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1.
Gynecol Obstet Invest ; 87(1): 79-88, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35500567

RESUMO

OBJECTIVE: In the present study, we attempted to identify the effects of fenofibrate on human cervical cancer cells. METHODS: The cytotoxicity of fenofibrate in cervical cancer cells was determined by Cell Counting Kit-8. Immunoblotting assay was used to determine the protein expression of caspase-3, poly ADP-ribose polymerase cleavage, B-cell lymphoma 2 family protein expression, microtubule-associated protein 1A/1B-light chain 3 (LC3), as well as cyclins and cyclin-dependent kinases. Immunofluorescence imaging was used to determine the expression of cleaved caspase-3 and LC3. Flow cytometry was used to determine cell cycle and apoptosis. RESULTS: We first showed that fenofibrate treatment reduced cell viability in HeLa cervical cancer cells in a dose-dependent manner at 24 h and 48 h. Importantly, fenofibrate-induced cell death was mediated through cell cycle arrest in the G0-G1 phase and caspase-dependent apoptosis. Moreover, fenofibrate also induced autophagy activation in a dose-dependent manner and pharmacological inhibition of autophagy led to increase of sub-G1 phase and caspase-dependent cell death in HeLa cells. CONCLUSION: In conclusion, these data demonstrated that fenofibrate initially induced cell cycle arrest, followed by caspase-3-dependent cell death in cervical cancer HeLa cells. However, fenofibrate also induced autophagy activation, which is closely related to the survival of diverse cancer cells, thus reducing the anticancer effects of fenofibrate. Therefore, the combination of an autophagy inhibitor and fenofibrate might have the potential to become a new therapeutic strategy for cervical cancer.


Assuntos
Fenofibrato , Neoplasias do Colo do Útero , Apoptose , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular , Feminino , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Células HeLa , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo
2.
Life Sci Alliance ; 5(7)2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35396335

RESUMO

The InterFeron-Induced TransMembrane proteins (IFITMs) are members of the dispanin/CD225 family that act as broad viral inhibitors by preventing viral-to-cellular membrane fusion. In this study, we uncover egress from the Golgi as an important step in the biology of IFITM3 by identifying the domain that regulates this process and that similarly controls the egress of the dispanins IFITM1 and PRRT2, protein linked to paroxysmal kinesigenic dyskinesia. In the case of IFITM3, high levels of expression of wild-type, or mutations in the Golgi egress domain, lead to accumulation of IFITM3 in the Golgi and drive generalized glycoprotein trafficking defects. These defects can be relieved upon incubation with Amphotericin B, compound known to relieve IFITM-driven membrane fusion defects, as well as by v-SNARE overexpression, suggesting that IFITM3 interferes with membrane fusion processes important for Golgi functionalities. The comparison of glycoprotein trafficking in WT versus IFITMs-KO cells indicates that the modulation of the secretory pathway is a novel feature of IFITM proteins. Overall, our study defines a novel domain that regulates the egress of several dispanin/CD225 members from the Golgi and identifies a novel modulatory function for IFITM3.


Assuntos
Fenofibrato , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Via Secretória , Internalização do Vírus
3.
Intern Med J ; 52(4): 676-679, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35419960

RESUMO

Retinal vessel calibre metrics were evaluated at baseline and 2 years in a FIELD substudy (n = 208). Central retinal venule calibre was significantly reduced by fenofibrate and unchanged by placebo. Arteriole metrics did not change. Larger studies relating retinal vessel calibre to future diabetes complications and response to therapy are merited.


Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Fenofibrato , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/prevenção & controle , Fenofibrato/uso terapêutico , Humanos , Vasos Retinianos , Vênulas
4.
Arch Biochem Biophys ; 723: 109237, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35430215

RESUMO

Benign prostatic hyperplasia (BPH) is one of the most age-related health problems that commonly affect men. Regrettably, many individuals may not respond to current medical therapies or develop resistance to them. Accordingly, this study aimed to uncover how potentially fenofibrate, a lipid lowering agent, can ameliorate the induced BPH in rats. Forty rats were categorized randomly into four groups; the control group was given the vehicle (olive oil); the BPH model received testosterone propionate (20 mg/kg daily; s.c.) for 4 weeks; BPH-induced group received finasteride (10 mg/kg daily; p.o.) and BPH-induced group received fenofibrate (80 mg/kg daily; p.o.). After testosterone administration, both weight and relative weight of the prostate increased. Additionally, testosterone upregulated androgen receptor (AR), 5α-reductase gene expression and increased prostate proliferation. Histopathological examination confirmed that testosterone disrupted the histo-architecture of the prostate and caused marked hyperplasia of glands and stroma. On the other hand, fenofibrate administration reverted most hyperplastic changes of testosterone, it significantly reduced weight, relative weight of the prostate and dihydrotestosterone (DHT) level compared to BPH group. Also fenofibrate significantly decreased AR and 5α-reductase gene expression. Fenofibrate significantly suppressed ps473 Akt expression causing FOXO3a nuclear inclusion, which triggered induction of apoptosis. As well, Bax/Bcl2 ratio and caspase 3 content were significantly enhanced. Fenofibrate significantly diminished cyclin D1 immunoexpression and restored normal histo-architecture. In conclusion, this study emphasizes the preventive effect of fenofibrate in BPH rat model. This can be accredited, at least partly, to inhibiting AR and 5α-reductase expressions, the anti-proliferative, and pro-apoptotic activity of fenofibrate via modulation of Akt/FOXO3a pathway.


Assuntos
Fenofibrato , Hiperplasia Prostática , Animais , Apoptose , Proliferação de Células , Fenofibrato/efeitos adversos , Humanos , Masculino , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Sprague-Dawley , Testosterona/metabolismo
5.
Int J Biol Macromol ; 208: 1082-1089, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35378162

RESUMO

Inflammation and oxidative stress are processes associated with different human diseases. They are treated using drugs that have several side effects. Seaweed are sources of potentially relevant natural compounds for use as treatment of these disorders. Lectins are able to reversibly interact with complex carbohydrates and modulate cell membrane glycosylated receptors through this interaction. This study aimed to determine the antinociceptive and anti-inflammatory potential of CiL-1 in adult zebrafish by modulation of TRPA1 through lectin-glycan binding. Possible neuromodulation by TRPA1 channel was also evaluated by camphor pretreatment. CiL-1 was efficacious at all tested doses, revealing anti-nociceptive and anti-inflammatory effects in adult zebrafish. This galactose-binding lectin was also able to reduce the content of ROS in brain and liver. In silico analyses showed CiL-1 interactions with both ligands tested. LacNac2 presents the most favorable binding energy with the protein. The interaction occurs at 4 subsites as an extended conformation at the site. LacNac2-Sia had a less favorable curved-shape interaction energy. Based on the predictions made for the oligosaccharides, a tetra-antenate putative glycan was schematically constructed, illustrating an interaction between TRPA1 N-glycan and CiL-1. This binding seems to be related to CiL-1 anti-inflammatory activity as result of receptor modulation.


Assuntos
Fenofibrato , Peixe-Zebra , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Lectinas/química , Polissacarídeos/química , Polissacarídeos/farmacologia
6.
J Virol ; 96(7): e0005722, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35319225

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused over 5 million deaths worldwide. Pneumonia and systemic inflammation contribute to its high mortality. Many viruses use heparan sulfate proteoglycans as coreceptors for viral entry, and heparanase (HPSE) is a known regulator of both viral entry and inflammatory cytokines. We evaluated the heparanase inhibitor Roneparstat, a modified heparin with minimum anticoagulant activity, in pathophysiology and therapy for COVID-19. We found that Roneparstat significantly decreased the infectivity of SARS-CoV-2, SARS-CoV-1, and retroviruses (human T-lymphotropic virus 1 [HTLV-1] and HIV-1) in vitro. Single-cell RNA sequencing (scRNA-seq) analysis of cells from the bronchoalveolar lavage fluid of COVID-19 patients revealed a marked increase in HPSE gene expression in CD68+ macrophages compared to healthy controls. Elevated levels of HPSE expression in macrophages correlated with the severity of COVID-19 and the expression of inflammatory cytokine genes, including IL6, TNF, IL1B, and CCL2. In line with this finding, we found a marked induction of HPSE and numerous inflammatory cytokines in human macrophages challenged with SARS-CoV-2 S1 protein. Treatment with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-mediated inflammatory cytokine release from human macrophages, through disruption of NF-κB signaling. HPSE knockdown in a macrophage cell line also showed diminished inflammatory cytokine production during S1 protein challenge. Taken together, this study provides a proof of concept that heparanase is a target for SARS-CoV-2-mediated pathogenesis and that Roneparstat may serve as a dual-targeted therapy to reduce viral infection and inflammation in COVID-19. IMPORTANCE The complex pathogenesis of COVID-19 consists of two major pathological phases: an initial infection phase elicited by SARS-CoV-2 entry and replication and an inflammation phase that could lead to tissue damage, which can evolve into acute respiratory failure or even death. While the development and deployment of vaccines are ongoing, effective therapy for COVID-19 is still urgently needed. In this study, we explored HPSE blockade with Roneparstat, a phase I clinically tested HPSE inhibitor, in the context of COVID-19 pathogenesis. Treatment with Roneparstat showed wide-spectrum anti-infection activities against SARS-CoV-2, HTLV-1, and HIV-1 in vitro. In addition, HPSE blockade with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-induced inflammatory cytokine release from human macrophages through disruption of NF-κB signaling. Together, this study provides a proof of principle for the use of Roneparstat as a dual-targeting therapy for COVID-19 to decrease viral infection and dampen the proinflammatory immune response mediated by macrophages.


Assuntos
COVID-19 , Heparina/análogos & derivados , COVID-19/tratamento farmacológico , Linhagem Celular , Citocinas/metabolismo , Fenofibrato , Técnicas de Silenciamento de Genes , Glucuronidase/genética , Glucuronidase/metabolismo , Heparina/uso terapêutico , Humanos , Imunidade/efeitos dos fármacos , Inflamação , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , NF-kappa B , SARS-CoV-2
7.
J Cell Biol ; 221(4)2022 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-35293964

RESUMO

Contact inhibition of locomotion (CIL) is a process that regulates cell motility upon collision with other cells. Improper regulation of CIL has been implicated in cancer cell dissemination. Here, we identify the cell adhesion molecule JAM-A as a central regulator of CIL in tumor cells. JAM-A is part of a multimolecular signaling complex in which tetraspanins CD9 and CD81 link JAM-A to αvß5 integrin. JAM-A binds Csk and inhibits the activity of αvß5 integrin-associated Src. Loss of JAM-A results in increased activities of downstream effectors of Src, including Erk1/2, Abi1, and paxillin, as well as increased activity of Rac1 at cell-cell contact sites. As a consequence, JAM-A-depleted cells show increased motility, have a higher cell-matrix turnover, and fail to halt migration when colliding with other cells. We also find that proper regulation of CIL depends on αvß5 integrin engagement. Our findings identify a molecular mechanism that regulates CIL in tumor cells and have implications on tumor cell dissemination.


Assuntos
Inibição de Contato , Fenofibrato , Adesão Celular , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Movimento Celular , Inibição de Contato/genética , Receptores de Vitronectina , Tetraspaninas
8.
Diabetes Res Clin Pract ; 186: 109835, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35314259

RESUMO

AIMS: To evaluate the risk algorithm by Aspelund et al. for predicting sight-threatening diabetic retinopathy (STDR) in Type 2 diabetes (T2D), and to develop a new STDR prediction model. METHODS: The Aspelund et al. algorithm was used to calculate STDR risk from baseline variables in 1012 participants in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) ophthalmological substudy, compared to on-trial STDR status, and receiver operating characteristic analysis performed. Using multivariable logistic regression, traditional risk factors and fenofibrate allocation as STDR predictors were evaluated, with bootstrap-based optimism-adjusted estimates of predictive performance calculated. RESULTS: STDR developed in 28 participants. The Aspelund et al. algorithm predicted STDR at 2- and 5-years with area under the curve (AUC) 0.86 (95% CI 0.77-0.94) and 0.86 (0.81-0.92), respectively. In the second model STDR risk factors were any DR at baseline (OR 24.0 [95% CI 5.53-104]), HbA1c (OR 1.95 [1.43-2.64]) and male sex (OR 4.34 [1.32-14.3]), while fenofibrate (OR 0.13 [0.05-0.38]) was protective. This model had excellent discriminatory ability (AUC = 0.89). CONCLUSIONS: The algorithm by Aspelund et al. predicts STDR well in the FIELD ophthalmology substudy. Logistic regression analysis found DR at baseline, male sex, and HbA1c were predictive of STDR and, fenofibrate was protective.


Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Fenofibrato , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologia , Fenofibrato/uso terapêutico , Hemoglobina A Glicada , Humanos , Masculino , Fatores de Risco
9.
Lipids Health Dis ; 21(1): 19, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35144636

RESUMO

BACKGROUND: Current guidelines for dyslipidemia management recommend that the LDL-C goal be lower than 70 mg/dL. The present study investigated the prognostic significance of visit-to-visit variability in LDL-C, and minimum and maximum LDL-C during follow-up in diabetes mellitus. METHODS: The risk of outcomes in relation to visit-to-visit LDL-C variability was investigated in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial. LDL-C variability indices were coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV). Multivariable Cox proportional hazards models were employed to estimate the adjusted hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Compared with the placebo group (n=2667), the fenofibrate therapy group (n=2673) had a significantly (P<0.01) lower mean plasma triglyceride (152.5 vs. 178.6 mg/dL), and total cholesterol (158.3 vs.162.9 mg/dL) but a similar mean LDL-C during follow-up (88.2 vs. 88.6 mg/dL, P>0.05). All three variability indices were associated with primary outcome, total mortality and cardiovascular mortality both in the total population and in the fenofibrate therapy group but only with primary outcome in the placebo group. The minimum LDL-C but not the maximum during follow-up was significantly associated with various outcomes in the total population, fenofibrate therapy and placebo group. The minimum LDL-C during follow-up ≥70 mg/dL was associated with an increased risk for various outcomes. CONCLUSIONS: Visit-to-visit variability in LDL-C was a strong predictor of outcomes, independent of mean LDL-C. Patients with LDL-C controlled to less than 70 mg/dL during follow-up might have a benign prognosis. ClinicalTrials.gov number: NCT00000620.


Assuntos
LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Colesterol/sangue , Doença das Coronárias/diagnóstico , Doença das Coronárias/mortalidade , Doença das Coronárias/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Dislipidemias/tratamento farmacológico , Feminino , Fenofibrato/uso terapêutico , Humanos , Hipolipemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Tempo , Triglicerídeos/sangue
10.
Sci Rep ; 12(1): 2512, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35169201

RESUMO

Peroxisomes play an important role in the metabolism of a variety of biomolecules, including lipids and bile acids. Peroxisomal Membrane Protein 4 (PXMP4) is a ubiquitously expressed peroxisomal membrane protein that is transcriptionally regulated by peroxisome proliferator-activated receptor α (PPARα), but its function is still unknown. To investigate the physiological function of PXMP4, we generated a Pxmp4 knockout (Pxmp4-/-) mouse model using CRISPR/Cas9-mediated gene editing. Peroxisome function was studied under standard chow-fed conditions and after stimulation of peroxisomal activity using the PPARα ligand fenofibrate or by using phytol, a metabolite of chlorophyll that undergoes peroxisomal oxidation. Pxmp4-/- mice were viable, fertile, and displayed no changes in peroxisome numbers or morphology under standard conditions. Also, no differences were observed in the plasma levels of products from major peroxisomal pathways, including very long-chain fatty acids (VLCFAs), bile acids (BAs), and BA intermediates di- and trihydroxycholestanoic acid. Although elevated levels of the phytol metabolites phytanic and pristanic acid in Pxmp4-/- mice pointed towards an impairment in peroxisomal α-oxidation capacity, treatment of Pxmp4-/- mice with a phytol-enriched diet did not further increase phytanic/pristanic acid levels. Finally, lipidomic analysis revealed that loss of Pxmp4 decreased hepatic levels of the alkyldiacylglycerol class of neutral ether lipids, particularly those containing polyunsaturated fatty acids. Together, our data show that while PXMP4 is not critical for overall peroxisome function under the conditions tested, it may have a role in the metabolism of (ether)lipids.


Assuntos
Ácidos Graxos Insaturados/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais/genética , Animais , Ácidos e Sais Biliares/metabolismo , Sistemas CRISPR-Cas , Dieta/métodos , Feminino , Fenofibrato/administração & dosagem , Edição de Genes/métodos , Técnicas de Inativação de Genes/métodos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução/efeitos dos fármacos , PPAR alfa/metabolismo , Peroxissomos/efeitos dos fármacos , Peroxissomos/metabolismo , Ácido Fitânico/metabolismo , Fitol/administração & dosagem
11.
J Immunol ; 208(3): 562-570, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35031578

RESUMO

Aging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered Ags. The mechanisms that underlie this phenomenon have nonetheless remained unclear. We found that naive CD8+ T cells in elderly humans were prone to apoptosis and proliferated suboptimally in response to stimulation via the TCR. These abnormalities were associated with dysregulated lipid metabolism under homeostatic conditions and enhanced levels of basal activation. Importantly, reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, almost completely restored the Ag responsiveness of naive CD8+ T cells. Interventions that favor lipid catabolism may therefore find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against targetable cancers and emerging pathogens, such as seasonal influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).


Assuntos
Envelhecimento/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunocompetência/efeitos dos fármacos , Metabolismo dos Lipídeos , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Linfócitos T CD8-Positivos/metabolismo , COVID-19/imunologia , Vacinas Anticâncer/imunologia , Divisão Celular , Feminino , Fenofibrato/farmacologia , Glucose/metabolismo , Antígeno HLA-A2/imunologia , Humanos , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Influenza Humana/imunologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Ativação Linfocitária , Antígeno MART-1/química , Antígeno MART-1/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Fragmentos de Peptídeos/imunologia , Rosiglitazona/farmacologia , Método Simples-Cego , Vacinação , Vacinas Virais/imunologia , Adulto Jovem
12.
Biomolecules ; 12(1)2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-35053222

RESUMO

Abdominal aortic aneurysm (AAA) is a life-threatening disease; however, there is no established treatment for patients with AAA. Fibrates are agonists of peroxisome proliferator-activated receptor alpha (PPARα) that are widely used as therapeutic agents to treat patients with hypertriglyceridemia. They can regulate the pathogenesis of AAA in multiple ways, for example, by exerting anti-inflammatory and anti-oxidative effects and suppressing the expression of matrix metalloproteinases. Previously, basic and clinical studies have evaluated the effects of fenofibrate on AAA. In this paper, we summarize the results of these studies and discuss the problems associated with using fenofibrate as a therapeutic agent for patients with AAA. In addition, we discuss a new perspective on the regulation of AAA by PPARα agonists.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/tratamento farmacológico , Fenofibrato/uso terapêutico , Animais , Aneurisma da Aorta Abdominal/metabolismo , Humanos , Metaloproteinases da Matriz/metabolismo
14.
Br J Pharmacol ; 179(6): 1237-1250, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34553378

RESUMO

BACKGROUND AND PURPOSE: Duchenne muscular dystrophy (DMD) is a degenerative muscle disease with no effective drug treatment. This study investigated the positive effects of fenofibrate on dystrophic muscles. EXPERIMENTAL APPROACH: Myostatin expression in serum and muscle tissue from patients with Duchenne muscular dystrophy and mdx mice were tested. Primary myoblasts isolated from mdx mice were challenged with an inflammatory stimulus and treated with fenofibrate. In animal experiments, 6-week-old male mdx mice were treated with fenofibrate (100 mg kg-1 ) administered orally once per day for 6 weeks. Effects of fenofibrate were evaluated by tests of muscle function plus histology and biochemical analyses of serum. Expression of myostatin, MuRF1, and atrogin-1 in skeletal muscle was evaluated by western blotting and real-time PCR. Total and oxidative myosin heavy chain (MHC) were assessed via immunofluorescence. KEY RESULTS: Expression of myostatin protein was increased in dystrophic muscle of patients with Duchenne muscular dystrophy and mdx mice. Fenofibrate enhanced myofibre differentiation by down-regulating the expression of myostatin protein but not mRNA in primary myoblasts of mdx mice. Fenofibrate significantly improved muscle function while ameliorating muscle damage in mdx mice. These benefits were accompanied by an anti-inflammatory effect. Fenofibrate treatment returned myofibre function by inhibiting the expressions of myostatin, MuRF1, and atrogin-1 protein in the gastrocnemius muscle and diaphragm, while leaving the mRNA level of myostatin unaffected. CONCLUSIONS AND IMPLICATIONS: Fenofibrate substantially slows muscle dystrophy by promoting the degradation of myostatin protein, which may indicate a new therapeutic focus for patients with Duchenne muscular dystrophy.


Assuntos
Fenofibrato , Distrofia Muscular de Duchenne , Animais , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/metabolismo , Miostatina/metabolismo , Miostatina/farmacologia , Miostatina/uso terapêutico
15.
Diabetes Care ; 45(1): 241-250, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34785535

RESUMO

OBJECTIVE: The haptoglobin (Hp)2-2 phenotype (∼35-40% of people) is associated with increased oxidation and dysfunctional HDL in hyperglycemia and may explain why drugs designed to pharmacologically raise HDL cholesterol and lower triglycerides have not reliably prevented cardiovascular disease in diabetes. We aimed to determine whether the effect of adding fenofibrate versus placebo to simvastatin on the risk of coronary artery disease (CAD) events depends on Hp phenotype in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial. RESEARCH DESIGN AND METHODS: Cox proportional hazards regression models quantified the relationship between fenofibrate therapy and CAD events in the ACCORD lipid trial in participants with the Hp2-2 phenotype (n = 1,795) separately from those without (n = 3,201). RESULTS: Fenofibrate therapy successfully lowered the risk of CAD events in participants without the Hp2-2 phenotype (multivariable adjusted hazard ratio 0.74 [95% CI 0.60-0.90] compared with no fenofibrate therapy) but not in participants with the Hp2-2 phenotype (1.16 [0.87-1.56]; P interaction = 0.009). Subgroup analyses revealed that this protective effect of fenofibrate against CAD events among the non-Hp2-2 phenotype group was pronounced in participants with severe dyslipidemia (P interaction = 0.01) and in males (P interaction = 0.02) with an increased CAD risk from fenofibrate treatment observed in females with the Hp2-2 phenotype (P interaction = 0.002). CONCLUSIONS: The effect of fenofibrate added to simvastatin on risk of CAD events depends on Hp phenotype in the ACCORD lipid trial.


Assuntos
Diabetes Mellitus Tipo 2 , Fenofibrato , HDL-Colesterol , Diabetes Mellitus Tipo 2/complicações , Feminino , Fenofibrato/uso terapêutico , Haptoglobinas , Fatores de Risco de Doenças Cardíacas , Humanos , Hipolipemiantes/uso terapêutico , Masculino , Fenótipo
17.
Pharmacology ; 107(1-2): 54-68, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34814141

RESUMO

INTRODUCTION: The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. METHODS: The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic db/db mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. RESULTS: From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound 14b) improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic db/db mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound 14b treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound 14b decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound 14b were associated with the activation of the G-protein-coupled bile acid receptor TGR5. CONCLUSION: Compound 14b exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Pregnanos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/efeitos dos fármacos , Linhagem Celular , Cricetinae , Diabetes Mellitus Experimental/metabolismo , Dislipidemias/metabolismo , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Transportador de Glucose Tipo 4/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/uso terapêutico , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Pregnanos/química , Pregnanos/farmacocinética , Pregnanos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo
18.
Mol Nutr Food Res ; 66(2): e2100192, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34808036

RESUMO

SCOPE: The drug fenofibrate and dietary fish oils can effectively lower circulating triglyceride (TG) concentrations. However, a detailed comparative analysis of the effects on the plasma metabolome is missing. METHODS AND RESULTS: Twenty overweight and obese subjects participate in a double-blind, cross-over intervention trial and receive in a random order 3.7 g day-1 n-3 fatty acids, 200 mg fenofibrate, or placebo treatment for 6 weeks. Four hundred twenty plasma metabolites are measured via gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). Among the treatments, 237 metabolites are significantly different, of which 22 metabolites change in the same direction by fish oil and fenofibrate, including a decrease in several saturated TG-species. Fenofibrate additionally changes 33 metabolites, including a decrease in total cholesterol, and total lysophosphatidylcholine (LPC), whereas 54 metabolites are changed by fish oil, including an increase in unsaturated TG-, LPC-, phosphatidylcholine-, and cholesterol ester-species. All q < 0.05. CONCLUSION: Fenofibrate and fish oil reduce several saturated TG-species markedly. These reductions have been associated with a decreased risk for developing cardiovascular disease (CVD). Interestingly, fish oil consumption increases several unsaturated lipid species, which have also been associated with a reduced CVD risk. Altogether, this points towards the power of fish oil to change the plasma lipid metabolome in a potentially beneficial way.


Assuntos
Ácidos Graxos Ômega-3 , Fenofibrato , Método Duplo-Cego , Ácidos Graxos Ômega-3/farmacologia , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Óleos de Peixe/farmacologia , Humanos , Obesidade/tratamento farmacológico , Sobrepeso , Triglicerídeos
19.
Acta Pharmacol Sin ; 43(1): 167-176, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33772142

RESUMO

Recent studies show that intracellular accumulation of cholesterol leads to acquired resistance to gefitinib in non-small cell lung cancer (NSCLC) cells. In this study we investigated how to regulate the cholesterol levels in gefitinib-resistant NSCLC cells. We showed that intracellular cholesterol levels in gefitinib-resistant cell lines (PC-9/GR, H1975, H1650, and A549) were significantly higher than that in gefitinib-sensitive cell line (PC-9). Treatment with gefitinib (5 µM) significantly increased intracellular cholesterol levels in PC-9/GR, H1975, and H1650 cells. Gefitinib treatment downregulated the expression of PPARα, LXRα, and ABCA1, leading to dysregulation of cholesterol efflux pathway. We found that a lipid-lowering drug fenofibrate (20, 40 µM) dose-dependently increased the expression of PPARα, LXRα, and ABCA1, decreased the intracellular cholesterol levels, and enhanced the antiproliferative effects of gefitinib in PC-9/GR, H1975, and H1650 cells. We revealed that fenofibrate increased the gefitinib-induced apoptosis via regulating the key proteins involved in the intrinsic apoptosis pathway. In PC-9/GR, H1975 and H1650 cells, fenofibrate dose-dependently increased the expression of AMPK, FoxO1, and decreased the expression of AKT, which were remarkably weakened by knockdown of PPARα. In PC-9/GR cell xenograft mice, combined administration of gefitinib (25 mg · kg-1 · d-1) and fenofibrate (100 mg · kg-1 · d-1) caused remarkable inhibition on tumor growth as compared to treatment with either drug alone. All the results suggest that fenofibrate relieves acquired resistance to gefitinib in NSCLC by promoting apoptosis via regulating PPARα/AMPK/AKT/FoxO1 pathway. We propose that combination of gefitinib and fenofibrate is a potential strategy for overcoming the gefitinib resistance in NSCLC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fenofibrato/farmacologia , Gefitinibe/farmacologia , Hipolipemiantes/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fenofibrato/química , Proteína Forkhead Box O1/metabolismo , Gefitinibe/química , Humanos , Hipolipemiantes/química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estrutura Molecular , PPAR alfa/agonistas , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade
20.
J Diabetes Investig ; 13(2): 397-401, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34460997

RESUMO

Maternally inherited diabetes and deafness is a rare genetic disease mainly caused by a point mutation in mitochondrial deoxyribonucleic acid. Lipoprotein lipase gene mutations are associated with familial dyslipidemias, which are difficult to manage. We reported for the first time a case that had both maternally inherited diabetes and severe hyperlipidemia caused by lipoprotein lipase gene mutation (C.347(exon3)G>C) that was resistant to fenofibrate and atorvastatin. We were able to manage the patient's hyperlipidemia with bezafibrate, and her diabetes was well controlled with insulin. In conclusion, genetic testing is helpful in identifying rare and interesting cases when clinicians suspect inheritable diseases. Additionally, when one fibrate drug is ineffective in treating hyperlipidemia, it might be worthwhile trying another fibrate.


Assuntos
Diabetes Mellitus Tipo 2 , Fenofibrato , Hiperlipidemias , Lipase Lipoproteica/genética , Atorvastatina/uso terapêutico , Bezafibrato/uso terapêutico , Surdez , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Feminino , Fenofibrato/uso terapêutico , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/genética , Doenças Mitocondriais , Mutação
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