through MitoNEET modulation. Recent RSG-based strategies specifically target white adipocytes, avoiding side effects. Our aim was to investigate whether sex-specific differences in the insulin-sensitizing effects of RSG exist on WAT during obesity and inflammation. We used Wistar rats of both sexes fed a high-fat diet (HFD, 22.5% fat content) for 16 weeks. Two weeks before sacrifice, a group of HFD-fed rats received RSG treatment (4 mg/kg of body weight per day) within the diet. HFD male rats showed greater insulin resistance, inflammation, mitochondrial dysfunction, and dyslipidemia than females. RSG had more pronounced effects in males, significantly improving insulin sensitivity, fat storage, mitochondrial function, and lipid handling in WAT while reducing ectopic fat deposition and enhancing adiponectin signaling in the liver. Our study suggests a significant sexual dimorphism in the anti-diabetic effects of RSG on WAT, correlating with the severity of metabolic dysfunction.
Assuntos
Tecido Adiposo Branco , Dieta Hiperlipídica , Resistência à Insulina , Ratos Wistar , Rosiglitazona , Animais , Rosiglitazona/farmacologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Masculino , Feminino , Dieta Hiperlipídica/efeitos adversos , Ratos , Hipoglicemiantes/farmacologia , Fatores Sexuais , Obesidade/tratamento farmacológico , Obesidade/metabolismo , PPAR gama/metabolismo , PPAR gama/agonistas , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Caracteres Sexuais , Inflamação/tratamento farmacológico , Fígado/metabolismo , Fígado/efeitos dos fármacos , Adiponectina/metabolismoRESUMO
Background/Objective: This study examined the anti-obesity effect of royal jelly (RJ) in rats fed with a high-fat diet by targeting the major pathways involved in adipogenesis and lipolysis. In addition, it examined whether this effect is AMPK-dependent. Methods: Five groups of adult male albino rats were used (n = 6 each as 1); the control rats were fed with a normal diet (2.9 kcal), and the other groups were as follows: control + RJ (300 mg/kg), HFD (4.75 kcal), HFD + RJ (300 mg/kg), and HFD + RJ (300 mg/kg) + dorsomorphin (an AMPK inhibitor) (0.2 mg/kg). Results: RJ was administered orally to all rats. With no changes in food and energy intake, RJ significantly reduced gains in body weight, fat weight, body mass index (BMI), the Lee index, abdominal circumference (AC), and the adiposity index (AI). It also reduced fasting glucose and insulin levels, HOMA-IR, and the circulatory levels of free fatty acids (FFAs), triglycerides, cholesterol, and LDL-c in the HFD-fed rats. RJ also increased serum glycerol levels and adiponectin levels, but reduced the serum levels of leptin, IL-6, and TNF-α. Moreover, RJ reduced the secretion of IL-6 and TNF-α from isolated WAT. At the tissue level, the HFD + RJ rats exhibited a smaller adipocyte size compared to the HFD rats. At the molecular level, RJ increased the phosphorylation of AMPK, SREBP1, and ACC-1 and increased the mRNA and protein levels of HSL and ATG in the WAT of the HFD rats. In concomitance, RJ increased the mRNA levels of PGC-α1, reduced the protein levels of PPARγ, and repressed the transcriptional activities of PPARγ, SREBP1, and C/EBPαß in the WAT of these rats. All the aforementioned effects of RJ were prevented by co-treatment with dorsomorphin. Conclusions: RJ exerts a potent anti-obesity effect in rats that is mediated by the AMPk-dependent suppression of WAT adipogenesis and the stimulation of lipolysis.
Assuntos
Adipogenia , Fármacos Antiobesidade , Dieta Hiperlipídica , Ácidos Graxos , Lipólise , Obesidade , Animais , Lipólise/efeitos dos fármacos , Masculino , Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Ratos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , PPAR gama/metabolismoRESUMO
Diastolic dysfunction is increasingly common in preterm infants exposed to supplemental oxygen (hyperoxia). Previous studies in neonatal mice showed hyperoxia suppresses fatty acid synthesis genes required for proliferation and survival of atrial cardiomyocytes. The loss of atrial cardiomyocytes creates a hypoplastic left atrium that inappropriately fills the left ventricle during diastole. Here, we show that hyperoxia stimulates adenosine monophosphate-activated kinase (AMPK) and peroxisome proliferator activated receptor-gamma (PPARγ) signaling in atrial cardiomyocytes. While both pathways can regulate lipid homeostasis, PPARγ was the primary pathway by which hyperoxia inhibits fatty acid gene expression and inhibits proliferation of mouse atrial HL-1 cells. It also enhanced the toxicity of hyperoxia by increasing expression of activating transcription factor (ATF) 5 and other mitochondrial stress response genes. Silencing PPARγ signaling restored proliferation and survival of HL-1 cells as well as atrial cardiomyocytes in neonatal mice exposed to hyperoxia. Our findings reveal PPARγ enhances the toxicity of hyperoxia on atrial cardiomyocytes, thus suggesting inhibitors of PPARγ signaling may prevent diastolic dysfunction in preterm infants.
Assuntos
Animais Recém-Nascidos , Átrios do Coração , Hiperóxia , Miócitos Cardíacos , PPAR gama , Transdução de Sinais , Animais , PPAR gama/metabolismo , PPAR gama/genética , Miócitos Cardíacos/metabolismo , Camundongos , Hiperóxia/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Mitocôndrias/metabolismo , Proliferação de Células , Proteínas Quinases Ativadas por AMP/metabolismo , HumanosRESUMO
Fibrosis is the basis of structural remodeling in atrial fibrillation (AF), during which inflammation is crucial. Programmed cell death factor 4 (PDCD4) is a newly identified inflammatory gene, with unknown mechanisms of action in AF. The present study aimed to elucidate the effects of PDCD4 on the inflammation and structural remodeling of atrial myocytes. For this purpose, a PDCD4 overexpression plasmid (oePDCD4) and PDCD4 small interfering (si)RNA (siPDCD4) were used to modulate PDCD4 expression in mouse atrial myocytes (HL1 cells). The expression of PDCD4 was detected using reverse transcriptionquantitative PCR and western blot analysis. The optimal drug concentrations of peroxisome proliferatoractivated receptor γ (PPARγ) agonist (pioglitazone hydrochloride), NFκB inhibitor (CBL0137), PPARγ inhibitor (GW9962) and NFκB agonist (betulinic acid) were screened using a Cell Counting Kit8 assay. The levels of inflammatory factors were detected using enzymelinked immunosorbent assays, the expression levels of fibrosisrelated proteins and NFκB subunits were detected using western blot analysis, and the expression of phosphorylated (p)p65/p65 was detected using immunofluorescence staining. The results revealed that PDCD4 overexpression increased the levels of fibrotic factors (collagen I, collagen III, fibronectin, αsmooth muscle actin and matrix metalloproteinase 2), proinflammatory cytokines (IFNγ, IL6, IL17A and TNFα) and pp65, whereas it reduced the levels of antiinflammatory cytokines (IL4) in HL1 cells. Additionally, treatment with the PPARγ agonist and NFκB inhibitor reversed the levels of fibrotic, proinflammatory and antiinflammatory factors in oePDCD4HL1 cells. By contrast, PDCD4 silencing exerted the opposite effects on fibrotic factors, proinflammatory cytokines, antiinflammatory cytokines and pp65. In addition, treatment with the PPARγ inhibitor and NFκB agonist reversed the levels of fibrotic, proinflammatory and antiinflammatory factors in siPDCD4HL1 cells. In conclusion, the present study demonstrated that PDCD4 may induce inflammation and fibrosis by activating the PPARγ/NFκB signaling pathway, thereby promoting the structural remodeling of atrial myocytes in AF.
Assuntos
Proteínas Reguladoras de Apoptose , Fibrose , Inflamação , Miócitos Cardíacos , NF-kappa B , PPAR gama , Proteínas de Ligação a RNA , Transdução de Sinais , Animais , PPAR gama/metabolismo , PPAR gama/agonistas , PPAR gama/genética , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/genética , NF-kappa B/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Linhagem CelularRESUMO
Hypospadias is one of the most common congenital anomalies of the male urogenital system, and di(2-ethylhexyl) phthalate (DEHP), a widely used endocrine-disrupting chemical (EDC), is considered a significant risk factor for this condition. Mono-2-ethylhexyl phthalate (MEHP), the toxic active metabolite of DEHP, has been proven to affect penile development and ultimately result in the hypospadias phenotype. However, while it is acknowledged that hypospadias arises from the aberrant development of multiple penile tissues, the specific impact of MEHP on human foreskin tissue development and its underlying molecular mechanisms of action remain unclear. In this study, we constructed an in vitro toxicity assay for MEHP using human foreskin fibroblasts and employed high-throughput RNA sequencing to investigate the molecular mechanisms subserving the defects in cellular function. We subsequently conducted multi-omics data analysis using public databases to analyze key target genes, and identified MMP11 as a chief downstream gene responsible for the effects of MEHP on HFF-1 cell migration. Through molecular docking analysis and molecular biology experiments, we further demonstrated that the nuclear receptor PPAR-gamma was activated upon binding with MEHP, leading to the suppression of MMP11 expression. Additionally, we found that epigenetic modifications induced by MEHP were also involved in its pathogenic effects on hypospadias. Our research highlights the crucial role of impaired cellular proliferation and migration in MEHP-induced hypospadias. We identified the MEHP/PPAR-gamma/MMP11 pathway as a novel pathogenic mechanism, providing important potential targets for future preventive strategies with respect to hypospadias.
Assuntos
Dietilexilftalato , Regulação para Baixo , Disruptores Endócrinos , Fibroblastos , Prepúcio do Pênis , Hipospadia , Metaloproteinase 11 da Matriz , Humanos , Masculino , Dietilexilftalato/toxicidade , Dietilexilftalato/análogos & derivados , Hipospadia/induzido quimicamente , Hipospadia/patologia , Fibroblastos/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Metaloproteinase 11 da Matriz/genética , Simulação de Acoplamento Molecular , Movimento Celular/efeitos dos fármacos , PPAR gama/metabolismo , PPAR gama/genéticaRESUMO
BACKGROUND: Kidney stone formation is a common disease that causes a significant threat to human health. The crystallization mechanism of calcium oxalate, the most common type of kidney stone, has been extensively researched, yet the damaging effects and mechanisms of calcium oxalate crystals on renal tubular epithelial cells remain incompletely elucidated. Regulated mitochondrial dynamics is essential for eukaryotic cells, but its role in the occurrence and progression of calcium oxalate (CaOx) nephrolithiasis is not yet understood. METHODS: An animal model of calcium oxalate-related nephrolithiasis was established in adult male SpragueâDawley (SD) rats by continuously administering drinking water containing 1% ethylene glycol for 28 days. The impact of calcium oxalate crystals on mitochondrial dynamics and apoptosis in renal tubular epithelial cells was investigated using HK2 cells in vitro. Blood samples and bilateral kidney tissues were collected for histopathological evaluation and processed for tissue injury, inflammation, fibrosis, oxidative stress detection, and mitochondrial dynamics parameter analysis. RESULTS: Calcium oxalate crystals caused higher levels of mitochondrial fission and apoptosis in renal tubular epithelial cells both in vivo and in vitro. Administration of a PPARγ agonist significantly alleviated mitochondrial fission and apoptosis in renal tubular epithelial cells, and improved renal function, accompanied by reduced levels of oxidative stress, increased antioxidant enzyme expression, alleviation of inflammation, and reduced fibrosis in vivo. CONCLUSION: Our results indicated that increased mitochondrial fission in renal tubular epithelial cells is a critical component of kidney injury caused by calcium oxalate stones, leading to the accumulation of reactive oxygen species within the tissue and the subsequent initiation of apoptosis. Regulating mitochondrial dynamics represents a promising approach for calcium oxalate nephrolithiasis.
Assuntos
Apoptose , Oxalato de Cálcio , Células Epiteliais , Túbulos Renais , Dinâmica Mitocondrial , Nefrolitíase , PPAR gama , Ratos Sprague-Dawley , Animais , Masculino , Dinâmica Mitocondrial/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Nefrolitíase/metabolismo , Nefrolitíase/tratamento farmacológico , Nefrolitíase/patologia , Ratos , PPAR gama/metabolismo , PPAR gama/agonistas , Oxalato de Cálcio/metabolismo , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Túbulos Renais/metabolismo , Apoptose/efeitos dos fármacos , Humanos , Linhagem Celular , Estresse Oxidativo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Animais de DoençasRESUMO
Pulmonary arterial hypertension is a progressive heart and lung disease that is caused by irreversible pulmonary vascular remodeling. Sinomenine hydrochloride is an alkaloid that is extracted from sinomenium acutum, which has strong anti-inflammatory effects. In this study, male rats were injected with monocrotaline, and endothelial cells were exposed to hypoxia for 24 hours to induce pulmonary arterial hypertension. Apoptosis, inflammation, and oxidative stress pathways were observed the in lungs and cells. Sinomenine hydrochloride repressed the increased right ventricular systolic pressure and attenuated the right ventricular hypertrophy and pulmonary artery remodeling in model rats. It reversed the expression of BCL2 and BAX and prevented the apoptosis of endothelial cells. Additionally, it increased the contents of IKBα and NRF2. P65, P-P65, TNFα, IL1ß, and IL6 levels in the lungs decreased by it. Malondialdehyde contents decreased, and the superoxide dismutase and glutathione peroxidase activity and HO-1 level increased in the treatment group. In vivo, it promoted apoptosis of pulmonary artery endothelial cells. Moreover, by activating PPAR-γ, sinomenine hydrochloride attains the above effects. These data suggested that sinomenine hydrochloride could protect endothelial cells, restrain inflammation and oxidative stress, and enhance pulmonary vascular remodeling.
Assuntos
Apoptose , Células Endoteliais , Hipertensão Pulmonar , Morfinanos , Estresse Oxidativo , PPAR gama , Morfinanos/farmacologia , Morfinanos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Masculino , Ratos , PPAR gama/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Ratos Sprague-Dawley , Modelos Animais de Doenças , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Remodelação Vascular/efeitos dos fármacos , Células CultivadasRESUMO
Cardiovascular diseases remain the leading cause of death in the world, and that is why finding an effective and multi-functional treatment alternative to combat these diseases has become more important. Fibrates and thiazolidinediones, peroxisome proliferator-activated receptors alpha and gamma are the pharmacological therapies used to treat dyslipidemia and type 2 diabetes, respectively. New mechanisms of action of these drugs have been found, demonstrating their pleiotropic effects, which contribute to preserving the heart by reducing or even preventing myocardial damage. Here, we review the mechanisms underlying the cardioprotective effects of PPAR agonists and regulating morphological and physiological heart alterations (metabolic flexibility, mitochondrial damage, apoptosis, structural remodeling, and inflammation). Moreover, clinical evidence regarding the cardioprotective effect of PPAR agonists is also addressed.
Assuntos
Miocárdio , PPAR alfa , PPAR gama , Humanos , PPAR gama/agonistas , PPAR gama/metabolismo , PPAR alfa/agonistas , PPAR alfa/metabolismo , Miocárdio/patologia , Miocárdio/metabolismo , Animais , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêuticoRESUMO
Prostate apoptosis response-4 (Par-4, also known as PAWR) is a ubiquitously expressed tumor suppressor protein that induces apoptosis selectively in cancer cells, while leaving normal cells unaffected. Our previous studies indicated that genetic loss of Par-4 promoted hepatic steatosis, adiposity, and insulin-resistance in chow-fed mice. Moreover, low plasma levels of Par-4 are associated with obesity in human subjects. The mechanisms underlying obesity in rodents and humans are multi-faceted, and those associated with adipogenesis can be functionally resolved in cell cultures. We therefore used pluripotent mouse embryonic fibroblasts (MEFs) or preadipocyte cell lines responsive to adipocyte differentiation cues to determine the potential role of Par-4 in adipocytes. We report that pluripotent MEFs from Par-4-/- mice underwent rapid differentiation to mature adipocytes with an increase in lipid droplet accumulation relative to MEFs from Par-4+/+ mice. Knockdown of Par-4 in 3T3-L1 pre-adipocyte cultures by RNA-interference induced rapid differentiation to mature adipocytes. Interestingly, basal expression of PPARγ, a master regulator of de novo lipid synthesis and adipogenesis, was induced during adipogenesis in the cell lines, and PPARγ induction and adipogenesis caused by Par-4 loss was reversed by replenishment of Par-4. Mechanistically, Par-4 downregulates PPARγ expression by directly binding to its upstream promoter, as judged by chromatin immunoprecipitation and luciferase-reporter studies. Thus, Par-4 transcriptionally suppresses the PPARγ promoter to regulate adipogenesis.