RESUMO
BACKGROUND: Single-cell RNA sequencing, also known as scRNA-seq, is a method profiling cell populations on an individual cell basis. It is particularly useful for more deeply understanding cell behavior in a complicated tumor microenvironment. Although several previous studies have examined scRNA-seq for hepatocellular carcinoma (HCC) tissues, no one has tested and analyzed HCC with different stages. METHODS: In this investigation, immune cells isolated from surrounding normal tissues and cancer tissues from 3 II-stage and 4 III-stage HCC cases were subjected to deep scRNA-seq. The analysis included 15 samples. We distinguished developmentally relevant trajectories, unique immune cell subtypes, and enriched pathways regarding differential genes. Western blot and co-immunoprecipitation were performed to demonstrate the interaction between fatty acid binding protein 1 (FABP1) and peroxisome proliferator-activated receptor gamma(PPARG). In vivo experiments were performed in a C57BL/6 mouse model of HCC established via subcutaneous injection. RESULTS: FABP1 was discovered to be overexpressed in tumor-associated macrophages (TAMs) with III-stage HCC tissues compared with II-stage HCC tissues. This finding was fully supported by immunofluorescence detection in significant amounts of HCC human samples. FABP1 deficiency in TAMs inhibited HCC progression in vitro. Mechanistically, FABP1 interacted with PPARG/CD36 in TAMs to increase fatty acid oxidation in HCC. When compared with C57BL/6 mice of the wild type, tumors in FABP1-/- mice consistently showed attenuation. The FABP1-/- group's relative proportion of regulatory T cells and natural killer cells showed a downward trend, while dendritic cells, M1 macrophages, and B cells showed an upward trend, according to the results of mass cytometry. In further clinical translation, we found that orlistat significantly inhibited FABP1 activity, while the combination of anti-programmed cell death 1(PD-1) could synergistically treat HCC progression. Liposomes loaded with orlistat and connected with IR780 probe could further enhance the therapeutic effect of orlistat and visualize drug metabolism in vivo. CONCLUSIONS: ScRNA-seq atlas revealed an FABP1-dependent immunosuppressive environment in HCC. Orlistat significantly inhibited FABP1 activity, while the combination of anti-PD-1 could synergistically treat HCC progression. This study identified new treatment targets and strategies for HCC progression, contributing to patients with advanced HCC from new perspectives.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/patologia , Proteínas de Ligação a Ácido Graxo/genética , Imunossupressores/uso terapêutico , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , Orlistate/farmacologia , Orlistate/uso terapêutico , PPAR gama/metabolismo , PPAR gama/farmacologia , PPAR gama/uso terapêutico , RNA/farmacologia , RNA/uso terapêutico , Microambiente TumoralRESUMO
Black phosphorus (BP) exhibits significant potential for clinical applications. However, further research is necessary to uncover the unknown biological functions of BP and broaden its applications across various fields. This study investigates the potential of BP as a targeting PPAR-γ agonist to overcome chemoresistance in the treatment of pancreatic adenocarcinoma (PAAD) using 2D and 3D cell lines, patient-derived organoids (PDOs), and mouse models. RNA-sequencing analysis shows that BP treatment enriches differentially expressed genes in the PPAR pathway, and molecular modeling predicts the potential docking site between BP and PPAR-γ. Transcriptional activity assays are further to verify the activation of PPAR-γ. BP-activated PPAR-γ inhibits cancer stem cell (CSC) properties and expression of biomarkers such as CD44 and c-Myc, which are involved in chemoresistance. Notably, CD44 overexpression in tumor cells renders them susceptible to BP while insensitive to gemcitabine. This indicates that BP preferentially targets stem-like cells, which exhibit heightened resistance to chemotherapeutic drugs. A combination treatment strategy involving BP and gemcitabine is developed, demonstrating enhanced treatment efficacy of PAAD in both in vitro and in vivo models. Thus, BP serves as a PPAR-γ agonist capable of reversing chemoresistance, establishing it as a potent anti-tumor approach for the treatment of PAAD.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Agonistas PPAR-gama , Resistencia a Medicamentos Antineoplásicos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Gencitabina , PPAR gama/metabolismo , PPAR gama/uso terapêutico , Organoides/patologia , Linhagem Celular Tumoral , Neoplasias PancreáticasRESUMO
BACKGROUND: Adiposity and non-alcoholic fatty liver disease (NAFLD) are common characteristics of metabolic syndrome (MS). Understanding the underlying pathogenesis is crucial for the development of new remedies. Resveratrol controls obesity and glycemic disorders in patients with MS. OBJECTIVES: This study aimed to evaluate the effect of resveratrol and dulaglutide on adipose tissues and liver in rats with MS, declaring their possible mechanisms. METHODS: Rats allocated as Control, MS (induced by a high fat/ high sucrose diet for eight weeks), MS + Resveratrol (30 mg/kg/day orally), and MS + Dulaglutide (0.6 mg/kg twice weekly SC); drugs administration was in the last four weeks. Serum biochemical measurements were done. Liver and visceral fat were processed for biochemistry, histopathology, and immunohistochemistry. RESULTS: MS results demonstrated significantly increased systolic and diastolic blood pressure, anthropometric measurements, serum levels of alanine aminotransferase (ALT), glycemic indices, and lipids with decreased HDL-C. Tissue levels of leptin, malondialdehyde (MDA), and TNF-α reactivity significantly increased. Expression of adiponectin, PPARγ, and insulin growth factor-1 (IGF-1) decreased. Also, Western blotting mRNA gene expression of liver SIRT-1 was down-regulated. Resveratrol and dulaglutide significantly and effectively reversed MS complexity, ameliorating all findings, particularly NAFLD and adiposity-induced inflammation. Resveratrol significantly appears superior to dulaglutide regarding the effects on hemodynamics, lipids, adipokines, IGF-1 levels, and adipocyte size. Parallel, dulaglutide has more influence on glycemic control. CONCLUSION: Protective effects of the drugs may be through correlations between SIRT-1/adipokines/IGF-1 and PPARγ, improving the cross-talk between insulin resistance, obesity markers, liver dysfunction, and TNF-α. Promising multi-beneficial therapies of resveratrol or dulaglutide in MS are recommended clinically for this purpose. Showing the Experimental Design.
Assuntos
Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Resveratrol/farmacologia , Resveratrol/metabolismo , Resveratrol/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Insulina , Adipocinas/metabolismo , Adipocinas/farmacologia , Adipocinas/uso terapêutico , PPAR gama/metabolismo , PPAR gama/farmacologia , PPAR gama/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Fator de Crescimento Insulin-Like I/uso terapêutico , Adiposidade , Fator de Necrose Tumoral alfa , Fígado , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Dieta , Lipídeos , Dieta HiperlipídicaRESUMO
The clinically used glitazones (rosiglitazone and pioglitazone) for type 2 diabetes mellitus therapy have been linked to serious side effects such as fluid retention, congestive heart failure, weight gain, bone loss, and an increased risk of bladder cancer. The complete activation of PPAR-γ receptors in target tissues is linked to these effects. Many studies have demonstrated that partial PPAR-γ activators (GW0072, PAT5A, GQ16) give equivalent therapeutic benefits to full PPAR-γ agonists without the associated side effects. These breakthroughs cleared the path for the development of partial agonists or selective PPAR-γ modulators (SPPARγMs). This study combined pharmacophore modeling, molecular docking, and an adipogenesis experiment to identify thiazolidine analogs as SPPARMs/partial agonists. A custom library of 220 molecules was created and virtual screened to discover 90 compounds as SPPARγMs/ partial agonists. The chosen eight compounds were synthesized and tested for adipogenesis using 3T3L1 cell lines. These compounds' partial agonistic activity was evaluated in 3T3L1 cell lines by comparing their capacity to stimulate PPAR-γ mediated adipogenesis to that of a full agonist, rosiglitazone. The findings of the adipogenesis experiment demonstrate that all eight compounds examined had a partial potential to stimulate adipogenesis when compared to the full agonist, rosiglitazone. The current investigation identified eight possible PPAR-γ partial agonists or SPPARγMs that may be effective in the treatment of type 2 diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2 , Tiazolidinedionas , Humanos , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , PPAR gama/agonistas , PPAR gama/metabolismo , PPAR gama/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Simulação de Acoplamento Molecular , Adipogenia , Farmacóforo , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêuticoRESUMO
The present study evaluated the effects of Hail Salvia officinalis total extract (SOTE) and its high flavonoid fraction (SOHFF) on the high-fat diet (HFD)-induced obesity and hepatorenal damage in rats. Salvia officinalis plants were collected from Hail region, Saudi Arabia. Rats were fed HFD and supplemented orally with SOTE (250 mg kg-1) or SOHFF (100 mg kg-1) or simvastatin (SVS; 10 mg kg-1) every day for 8 weeks. Compared to the controls, HFD-induced obesity led to significant increases in body weight, body weight gained, blood insulin, leptin, cardiac enzymes (LDH and CPK) activity, and atherogenic index (AI). HFD rats also showed higher levels of hepatic and renal function biomarkers (ALT, urea, and creatinine), as well as lower levels of PPARγ and Nrf2-gene expression and a disrupted lipid profile. Moreover, HFD rats had lower levels of hepatic and renal antioxidant biomarkers (CAT, GPx, SOD, GR, and GSH), accompanied by higher levels of hepatic and renal lipid peroxidation (LPO), nitric oxide (NO), and inflammatory mediators (interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α)). In addition, histological examination of hepatic and renal tissues revealed histopathological changes that validated the biochemical findings. Compared to HFD group, SOTE and SOHFF treatment led to marked amelioration of all the aforementioned parameters. Collectively, supplementation with SOTE and SOHFF effectively reversed HFD-induced alterations through its antioxidant, hypolipidemic, and anti-inflammatory properties. Hence, SOTE and SOHFF have therapeutic potential in controlling obesity and related pathologies.
Assuntos
Insulinas , Salvia officinalis , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Peso Corporal , Creatinina , Dieta Hiperlipídica/efeitos adversos , Flavonoides/farmacologia , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/farmacologia , Mediadores da Inflamação/uso terapêutico , Insulinas/metabolismo , Insulinas/farmacologia , Insulinas/uso terapêutico , Interleucina-1beta/metabolismo , Leptina , Lipídeos , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/farmacologia , Obesidade , Estresse Oxidativo , PPAR gama/metabolismo , PPAR gama/farmacologia , PPAR gama/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Sinvastatina , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ureia/farmacologiaRESUMO
Poly-L-lactic acid (PLLA) is considered to be a promising candidate material for biodegradable vascular scaffolds (BVS) in percutaneous coronary intervention (PCI). But, PLLA-BVS also faces the challenge of thrombosis (ST) and in-stent restenosis (ISR) caused by in-stent neo-atherosclerosis (ISNA) associated with inflammatory reactions in macrophage-derived foam cells. Our previous studies have confirmed that curcumin alleviates PLLA-induced injury and inflammation in vascular endothelial cells, but it remains unclear whether curcumin can alleviate the effect of inflammatory reactions in macrophage-derived foam cells while treated with degraded product of PLLA. In this study, PLLA-BVS was implanted in the porcine coronary artery to examine increased macrophages and inflammatory cytokines such as NF-κb and TNF-α by histology and immunohistochemistry. In vitro, macrophage-derived foam cells were induced by Ox-LDL and observed by Oil Red Staining. Foam cells were treated with pre-degraded PLLA powder, curcumin and PPARγ inhibitor GW9662, and the expression of IL-6, IL-10, TNF-α, NF-κb, PLA2 and PPARγ were investigated by ELISA or RT-qPCR. This study demonstrated that the macrophages and inflammatory factors increased after PLLA-BVS implantation in vivo, and foam cells derived from macrophages promoted inflammation by products of PLLA degradation in vitro. This present study was found that the inflammation of foam cells at the microenvironment of PLLA degraded products were significantly increased, and curcumin can attenuate the inflammation caused by the PLLA degradation via PPARγ signal pathway. In addition, curcumin should be further studied experimentally in vivo experiments on animal models as a potential therapeutic to reduce ISNA of PLLA-BVS. Graphical abstract.
Assuntos
Aterosclerose , Curcumina , Intervenção Coronária Percutânea , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Curcumina/farmacologia , Curcumina/uso terapêutico , Células Endoteliais , Células Espumosas/patologia , Inflamação/patologia , Macrófagos/metabolismo , PPAR gama/metabolismo , PPAR gama/farmacologia , PPAR gama/uso terapêutico , Poliésteres , Transdução de Sinais , SuínosRESUMO
Introduction. Diabetes is a chronic disease associated with important comorbidities. Type 2 diabetes (T2DM) is associated with a three times increased risk of hip fracture but reports describing potential associations with vertebral fractures (VF) are contradictory. Our objective was to evaluate the factors involved in the prevalent VF in women with and without T2DM. Materials and methods. A cross-sectional design was used and the relationship between morphometric VF and T2DM in adult women was evaluated. The cases were adult women with morphometric VF and the controls were adult women without VF. Thoracic and spinal radiographs in lateral and antero-posterior projections were obtained. Bone mineral density (BMD) values of the lumbar spine (L-BMD) were measured by DXA. Results. A greater number of women with T2DM were found in the VF group (61% vs 31.5%). Non-T2DM women with VF were significantly older and with lower L-BMD than non-T2DM without VF. We observed a negative correlation between age and L-BMD (r=-0.463) in non-T2DM women, but not in the T2DM with FV group. T2DM was a risk factor for prevalent VF with OR of 3.540 (IC95% 1.750-7.160). Conclusion. Our study showed a higher prevalence of T2DM in the VF group. T2DM women with VF were younger and had higher L-BMD than non-T2DM women, L-BMD did not correlate with age and VF were not distributed according to BMD-L and age. (AU)
Introducción. La diabetes es una enfermedad crónica asociada con comorbilidades importantes. La diabetes tipo 2 (DM2) se asocia con un riesgo tres veces mayor de fractura de cadera pero la asociación con fracturas vertebrales (FV) es contradictoria. Nuestro objetivo fue evaluar los factores involucrados en las FV prevalentes en mujeres adultas con y sin DM2. Materiales y métodos. Se realizó un diseño transversal y se evaluó la relación entre FV morfométrica y DM2 en mujeres adultas. Los casos fueron mujeres adultas con FV morfométricas y los controles fueron mujeres adultas sin FV. Se obtuvieron radiografías torácicas y espinales en proyecciones lateral y anteroposterior. Los valores de densidad mineral ósea (DMO) de la columna lumbar (DMO-L) se midieron por DXA. Resultados. Se observó un mayor número de mujeres con DM2 en el grupo de FV (61% frente a 31.5%). Las mujeres sin DM2 con FV eran significativamente mayores y con una DMO-L más baja que las mujeres sin DM2 sin FV. Observamos una correlación negativa entre la edad y la DMO-L (r= -0.463) en mujeres sin DM2 y FV, pero no en DM2 con FV. La DM2 fue un factor de riesgo para FV prevalente con un OR 3.540 (IC95% 1.750-7.160). Conclusión. Nuestro estudio demostró una mayor prevalencia de DM2 en el grupo de FV. Las mujeres con DM2 y FV eran más jóvenes y tenían mayor DMO-L que las mujeres sin DM2, la DMO-L no correlacionó con la edad y las FV no se distribuyeron de acuerdo a la DMO-L y edad. (AU)
Assuntos
Humanos , Feminino , Adulto , Adulto Jovem , Fraturas da Coluna Vertebral/microbiologia , Diabetes Mellitus Tipo 2/complicações , Osteoporose/complicações , Vitamina D/sangue , Absorciometria de Fóton , Densidade Óssea , Estudos Transversais , Fatores de Risco , Fraturas da Coluna Vertebral/induzido quimicamente , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fatores Etários , Tiazolidinedionas/uso terapêutico , PPAR gama/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Rosiglitazona/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Pioglitazona/uso terapêutico , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêuticoRESUMO
We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARγ activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-a]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPARγ ligands) was tolerable even with oral administration at 200â¯mg/kg in healthy mice.
Assuntos
Antineoplásicos/uso terapêutico , PPAR gama/uso terapêutico , Antineoplásicos/farmacologia , Humanos , Ligantes , PPAR gama/farmacologiaRESUMO
Peroxisome proliferator-activated receptor gamma (PPARγ) has been the focus of intense research because ligands for this receptor have emerged as potent insulin sensitizers used in the treatment of type 2 diabetes. There have been described three PPAR isotypes α, δ and γ which have an integrated role in controlling the expression of genes playing key roles in the storage and mobilization of lipids, in glucose metabolism, in morphogenesis and inflammatory response. Recent advances include the discovery of novel genes that are regulated by PPARγ, which helps to explain how activation of this adipocyte predominant transcription factor regulates glucose and lipid homeostasis. Increased levels of circulating free fatty acids and lipid accumulation in non-adipose tissue have been implicated in the development of insulin resistance. This situation is improved by PPARγ ligands, which promotes fatty acid storage in fat deposits and regulates the expression of adipocyte-secreted hormones that impacts on glucose homeostasis. So the net result of the pleiotropic effects of PPARγ ligands is improvement of insulin sensitivity. This review highlights the roles that PPAR gamma play in the regulation of gene expression of multiple diseases including obesity, diabetes and cancer and highlights the gene isolation transformation role. Further studies are needed for the transformation of PPAR gamma gene in plants and evaluate in animals for the treatment of type 2 diabetes.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , PPAR alfa/agonistas , PPAR gama/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Regulação da Expressão Gênica , Homeostase , Humanos , Resistência à Insulina/genética , Ligantes , Terapia de Alvo Molecular , PPAR gama/genética , PPAR gama/uso terapêutico , Transcrição GênicaRESUMO
Recent research has drawn attention to protective effects of chemopreventive agents that reverse, suppress, or prevent the carcinogenic progression using pharmacological or nutritional agents. Aspirin and celecoxib are the promising preventive agents to effectively reduce the risk of colorectal cancer, but such agents are associated with severe gastrointestinal and cardiovascular side effects in long-term administration at high doses. Recently, the strategy that combinational use with several chemopreventive agents at low doses induces greater inhibition of carcinogenesis has become the focus. The nonsteroidal anti-inflammatory drugs (NSAIDs) may combine with ornithine decarboxylase inhibitors, hydroxymethylglutaryl-CoA reductase inhibitors, epidermal growth factor signaling inhibitors, peroxisome proliferator-activated receptor-γ ligands, and tumor necrosis factor-related apoptosis-inducing ligand, to magnify the chemoprophylactic effect. It is noteworthy that the phase III trial of difluoromethylornithine combination with sulidac has shown greater and effective preventive roles, which pave the way for the use of combinations of other agents. The long-term statins and low-dose NSAIDs have also been associated with risk reduction in vitro, in vivo, and in retrospective studies; however, the data are inconsistent. Epidermal growth factor signaling inhibitors, peroxisome proliferator-activated receptor-γ ligands and tumor necrosis factor-related apoptosis-inducing ligand have been demonstrated to potentiate the preventive effects of NSAIDs in vitro and in vivo, but these combinational regimens have not yet been applied to clinical research. The major goal of this study was to review combination chemoprevention for colorectal cancer by means of combining low doses of potential preventive agents to increase their chemoprophylaxis efficacy and to minimize toxicity.
Assuntos
Anticarcinógenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/prevenção & controle , Anti-Inflamatórios não Esteroides/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Eflornitina/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/uso terapêutico , Previsões , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , PPAR gama/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêuticoRESUMO
Pulmonary hypertension is a rare disease in neonates, infants, and children, and is associated with substantial morbidity and mortality. An adequate understanding of the controlling pathophysiologic mechanisms is lacking. Moreover, a minority of research is focused specifically on neonatal and pediatric populations. Although therapeutic options have increased over the past several decades, they remain limited. In advanced pulmonary hypertension, progressive pulmonary vascular functional and structural changes ultimately cause increased pulmonary vascular impedance, right-ventricular failure, and death. Management includes the prevention and/or treatment of active pulmonary vasoconstriction, the support of right-ventricle function, treatment of the underlying disease (if possible), and the promotion of regressive remodeling of structural pulmonary vascular changes. Most currently available therapies augment or inhibit factors, or mediators of their downstream signaling cascades, that originate in the pulmonary vascular endothelium. These pathways include nitric-oxide/cyclic guanosine monophosphate (cGMP), prostacyclin, and endothelin-1. The ability to reverse advanced structural changes remains an as yet unattained goal. This paper reviews the epidemiology, pathophysiology, current treatments, and emerging therapies related to neonatal and pediatric pulmonary hypertension.
Assuntos
Hipertensão Pulmonar/terapia , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Bosentana , Criança , Citrulina/farmacologia , Citrulina/uso terapêutico , Quimioterapia Combinada , Endotélio Vascular/fisiopatologia , Hemodinâmica , Humanos , Hipertensão Pulmonar/classificação , Hipertensão Pulmonar/fisiopatologia , Lactente , Recém-Nascido , Contração Muscular/fisiologia , PPAR gama/farmacologia , PPAR gama/uso terapêutico , Síndrome da Persistência do Padrão de Circulação Fetal/fisiopatologia , Síndrome da Persistência do Padrão de Circulação Fetal/terapia , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Prostaglandinas/farmacologia , Prostaglandinas/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Citrato de Sildenafila , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Sulfonas/farmacologia , Sulfonas/uso terapêutico , Resistência Vascular/fisiologia , Vasoconstrição/fisiologia , Função Ventricular DireitaRESUMO
Pulmonary alveolar proteinosis (PAP) is a lung disease characterized by a deficiency of functional granulocyte macrophage colony-stimulating factor (GM-CSF) resulting in surfactant accumulation and lipid-engorged alveolar macrophages. GM-CSF is a positive regulator of PPARγ that is constitutively expressed in healthy alveolar macrophages. We previously reported decreased PPARγ and ATP-binding cassette transporter G1 (ABCG1) levels in alveolar macrophages from PAP patients and GM-CSF knockout (KO) mice, suggesting PPARγ and ABCG1 involvement in surfactant catabolism. Because ABCG1 represents a PPARγ target, we hypothesized that PPARγ restoration would increase ABCG1 and reduce macrophage lipid accumulation. Upregulation of PPARγ was achieved using a lentivirus expression system in vivo. GM-CSF KO mice received intratracheal instillation of lentivirus (lenti)-PPARγ or control lenti-eGFP. Ten days postinstillation, 79% of harvested alveolar macrophages expressed eGFP, demonstrating transduction. Alveolar macrophages showed increased PPARγ and ABCG1 expression after lenti-PPARγ instillation, whereas PPARγ and ABCG1 levels remained unchanged in lenti-eGFP controls. Alveolar macrophages from lenti-PPARγ-treated mice also exhibited reduced intracellular phospholipids and increased cholesterol efflux to HDL, an ABCG1-mediated pathway. In vivo instillation of lenti-PPARγ results in: 1) upregulating ABCG1 and PPARγ expression of GM-CSF KO alveolar macrophages, 2) reducing intracellular lipid accumulation, and 3) increasing cholesterol efflux activity.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , PPAR gama/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Colesterol/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/deficiência , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Humanos , Lipídeos/fisiologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Camundongos Knockout , PPAR gama/metabolismo , PPAR gama/uso terapêutico , Proteinose Alveolar Pulmonar/tratamento farmacológico , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/metabolismo , Surfactantes Pulmonares/metabolismoRESUMO
OBJECTIVE: The pathogenesis of non-alcoholic steatohepatitis is still unclear. We have demonstrated previously that peroxisome proliferator activated receptor gamma (PPARγ) ligand protects against inflammation and fibrogenesis in experimental non-alcoholic steatohepatitis. We aim to elucidate the effect and the mechanism of PPARγ itself on nutritional fibrotic steatohepatitis in mice. METHODS: C57BL/6J mice were fed with methionine-choline deficient (MCD) diet for 8 weeks to induce fibrotic steatohepatitis. Mice fed the MCD diet were treated with adenovirus carrying PPARγ (Ad-PPARγ), Ad-PPARγ plus PPARγ agonist rosiglitazone, or PPARγ antagonist 2-chloro-5-nitrobenzaniliden (GW9662), respectively. The effects of up-regulation of PPARγ in the presence or absence of its agonist/or antagonist were assessed by comparing the severity of hepatic injury, activation of hepatic stellate cells and the expression of adiponectin, heme oxygenase-1, and fibrogenic related genes. RESULTS: Mice fed with MCD diet for 8 weeks showed severe hepatic injury including hepatic steatosis, inflammatory infiltration, and fibrosis. Administration of Ad-PPARγ significantly lowered serum alanine aminotransferase level and ameliorated hepatic steatosis, necroinflammation, and fibrosis. These effects were associated with enhanced expression of PPARγ, up-regulated expression of adiponectin and heme oxygenase-1, and down-regulated expression of tumor necrosis factor alpha, interleukin-6, α-smooth muscle actin, transforming growth factor beta 1, matrix metallopeptidase-2, and -9. Administration of GW9662 promoted the severity of liver histology. CONCLUSIONS: The present study provided evidences for the protective role of overexpressing PPARγ in ameliorating hepatic fibrosing steatohepatitis in mice. Modulation of PPARγ expression might serve as a therapeutic approach for fibrotic steatohepatitis.
Assuntos
Fígado Gorduroso/prevenção & controle , Vetores Genéticos/administração & dosagem , PPAR gama/biossíntese , PPAR gama/uso terapêutico , Adenoviridae/genética , Anilidas/administração & dosagem , Animais , Colina , Dieta , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Inflamação/genética , Inflamação/fisiopatologia , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Cirrose Hepática Experimental , Masculino , Metionina/deficiência , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/administração & dosagem , PPAR gama/genética , Distribuição Aleatória , Rosiglitazona , Tiazolidinedionas/administração & dosagem , Transfecção , beta-Galactosidase/administração & dosagem , beta-Galactosidase/genéticaRESUMO
Progressive hepatic fibrosis is the final common pathway for most chronic liver injuries, leading to cirrhosis with risk of liver failure and hepatocellular carcinoma. It is now recognized that fibrosis is a dynamic process, and may be reversible prior to the establishment of advanced architectural changes to the liver. The most effective antifibrotic strategy is to cure the underlying disease process before advanced fibrosis has developed. Unfortunately, this is often not possible, and specific antifibrotic therapies are needed. Advances in the understanding of the pathogenesis of liver fibrosis have identified several potential novel therapeutic targets, but unfortunately clinical development has been disappointing. One major limitation has been the often prolonged natural history of fibrosis compared to experimental models, and difficulties in accurate noninvasive fibrosis assessment, thus making clinical trial design difficult. In this review, we highlight the most promising current antifibrotic strategies.
Assuntos
Angiotensina II/antagonistas & inibidores , Inibidores de Caspase , Interferon gama/uso terapêutico , Cirrose Hepática/tratamento farmacológico , PPAR gama/uso terapêutico , Humanos , Interferon-alfa/uso terapêuticoRESUMO
The acute phase of Trypanosoma cruzi infection is associated with a strong inflammatory reaction in the heart characterised by a massive infiltration of immune cells that is dependent on the T. cruzi strain and the host response. 15d-PGJ2 belongs to a new class of anti-inflammatory compounds with possible clinical applications. We evaluated the effects of 15d-PGJ2 administered during the acute phase of T. cruzi infection in mice. Mice were infected with the Colombian strain of T. cruzi and subsequently treated with 15d-PGJ2 repeatedly for seven days. The inflammatory infiltrate was examined by histologic analysis. Slides were immunohistochemically stained to count the number and the relative size of parasite nests. Infection-induced changes in serum cytokine levels were measured by ELISA. The results demonstrated that treatment with 15d-PGJ2 reduced the inflammatory infiltrate in the skeletal muscle at the site of infection and decreased the number of lymphocytes and neutrophils in the blood. In addition, we found that 15d-PGJ2 led to a decrease in the relative volume density of amastigote nests in cardiac muscle. T. cruzi-infected animals treated with 15d-PGJ2 displayed a statistically significant increase in IL-10 levels with no change in IFN-ã levels. Taken together, we demonstrate that treatment with 15d-PGJ2 in the acute phase of Chagas disease led to a controlled immune response with decreased numbers of amastigote nests, as measured by the volume density.
Assuntos
Animais , Masculino , Camundongos , Doença de Chagas/tratamento farmacológico , Interferon gama/imunologia , /imunologia , PPAR gama/agonistas , /análogos & derivados , Doença de Chagas/imunologia , Doença de Chagas/patologia , Ensaio de Imunoadsorção Enzimática , Imunidade Celular , Imuno-Histoquímica , PPAR gama/uso terapêutico , /uso terapêuticoRESUMO
Accumulating evidences have shown that thiazolidinediones (TZDs), PPARgamma ligands, could exert anti-cancer actions in several human cancer cells. TZDs are capable to inducing growth inhibition, apoptosis and inhibition of cell invasion, thereby leading to their anti-cancer effects. The growth inhibition was mediated by a cyclin-dependent kinase inhibitor, p27(Kip1), accumulation which is induced by both inhibition of ubiquitylation of p27(Kip1) and reduction of degradation activity of p27(Kip1) by proteasome. In addition, a recent clinical observation has showed a 33% reduction in lung cancer risk among TZD users who have diabetes mellitus compared with nonusers, strongly suggesting TZDs possess clinically relevant actions. These results suggest that TZDs may be novel agents to treat malignant tumor.
Assuntos
Antineoplásicos/farmacologia , PPAR gama/farmacologia , Tiazolidinedionas/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Ligantes , Neoplasias/tratamento farmacológico , PPAR gama/uso terapêutico , Tiazolidinedionas/uso terapêuticoAssuntos
Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , Síndrome do Ovário Policístico/tratamento farmacológico , Reprodução/efeitos dos fármacos , Tiazolidinedionas/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Feminino , Hormônio Foliculoestimulante/sangue , Seguimentos , Humanos , Incidência , Hormônio Luteinizante/sangue , PPAR gama/administração & dosagem , PPAR gama/uso terapêutico , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Radioimunoensaio , Fatores de Risco , Rosiglitazona , Federação Russa/epidemiologia , Testosterona/sangue , Tiazolidinedionas/administração & dosagem , Resultado do Tratamento , Adulto JovemRESUMO
Glioblastoma represent the most common primary brain tumor in adults and are currently considered incurable. We investigated antiproliferative and anti-invasive mechanisms of 6-OH-11-O-hydroxyfenantrene (IIF), a retinoid X receptor ligand, and pioglitazone (PGZ), a peroxisome proliferator-activated receptor gamma activator, in three different glioblastoma cell lines. A dose-dependent reduction of tumor invasion and strong decrease of matrix metalloproteinases 2 and 9 expression was observed, especially when a combination therapy of IIF and PGZ was administered. Combined treatment also markedly reduced proliferation and induced apoptosis in all glioma cell lines tested. This was in particular accompanied by decrease of antiapoptotic proteins Bcl2 and p53, while simultaneously pro-apoptotic cytochrome c, cleaved caspase 3, Bax and Bad levels increased. These in vitro findings were further substantiated in a murine glioma model in vivo, where oral administration of PGZ and IIF resulted in significantly reduced tumor volume and proliferation. Of note, treatment with nuclear receptor ligands was not only effective when the treatment was initiated shortly after the intraparenchymal seeding of the glioma cells, but even when initiated in the last third of the observation period. Collectively, our results demonstrate the effectiveness of a combined treatment of ligands of proliferator-activated receptor and retinoid X receptor against glioblastoma.