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1.
Life Sci ; 258: 118155, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735887

RESUMO

AIMS: Aim of the present study was to investigate the effect of co-administration coenzyme Q10 and pioglitazone on the mRNA expression of adipocytokines in white adipose tissues of chemically induced type 2 diabetes mellitus in rats. MAIN METHODS: Diabetes was induced by administration of streptozotocin (65 mg/kg, i.p.), followed by nicotinamide (110 mg/kg, i.p.) 15 min later. The diabetic rats were treated coenzyme Q10 (Q10, 10 mg/kg, p.o.) or pioglitazone (PIO, 20 mg/kg, p.o.) alone and their combination for four weeks. Biochemical parameters like FBS level, insulin and HbA1c along with tissue levels of MDA, SOD, CAT and GSH were estimated. The mRNA levels of ADIPOQ, RBP4, RETN, IL-6 and TNF-α in White Adipose Tissue (WAT) were measured. KEY FINDINGS: Treatment with Q10 + PIO showed a significant reduction in the levels of FBS, HbA1c and a significant increase in insulin levels as compared to normal control group. Additionally, there was a significant change in the levels of biomarkers of oxidative stress after treatment with Q10 + PIO as compared to streptozotocin-nicotinamide group. Treatment with Q10 + PIO also significantly altered the mRNA expression of ADIPOQ, RETN, IL-6 and TNF-α when compared to monotherapy. However, mRNA expression of RBP4 did not alter in Q10 + PIO treated animal as compared to Q10 or PIO alone. SIGNIFICANCE: It is concluded that co-administration of Q10 and PIO has been shown the better therapeutic effect on the mRNA expression of adipocytokines and oxidative stress parameters as compared to either Q10 or PIO.


Assuntos
Adipocinas/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Pioglitazona/uso terapêutico , Ubiquinona/análogos & derivados , Vitaminas/uso terapêutico , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Masculino , Pioglitazona/farmacologia , RNA Mensageiro/genética , Ratos , Ratos Wistar , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Vitaminas/farmacologia
2.
Diabetes Metab Syndr ; 14(5): 829-831, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32540737

RESUMO

BACKGROUND AND AIMS: People with type 2 diabetes mellitus (T2DM) have increased morbidity and mortality due to coronavirus disease-19(COVID-19). It has been speculated that use of pioglitazone might increase such risk. The aim of our brief commentary is to review the safety of pioglitazone in people with T2DM and mild/moderate COVID-19. METHODS: We searched PubMed database using specific keywords related to our aims till May 15, 2020. Full text of relevant articles published in English language were retrieved and reviewed. RESULTS: Medications, including pioglitazone, that upregulate tissue expression of angiotensin converting enzyme 2 (ACE2), might have a dual role in COVID-19; on the one hand they might increase risk of infection as SARS-CoV2 uses ACE2 as a coreceptor to enter alveolar cells, but on the other hand, by reducing angiotensin II levels, they can protect against acute lung injury. There is no evidence to date that pioglitazone upregulates ACE2 in the alveolar cells; rather, there is evidence from animal studies of upregulation of ACE2 in insulin sensitive tissues, which might have a protective effect on lung injury. Moreover by moderating the exaggerated host proinflammatory response, pioglitazone can potentially reduce SARS-CoV-2 driven hyperinflammation. CONCLUSIONS: Pioglitazone has more potential for benefit than harm, and can be continued in people with T2DM and mild/moderate COVID-19, unless there are specific contraindications for its use. There is an urgent need to assess clinically relevant outcomes in people with diabetes and COVID-19 based upon baseline antidiabetes therapy, in particular pioglitazone.


Assuntos
Infecções por Coronavirus/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Pioglitazona/uso terapêutico , Pneumonia Viral/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/virologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Betacoronavirus/metabolismo , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/virologia , Humanos , Inflamação/prevenção & controle , Inflamação/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pioglitazona/farmacologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Fatores de Risco
3.
Neoplasma ; 67(4): 834-842, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32386478

RESUMO

Breast cancer, especially triple-negative breast cancer, is one of the deadliest cancers in women. To date, there is a lack of a good therapeutic regimen for it. PPARγ has been reported to be a tumor suppressor and could be activated by many agonists involved in cancer inhibition. Therefore, the expression of PPARγ in breast cancer was analyzed by online software UALCAN whose data were from the TCGA database. The results revealed that the PPARγ expression was reduced in breast cancer tissues. Furthermore, the methylation in the PPARγ promoter was also assayed and the results indicated that the methylation level in the PPARγ promoter in breast cancer tissue was higher than that in normal tissue. In order to verify the methylation in promoter involved in the regulation of gene PPARγ expression, the 5'-Aza and fluorescence assays were performed and the results proved that methylation in promoter participated in gene PPARγ expression regulation. Pioglitazone, a PPARγ agonist, still was not investigated in breast cancer. Therefore, the effects of pioglitazone on breast cancer cells were tested by cell viability, scratch and transwell assays, and results indicated that the pioglitazone has the inhibition effect on the proliferation and migration of breast cancer cells by PPARγ which was correlated with the JAK2/STAT3 pathway. In order to further confirm the inhibition effect of pioglitazone on breast cancer in vivo, the nude mice model was administrated by gavage with pioglitazone. And the results indicated that pioglitazone could inhibit the growth of breast cancer in the PPARγ overexpression group in vivo. In summary, the expression of gene PPARγ was decreased in breast cancer tissues, which was correlated with its methylation in the promoter region. Moreover, pioglitazone could exert its inhibition on breast cancer proliferation and migration by the JAK2/STAT3 pathway.


Assuntos
Neoplasias da Mama , Pioglitazona , Tiazolidinedionas , Animais , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células , Sobrevivência Celular , Feminino , Humanos , Janus Quinase 2/efeitos dos fármacos , Camundongos , Camundongos Nus , PPAR gama/genética , PPAR gama/metabolismo , Pioglitazona/farmacologia , Fator de Transcrição STAT3/efeitos dos fármacos , Tiazolidinedionas/farmacologia
4.
Clin Exp Hypertens ; 42(7): 614-621, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-32349626

RESUMO

OBJECTIVE: To investigate if insulin resistance per se or the accompanying hyperinsulinemia induced hypertension and its underlying mechanisms. METHODS: Sprague-Dawley rats were randomized into normal diet-fed group (ND group) and high-fat diet-fed group (HFD group). Then, the HFD group was further randomly divided into the control group (HFD_C group), the PIO group (treated with pioglitazone), the STZ_DM group (to induce diabetes with streptozotocin) and the DM+Ins group (streptozotocin injection followed by insulin treatment). Insulin sensitivity, plasma insulin, endothelin-1, norepinephrine, aldosterone, angiotensinⅡ and 24-h urinary sodium excretion (USE) levels of the groups were measured and analyzed. A multiple stepwise regression analysis method was applied to exam our hypothesis. RESULTS: Compared to HFD_C group, the groups with lower plasma insulin, the PIO group and STZ_DM group, showed higher USE and lower blood pressure. The groups with higher plasma insulin (but same level of insulin resistance), the HFD_C group and DM+Ins group, showed lower USE and higher blood pressure. The 24-h urinary sodium excretion was the most important contributor to the significant changes of blood pressure with an R2 of 25.2% in this animal experiment. CONCLUSIONS: It is the compensatory hyperinsulinemia rather than insulin resistance per se that causes blood pressure elevation. The urinary sodium excretion is the key mediator among the multiple mechanisms. Therapies targeting hyperinsulinemia and restricting salt intake may favor a better control of hypertension associated with insulin resistance.


Assuntos
Pressão Sanguínea , Diabetes Mellitus Experimental/fisiopatologia , Hiperinsulinismo/fisiopatologia , Resistência à Insulina/fisiologia , Insulina/sangue , Sódio/urina , Animais , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Dieta Hiperlipídica , Hiperinsulinismo/etiologia , Hipertensão/complicações , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Pioglitazona/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
5.
Diabetes Metab Syndr ; 14(4): 713-714, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470851

RESUMO

BACKGROUND AND AIMS: Older adults and people who have cardiovascular disorders (their common pathogenetic mechanism is progressive atherosclerosis) are at higher risk for severe illness from COVID-19 (coronavirus disease 2019). Their common pathogenetic mechanism is progressive atherosclerosis in which oxLDL (oxidized LDL) plays major role. Receptor-mediated uptake of oxLDL by the monocyte-derived macrophages activates the long-term epigenetic reprogramming of innate immunity, which is termed "trained immunity." The aim of this work is to investigate the mechanisms and treatment possibilities that can control the activities of these specific macrophages. METHODS: Search in Medline and PubMed relevant articles on the trained immunity and cytokine storm of COVID-19. RESULTS AND CONCLUSIONS: When oxLDL-trained macrophages encounter SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in the lung, it causes unregulated cytokine secretion, leading to the alveolar damage. Therefore, blocking macrophage training by pioglitazone, a thiazolidinedione, could control the hyperactivation that the virus would trigger.


Assuntos
Aterosclerose/fisiopatologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Lipoproteínas LDL/uso terapêutico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Pioglitazona/uso terapêutico , Pneumonia Viral/imunologia , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Humanos , Imunidade Inata , Mediadores da Inflamação , Pandemias , Pioglitazona/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Transdução de Sinais
6.
Nat Commun ; 11(1): 2024, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332780

RESUMO

Crosstalk between liver and skeletal muscle is vital for glucose homeostasis. Hepatokines, liver-derived proteins that play an important role in regulating muscle metabolism, are important to this communication. Here we identify apolipoprotein J (ApoJ) as a novel hepatokine targeting muscle glucose metabolism and insulin sensitivity through a low-density lipoprotein receptor-related protein-2 (LRP2)-dependent mechanism, coupled with the insulin receptor (IR) signaling cascade. In muscle, LRP2 is necessary for insulin-dependent IR internalization, an initial trigger for insulin signaling, that is crucial in regulating downstream signaling and glucose uptake. Of physiologic significance, deletion of hepatic ApoJ or muscle LRP2 causes insulin resistance and glucose intolerance. In patients with polycystic ovary syndrome and insulin resistance, pioglitazone-induced improvement of insulin action is associated with an increase in muscle ApoJ and LRP2 expression. Thus, the ApoJ-LRP2 axis is a novel endocrine circuit that is central to the maintenance of normal glucose homeostasis and insulin sensitivity.


Assuntos
Clusterina/metabolismo , Glucose/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Síndrome do Ovário Policístico/metabolismo , Adulto , Animais , Linhagem Celular , Clusterina/sangue , Clusterina/genética , Modelos Animais de Doenças , Feminino , Técnica Clamp de Glucose , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Fígado/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/tratamento farmacológico , Receptor de Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Life Sci ; 252: 117679, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32325134

RESUMO

AIM: The neuronal damage and accompanied functional deficits induced by cerebral ischemia are among the most common causes of disabilities in adults. Activation of subtypes of peroxisome proliferator-activated receptors (PPARs); PPAR-α and PPAR-γ have shown neuroprotective effects in different neurodegenerative diseases including stroke. Thus, this study aimed to compare the effects of two different agonists: PPAR-α (fenofibrate) and PPAR-γ (pioglitazone) as well as the effect of their combination in ameliorating post-ischemia behavioral deficits. METHODS: Male Wistar rats were either pretreated with vehicle, fenofibrate (100 mg/kg/day p.o), pioglitazone (10 mg/kg/day p.o) or their combination for 14 days prior to bilateral common carotid artery occlusion followed by reperfusion for 24 hoursh. The sensory motor functions of rats were assessed, then rats were sacrificed to determine infarct volume and histopathological changes as well as oxidative stress, inflammatory and apoptotic markers in the brain tissue. KEY FINDINGS: Pre-treatment with fenofibrate and pioglitazone in addition to their combination improved neurobehavioral dysfunction, reduced cerebral infarct volume, attenuated inflammatory and apoptotic markers and ameliorated histopathological changes in I/R injured rats. The effect of pioglitazone in cerebral cortex was higher than its corresponding effect in fenofibrate while the combined administration of both drugs had additive neuroprotective effect and normalized inflammatory and apoptotic mediators in ischemic rats. SIGNIFICANCE: The study compared the neuroprotective effects of PPAR-α and PPAR-γ agonists, and tested the impact of their combination. We concluded that no additional benefits on the functional outcomes might be gained upon their combination.


Assuntos
Isquemia Encefálica/prevenção & controle , Fenofibrato/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Pioglitazona/farmacologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Infarto Cerebral/prevenção & controle , Modelos Animais de Doenças , Quimioterapia Combinada , Fenofibrato/administração & dosagem , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pioglitazona/administração & dosagem , Ratos , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico
8.
Ann Vasc Surg ; 67: 490-496, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32173476

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is a progressive dilation of the aortic wall, determined by the unbalanced activity of matrix metalloproteinase (MMPs). In vitro and in vivo studies support the pivotal role of MMP-9 to AAA pathogenesis. In our experience, we elucidated the expression of MMP-9 in an ex vivo model of human mesenchymal stem cells isolated from AAA specimen (AAA-MSCs). Thus, MMP-9 inhibition could be an attractive therapeutic strategy for inhibiting AAA degeneration and rupture. Our study was aimed at testing the effect of 3 different drugs (pioglitazone, doxycycline, simvastatin) on MMP-9 and peroxisome proliferator-activated receptor (PPAR)-γ expression in AAA-MSCs. METHODS: Aneurysmal aortic wall segments were taken from AAA patients after the open surgical treatment. MSCs were isolated from AAA (n = 20) tissues through enzymatic digestion. AAA-MSCs were exposed to different doses of pioglitazone (5-10-25 µM), doxycycline (10-25 µM), and simvastatin (10 µM) for 24 h. The effect of each drug was evaluated in terms of cell survival, by crystal violet stain. MMP-9 and PPAR-γ mRNA were analyzed using real-time PCR. RESULTS: AAA-MSCs were not affected by the exposure to the selected drugs, as shown by the analysis of cell viability. Interestingly, MMP-9 mRNA resulted significantly decreased after each treatment, recording a downregulation of 50% in presence of pioglitazone, 90% with doxycycline, and 40% with exposed to simvastatin, in comparison to untreated cells. We further analyzed the expression of PPAR-γ, target of pioglitazone, observing an upregulation in exposed AAA-MSCs to controls. CONCLUSIONS: Our data support the potential therapeutic effect of pioglitazone, doxycycline, and simvastatin on AAA by reducing the MMP-9 expression in a patient-specific model (AAA-MSCs). In addition, pioglitazone drives the increase of PPAR-G, another promising target for AAA therapy. Further studies are necessary to elucidate the mechanism driving this inhibitory pathway, which can reduces the mortality risk associated with AAA rupture.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/tratamento farmacológico , Doxiciclina/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Pioglitazona/farmacologia , Sinvastatina/farmacologia , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Separação Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Pessoa de Meia-Idade , PPAR gama/genética , PPAR gama/metabolismo , Transdução de Sinais
9.
Z Naturforsch C J Biosci ; 75(3-4): 103-112, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32187019

RESUMO

The current study aimed to evaluate the in vivo hypoglycemic potential of Myristica fragrans seed extract co-administered with glimepiride in Swiss albino mice. Computational tools were used to further verify the in vivo findings and to help compare this combination to the glimepiride-pioglitazone combination in terms of the binding affinity of the ligands to their respective target protein receptors and the relative stability of the drug-protein complexes. The effect of the combined therapy was observed both in alloxan- and glucose-induced hyperglycemic Swiss albino mice. The mean fasting blood glucose level of the test groups was measured and statistically evaluated using Student's t test. The combined therapy significantly reduced the blood glucose level in a time-dependent manner compared to glimepiride alone. The binding affinity of glimepiride was found to be -7.6 kcal/mol with sulfonylurea receptor 1 in molecular docking. Conversely, macelignan-peroxisome proliferator-activated receptor (PPAR) α and macelignan-PPAR γ complexes were stabilized with -9.2 and -8.3 kcal/mol, respectively. Molecular dynamic simulation revealed that macelignan-PPAR α and γ complexes were more stable than pioglitazone complexes. The combination shows promise in animal and computer models and requires further trials to provide evidence of its activity in humans.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Lignanas/administração & dosagem , Myristica/química , Compostos de Sulfonilureia/administração & dosagem , Aloxano/efeitos adversos , Animais , Diabetes Mellitus Tipo 2/induzido quimicamente , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Glucose/efeitos adversos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Lignanas/química , Lignanas/farmacologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Pioglitazona/administração & dosagem , Pioglitazona/farmacologia , Extratos Vegetais/química , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Fatores de Tempo
10.
Sci Rep ; 10(1): 1672, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015419

RESUMO

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common monogenic disorders, characterized by the progressive formation of fluid-filled cysts. Tolvaptan is an approved drug for ADPKD patients, but is also associated with multiple side effects. The peroxisome proliferator-activator receptor gamma (PPARγ) agonist pioglitazone slows disease progression in the PCK rat model for PKD. Here, we tested whether a combination treatment of relevant doses of tolvaptan and pioglitazone leads to improved efficacy in an adult-onset PKD mouse model. Tolvaptan indeed slowed PKD progression, but the combination treatment was not more effective than tolvaptan alone. In addition, although pioglitazone raised plasma levels of its surrogate drug marker adiponectin, the drug unexpectedly failed to slow PKD progression. The pioglitazone target PPARγ was expressed at surprisingly low levels in mouse, rat and human kidneys. Other pioglitazone targets were more abundantly expressed, but this pattern was comparable across various species. The data suggest that several potential pharmacokinetic and pharmacodynamic (PK/PD) differences between different species may underlie whether or not pioglitazone is able to slow PKD progression. The ongoing phase II clinical trial with low-dose pioglitazone treatment (NCT02697617) will show whether pioglitazone is a suitable drug candidate for ADPKD treatment.


Assuntos
Cistos/tratamento farmacológico , Rim/efeitos dos fármacos , Pioglitazona/farmacologia , Rim Policístico Autossômico Dominante/tratamento farmacológico , Tolvaptan/farmacologia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Técnicas de Cultura de Células/métodos , Terapia Combinada/métodos , Cistos/metabolismo , Progressão da Doença , Humanos , Rim/metabolismo , Masculino , Camundongos , PPAR gama/metabolismo , Rim Policístico Autossômico Dominante/metabolismo , Ratos , Ratos Wistar
11.
Exp Neurol ; 327: 113234, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32044330

RESUMO

Paraoxonase-2 regulates reactive oxygen species production in mitochondria. Stimulating its expression has therapeutic potential for diseases where oxidative stress plays a significant role in the pathology. Evidence suggests that the anti-diabetic drug pioglitazone may provide neuroprotection in Parkinson's disease, Alzheimer's disease, brain trauma and ischemia, but the biochemical pathway(s) responsible has not been fully elucidated. Here we report that pioglitazone (10 mg/kg/day) for 5 days significantly increased paraoxonase-2 expression in mouse striatum. Thus, this result highlights paraoxonase-2 as a target for neuroprotective strategies and identifies pioglitazone as a tool to study the role of paraoxonase-2 in brain.


Assuntos
Arildialquilfosfatase/metabolismo , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pioglitazona/farmacologia , Animais , Encéfalo/metabolismo , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
Exp Neurol ; 327: 113243, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32057797

RESUMO

Mitochondrial dysfunction is a pivotal event in many neurodegenerative disease states including traumatic brain injury (TBI) and spinal cord injury (SCI). One possible mechanism driving mitochondrial dysfunction is glutamate excitotoxicity leading to Ca2+-overload in neuronal or glial mitochondria. Therapies that reduce calcium overload and enhance bioenergetics have been shown to improve neurological outcomes. Pioglitazone, an FDA approved compound, has shown neuroprotective properties following TBI and SCI, but the underlying mechanism(s) are unknown. We hypothesized that the interaction between pioglitazone and a novel mitochondrial protein called mitoNEET was the basis for neuroprotection following CNS injury. We discovered that mitoNEET is an important mediator of Ca2+-mediated mitochondrial dysfunction and show that binding mitoNEET with pioglitazone can prevent Ca2+-induced dysfunction. By utilizing wild-type (WT) and mitoNEET null mice, we show that pioglitazone mitigates mitochondrial dysfunction and provides neuroprotection in WT mice, though produces no restorative effects in mitoNEET null mice. We also show that NL-1, a novel mitoNEET ligand, is neuroprotective following TBI in both mice and rats. These results support the crucial role of mitoNEET for mitochondrial bioenergetics, its importance in the neuropathological sequelae of TBI and the necessity of mitoNEET for pioglitazone-mediated neuroprotection. Since mitochondrial dysfunction is a pathobiological complication seen in other diseases such as diabetes, motor neuron disease and cancer, targeting mitoNEET may provide a novel mitoceutical target and therapeutic intervention for diseases that expand beyond TBI.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Proteínas de Ligação ao Ferro/metabolismo , Proteínas de Membrana/metabolismo , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Pioglitazona/uso terapêutico , Animais , Lesões Encefálicas Traumáticas/metabolismo , Modelos Animais de Doenças , Proteínas de Ligação ao Ferro/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pioglitazona/farmacologia , Ratos , Ratos Sprague-Dawley
13.
Oncol Rep ; 43(3): 1019-1030, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020228

RESUMO

Kidney cancer is one of the most lethal urological malignancies associated with a high risk of mortality. Recent studies have shown that several antidiabetic drugs may limit the risk of the growth of different types of cancer. Pioglitazone (PIO) belongs to a novel class of antidiabetic drugs called thiazolidinediones (TZDs), which are commonly used in the treatment of type 2 diabetes. This drug has been demonstrated to exert an inhibitory effect on cell growth in colon, prostatic, breast and pancreatic cancer lines. The aim of the present study was to assess the inhibitory effect of PIO on the proliferation of the renal adenocarcinoma cell line 769­P. In addition, the proapoptotic potential of combined treatment with PIO and methotrexate (MTX) was evaluated, as well as the impact of the above drugs on the cell cycle of the 769­P cells. The present study showed that PIO efficaciously inhibited the proliferation and viability of renal cancer cells, and it induced sub­G1 cell cycle arrest and a decrease in the number of cells in the G2 phase, which indicated cytotoxic activity. PIO also exhibited proapoptotic properties at the lowest dose applied (10 µM). Furthermore, combined therapy with PIO and MTX increased the sensitivity of tumor cells to MTX while at the same time this combined therapy did not exhibit a cytotoxic effect to normal kidney cells. In renal adenocarcinoma cells, the combination of the above cytostatic agent at the lowest dose administered (MTX, 5 µM) with the peroxisome proliferator­activated receptor Î³ agonist PIO exhibited better efficacy in triggering the process of apoptosis than that displayed by MTX alone.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Metotrexato/farmacologia , PPAR gama/genética , Pioglitazona/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Rim/patologia , Tiazolidinedionas/uso terapêutico
14.
BMC Genomics ; 21(1): 64, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959126

RESUMO

BACKGROUND: The advent of Next Generation Sequencing has allowed transcriptomes to be profiled with unprecedented accuracy, but the high costs of full-length mRNA sequencing have posed a limit on the accessibility and scalability of the technology. To address this, we developed 3'Pool-seq: a simple, cost-effective, and scalable RNA-seq method that focuses sequencing to the 3'-end of mRNA. We drew from aspects of SMART-seq, Drop-seq, and TruSeq to implement an easy workflow, and optimized parameters such as input RNA concentrations, tagmentation conditions, and read depth specifically for bulk-RNA. RESULTS: Thorough optimization resulted in a protocol that takes less than 12 h to perform, does not require custom sequencing primers or instrumentation, and cuts over 90% of the costs associated with TruSeq, while still achieving accurate gene expression quantification (Pearson's correlation coefficient with ERCC theoretical concentration r = 0.96) and differential gene detection (ROC analysis of 3'Pool-seq compared to TruSeq AUC = 0.921). The 3'Pool-seq dual indexing scheme was further adapted for a 96-well plate format, and ERCC spike-ins were used to correct for potential row or column pooling effects. Transcriptional profiling of troglitazone and pioglitazone treatments at multiple doses and time points in HepG2 cells was then used to show how 3'Pool-seq could distinguish the two molecules based on their molecular signatures. CONCLUSIONS: 3'Pool-seq can accurately detect gene expression at a level that is on par with TruSeq, at one tenth of the total cost. Furthermore, its unprecedented TruSeq/Nextera hybrid indexing scheme and streamlined workflow can be applied in several different formats, including 96-well plates, which allows users to thoroughly evaluate biological systems under several conditions and timepoints. Care must be taken regarding experimental design and plate layout such that potential pooling effects can be accounted for and corrected. Lastly, further studies using multiple sets of ERCC spike-ins may be used to simulate differential gene expression in a system with known ground-state values.


Assuntos
RNA-Seq/métodos , Animais , Análise Custo-Benefício , Células Hep G2 , Humanos , Camundongos , Pioglitazona/farmacologia , RNA-Seq/economia , Transcriptoma/efeitos dos fármacos , Troglitazona/farmacologia
15.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G375-G389, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928220

RESUMO

Mixed acidic-alkaline refluxate is a major pathogenic factor in chronic esophagitis progressing to Barrett's esophagus (BE). We hypothesized that epidermal growth factor (EGF) can interact with COX-2 and peroxisome proliferator-activated receptor-γ (PPARγ) in rats surgically prepared with esophagogastroduodenal anastomosis (EGDA) with healthy or removed salivary glands to deplete salivary EGF. EGDA rats were treated with 1) vehicle, 2) EGF or PPARγ agonist pioglitazone with or without EGFR kinase inhibitor tyrphostin A46, EGF or PPARγ antagonist GW9662 respectively, 3) ranitidine or pantoprazole, and 4) the selective COX-2 inhibitor celecoxib combined with pioglitazone. At 3 mo, the esophageal damage and the esophageal blood flow (EBF) were determined, the mucosal expression of EGF, EGFR, COX-2, TNFα, and PPARγ mRNA and phospho-EGFR/EGFR protein was analyzed. All EGDA rats developed chronic esophagitis, esophageal ulcerations, and intestinal metaplasia followed by a fall in the EBF, an increase in the plasma of IL-1ß, TNFα, and mucosal PGE2 content, the overexpression of COX-2-, and EGF-EGFR mRNAs, and proteins, and these effects were aggravated by EGF and attenuated by pioglitazone. The rise in EGF and COX-2 mRNA was inhibited by pioglitazone but reversed by pioglitazone cotreated with GW9662. We conclude that 1) EGF can interact with PG/COX-2 and the PPARγ system in the mechanism of chronic esophagitis; 2) the deleterious effect of EGF involves an impairment of EBF and the overexpression of COX-2 and EGFR, and 3) agonists of PPARγ and inhibitors of EGFR may be useful in the treatment of chronic esophagitis progressing to BE.NEW & NOTEWORTHY Rats with EGDA exhibited chronic esophagitis accompanied by a fall in EBF and an increase in mucosal expression of mRNAs for EGF, COX-2, and TNFα, and these effects were exacerbated by exogenous EGF and reduced by removal of a major source of endogenous EGF with salivectomy or concurrent treatment with tyrphostin A46 or pioglitazone combined with EGF. Beneficial effects of salivectomy in an experimental model of BE were counteracted by PPARγ antagonist, whereas selective COX-2 inhibitor celecoxib synergistically with pioglitazone reduced severity of esophageal damage and protected esophageal mucosa from reflux. We propose the cross talk among EGF/EGFR, PG/COX-2, and proinflammatory cytokines with PPARγ pathway in the mechanism of pathogenesis of chronic esophagitis progressing to BE and EAC.


Assuntos
Esôfago de Barrett/metabolismo , Ciclo-Oxigenase 2/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Mucosa Esofágica/metabolismo , Esofagite/metabolismo , PPAR gama/metabolismo , Animais , Esôfago de Barrett/tratamento farmacológico , Esôfago de Barrett/genética , Esôfago de Barrett/patologia , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Modelos Animais de Doenças , Fator de Crescimento Epidérmico/antagonistas & inibidores , Fator de Crescimento Epidérmico/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Mucosa Esofágica/efeitos dos fármacos , Mucosa Esofágica/patologia , Esofagite/tratamento farmacológico , Esofagite/genética , Esofagite/patologia , Interleucina-1beta/metabolismo , Masculino , PPAR gama/agonistas , PPAR gama/genética , Pioglitazona/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Ratos Wistar , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
16.
Nat Commun ; 11(1): 438, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974378

RESUMO

Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.


Assuntos
Imunoterapia/métodos , Lipídeos/biossíntese , Células T Matadoras Naturais/fisiologia , Microambiente Tumoral/imunologia , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Colesterol/metabolismo , Galactosilceramidas/farmacologia , Regulação da Expressão Gênica , Humanos , Interferon gama/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/patologia , PPAR gama/genética , PPAR gama/metabolismo , Pioglitazona/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Microambiente Tumoral/efeitos dos fármacos
17.
Cancer Genomics Proteomics ; 17(1): 35-40, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31882549

RESUMO

BACKGROUND/AIM: Cisplatinum (CDDP) is a first-line drug in osteosarcoma treatment and the acquisition of resistance to CDDP is associated with a poor prognosis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that plays important roles in cell proliferation, differentiation, development, metabolism and cell death. Recently, PPARγ was reported to enhance the efficacy, overcome resistance, and decrease the toxicity of CDDP in various human cancers. In this study we tested whether pioglitazone (PIO), a PPARγ agonist, could overcome CDDP resistance in osteosarcoma. MATERIALS AND METHODS: In this study, we used a human osteosarcoma cell line and a patient-derived orthotopic xenograft (PDOX) models of osteosarcoma. We measured cell viability of 143B human osteosarcoma cells when treated with CDDP and PIO. We randomized PDOX models of osteosarcoma into four treatment groups: Group 1, Untreated control; Group 2, PIO alone; Group 3, CDDP alone; Group 4, a combination of CDDP and PIO. Each group comprised six mice. Mice were treated for 14 days and tumor size and body weight were measured. RESULTS: Cell viability of 143B human osteosarcoma cells was significantly reduced when PIO (50 µmol/l) was combined with CDDP compared to CDDP alone. PDOX osteosarcoma tumors treated with the CDDP-PIO combination showed the strongest tumor growth inhibition compared to other treatment groups. PDOX osteosarcoma tumors treated with the CDDP-PIO combination had the least cancer cells and the most necrosis in histological section. CONCLUSION: These results suggest that combining PIO along with CDDP could be an effective treatment strategy for osteosarcoma and has important clinical potential for patients.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Pioglitazona/farmacologia , Adolescente , Animais , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Apoptose , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Proliferação de Células , Doxorrubicina/farmacologia , Quimioterapia Combinada , Humanos , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Nus , Osteossarcoma/metabolismo , Osteossarcoma/patologia , PPAR gama/agonistas , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Cells ; 9(1)2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31877771

RESUMO

Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Chalconas/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Desenvolvimento de Medicamentos , Fígado Gorduroso , Humanos , Hipoglicemiantes/farmacologia , Inflamação/patologia , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Fenilpropionatos/farmacologia , Pioglitazona/farmacologia , Propionatos/farmacologia , Pirróis/farmacologia
19.
Oxid Med Cell Longev ; 2019: 4764071, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885796

RESUMO

Excessive compression, the main cause of intervertebral disc (IVD) degeneration, affected endogenous repair of the intervertebral disc. Pioglitazone (PGZ) is the agonist of peroxisome proliferator-activated receptor γ, which has been widely used in the treatment of diabetes mellitus. The present study aim at investigating whether pioglitazone has protective effects on compression-mediated cell apoptosis in nucleus pulposus mesenchymal stem cells (NP-MSCs) and further exploring the possible underlying mechanism. Our results indicated that the isolated cells satisfied the criteria of MSC stated by the International Society for Cellular Therapy. Besides, our research revealed that pioglitazone could protect cell viability, cell proliferation of NP-MSCs and alleviated the toxic effects caused by compression. The actin stress fibers was suppressed obviously under compression, and pioglitazone alleviated the adverse outcomes. Pioglitazone exerted protective effects on compression-induced NP-MSCs apoptosis according to annexin V/PI double-staining and TUNEL assays. Pioglitazone suppressed compression-induced NP-MSCs oxidative stress, including decreasing compression-induced overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA), and alleviated compression-induced mitochondrial membrane potential (MMP) decrease. Ultrastructure collapse of the mitochondria exhibited a notable improvement by pioglitazone in compression-induced NP-MSCs according to transmission electron microscopy (TEM). Furthermore, the molecular results showed that pioglitazone significantly decreased the expression of apoptosis-associated proteins, including cyto.cytochrome c, Bax, cleaved caspase-9, and cleaved caspase-3, and promoted Bcl-2 expression. These results indicated that pioglitazone alleviated compression-induced NP-MSCs apoptosis by suppressing oxidative stress and the mitochondrial apoptosis pathway, which may be a valuable candidate for the treatment of IVD degeneration.


Assuntos
Apoptose/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Células-Tronco Mesenquimais/metabolismo , Núcleo Pulposo/metabolismo , Pioglitazona/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Núcleo Pulposo/citologia , Estresse Oxidativo , Pioglitazona/farmacologia
20.
J Drugs Dermatol ; 18(12): 1276-1279, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31860218

RESUMO

Lichen planopilaris (LPP) is a cicatricial alopecia that often causes permanent hair loss. Pioglitazone, a peroxisome proliferator activated receptor-gamma (PPAR- γ) agonist, has demonstrated immunomodulatory properties that may offer an effective treatment modality. This retrospective analysis describes 23 patients with LPP treated with adjunctive pioglitazone. Most (18/25) demonstrated significant reduction in patient-reported symptoms and clinical signs of inflammation. No adverse effects were reported. J Drugs Dermatol. 2019;18(12):1276-1279.


Assuntos
Líquen Plano/tratamento farmacológico , PPAR gama/agonistas , Pioglitazona/administração & dosagem , Adulto , Idoso , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Masculino , Pessoa de Meia-Idade , Pioglitazona/farmacologia , Estudos Retrospectivos , Resultado do Tratamento
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