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1.
Talanta ; 237: 122918, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34736656

RESUMO

Pioglitazone is a Peroxisome Proliferator-Activated Receptor (PPAR) agonist of the thiazolidinedione class of compounds with promising anticancer activity. An innovative quantitative mass spectrometry imaging (MSI) method and a HPLC-UV method were developed and validated to investigate its distribution in tumor and liver tissues. The MSI method is based on stable isotope normalization and resulted highly specific and sensitive (0.2 pmol/spot). The correct identification of the drug ion signal is confirmed by MS/MS analysis on tissue. The method shows an optimal lateral resolution (25 µm) relying on the ionization efficiency and fine laser diameter of the atmospheric pressure MALDI source. The HPLC-UV method is simple and straightforward involving quick protein precipitation and shows good sensitivity (50ng/sample) using a small starting volume of biological sample. Thus, it is applicable to samples obtained from both preclinical models and clinical surgical procedures. MSI and HPLC-UV assays were validated assessing linearity, intra- and inter-day precision and accuracy, limit of quantification, selectivity and recovery. These are the first methods developed and validated for the analysis of pioglitazone in tissues, and they were applied successfully to myxoid liposarcoma xenograft-bearing mice, which received clinically relevant drug doses. Pioglitazone was measured by either method in sections of tumor and liver 2, 6 and 24 h post-treatment. Drug distribution was relatively homogeneous.


Assuntos
Pressão Atmosférica , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão , Camundongos , Pioglitazona , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
2.
Artigo em Chinês | MEDLINE | ID: mdl-34624942

RESUMO

Objective: To investigate the effect and mechanism of PPAR-γ agonist Pioglitazone (PGZ) on the proliferation of malignant mesothelioma (MM) cells. Methods: In December 2019, MM cell lines MSTO-211H and NCI-H2452 were incubated with different final concentrations of PGZ (0, 10, 50, 100, 150, and 200 µmol/L) for different periods of time (24 h, 48 h, and 72 h) , and then the cell proliferation level was detected by CCK8 assay. After given various final concentration of PGZ (0, 10, 50, 100, 150, 200 µmol/L) the for 72 hours, the changes of number and morphology of MM cells were observed under an inverted microscope. The expressions of PPAR-γ and HMGB1 mRNA were determined by real-time fluorescence quantitative reverse transcription-polymerase chain reaction (qRT-PCR) after treatment of MM cells with PGZ of 0, 10, 50, 100 µmol/L for 72 h. The MM cells were treated with PGZ at concentration of 0, 100 µmol/L for 72 h, and the protein expressions of HMGB1 were examined using Western blotting and immunofluorescence; the protein expressions of Ki67 were assessed by immunohistochemistry. Results: The cell viability rate of MM cells was decreased after treated with PGZ (P<0.05) . Cell number in PGZ-treated group was significantly less than that in control group and morphology changes were observed under light microscope. QRT-PCR results revealed significantly increased PPAR-γ mRNA expression in the PGZ-treated group compared to the control group (P<0.05) . There was a significant decrease in the mRNA expression level of HMGB1 in the PGZ-treated group (100 µmol/L) as compared to the control group in MSTO-211H (P<0.05) ; however, the expression level of HMGB1 in NCI-H2452 was an increase or no significant differences (P>0.05) . Western blotting and immunofluorescence results showed that the protein expression of HMGB1 was reduced in the PGZ-treated group compared with the control group in MSTO-211H (P<0.05) , but the protein expression of that in NCI-H2452 was no significant differences (P>0.05) . Immunohistochemistry results showed increased expression of proliferation marker Ki-67. Conclusion: Pioglitazone suppresses the proliferation of MM cells through inhibition of HMGB1 by the activation of PPAR-γ.


Assuntos
Proteína HMGB1 , Mesotelioma/tratamento farmacológico , PPAR gama/agonistas , Pioglitazona/farmacologia , Contagem de Células , Linhagem Celular Tumoral , Proliferação de Células , Humanos
3.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638771

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFß), and its receptors, all of which play a major role in PAH and kidney failure. TGFß is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFß. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone.


Assuntos
Rim/metabolismo , Pulmão/metabolismo , PPAR gama/metabolismo , Fibrose Pulmonar/metabolismo , Insuficiência Renal/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Animais , Humanos , PPAR gama/agonistas , Pioglitazona/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Insuficiência Renal/tratamento farmacológico
4.
Aliment Pharmacol Ther ; 54(7): 880-889, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34435378

RESUMO

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. There is a major need to understand the efficacy of different pharmacological agents for the treatment of NASH. AIM: To assess the relative rank-order of different pharmacological interventions in fibrosis improvement and NASH resolution. METHODS: A comprehensive search of several databases was conducted by an experienced librarian. We included randomised controlled-trials (RCTs) comparing pharmacological interventions in patients with biopsy-proven NASH. The primary outcome was ≥1 stage improvement in fibrosis. The secondary outcome was NASH resolution. RESULTS: A total of 26 RCTs with 23 interventions met the eligibility criteria. Lanifibranor and obeticholic acid had the highest probability of being ranked the most effective intervention for achieving ≥1 stage of fibrosis improvement (SUCRA 0.78) and (SUCRA 0.77), respectively. For NASH resolution, semaglutide, liraglutide and vitamin E plus pioglitazone had the highest probability of being ranked the most effective intervention for achieving NASH resolution (SUCRA 0.89), (SUCRA 0.84) and (SUCRA 0.83), respectively. Lanifibranor, obeticholic acid, pioglitazone and vitamin E were significantly better than placebo in achieving ≥1 stage of fibrosis improvement. Conversely, semaglutide, liraglutide, vitamine E plus pioglitazone, pioglitazone, lanifibranor and obeticholic acid were significantly better than placebo in achieving NASH resolution. CONCLUSION: These data provide relative rank-order efficacy of various NASH therapies in terms of their improvements in liver fibrosis and NASH resolution. Therapies that have been shown to improve NASH resolution may be combined with therapies that have an antifibrotic effect to further boost treatment response rate in future.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Biópsia , Humanos , Cirrose Hepática/tratamento farmacológico , Metanálise em Rede , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pioglitazona/uso terapêutico , Vitamina E/uso terapêutico
5.
BMC Womens Health ; 21(1): 302, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404415

RESUMO

BACKGROUND: Anovulation is one of the common causes of infertility. Polycystic ovary syndrome (PCOS) is the most common disorder with chronic Anovulation. To the best of our knowledge, insulin resistance relates significantly to PCOS. Therefore administration of insulin-sensitizing drugs such as pioglitazone can be used for ovulation stimulation in PCO patients. METHODS: After obtaining approval from the Ethics Committee of Mashhad University of Medical Sciences, 61 patients with PCOS were enrolled in the study based on inclusion/ exclusion criteria. Patients were divided into two groups. The first group received 30 mg (mg) of pioglitazone daily from the second day of the menstrual period. The second one received a placebo. 150 mg clomiphene citrate was administered from the third to the seventh day of the menstrual cycle. Vaginal sonography was performed in all women, and in cases with the mature follicle, intrauterine insemination was conducted after human chorionic gonadotropin injection. Ovary stimulation and pregnancy rate were compared between groups. RESULTS: There were no differences between groups regard to demographic characteristics and infertility type. Body mass index was higher in the pioglitazone group (28.3 ± 3.8 versus 26.2 ± 3.5, P value = 0.047). The size of the follicle was not significantly different between groups (2.2 ± 1.4 versus 1.3 ± 1.1, P value = 0.742). pregnancy rate [4 (12.9%) versus 4 (13.3%), P value = 1] had no differences between groups. CONCLUSION: Although the number of follicles was higher in the pioglitazone group, our study showed no differences in ovary stimulation and pregnancy rate.


Assuntos
Infertilidade Feminina , Síndrome do Ovário Policístico , Clomifeno/uso terapêutico , Feminino , Fármacos para a Fertilidade Feminina/uso terapêutico , Humanos , Infertilidade Feminina/tratamento farmacológico , Infertilidade Feminina/etiologia , Indução da Ovulação , Pioglitazona/uso terapêutico , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/tratamento farmacológico , Gravidez , Taxa de Gravidez
6.
Wiad Lek ; 74(7): 1617-1621, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34459761

RESUMO

OBJECTIVE: The aim: To study the association between the effectiveness of treatment with pioglitazone non-alcoholic fatty liver disease (NAFLD) in patients with obesity and PPARG rs1801282 (Pro12Ala)-polymorphism in Ukrainians. PATIENTS AND METHODS: Materials and methods: 123 patients with NAFLD in combination with obesity 1, 2, 3 classes were included in comprehensive weight loss program (5 visits, 12-weeks). The case group was treated with pioglitazone 15 mg / day, while the control group received only program. Ultrasound (US) steatometry and genetic testing rs1801282 polymorphism in PPARG gene were performed. RESULTS: Results: Pioglitazone, PPARG rs1801282 genotype, CAP before treatment, previous weight loss attempts, and duration of obesity were associated with the change in controlled attenuation parameter (CAP) during treatment. There was a significant association between the target CAP reduction achievement and pioglitazone treatment (adjusted odds ratio 0.23, 95% CI 0.07-0.73; p = 0.01) with the CC genotype of PPARG gene (adjusted odds ratio 92.9, 95% CI 7.4-1159; p < 0.001) compared to patients with the CG genotype. CONCLUSION: Conclusions: Pioglitazone and PPARG rs1801282 polymorphism could influence on dynamics of CAP reduction during treatment.


Assuntos
Hepatopatia Gordurosa não Alcoólica , PPAR gama , Predisposição Genética para Doença , Genótipo , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/complicações , Obesidade/genética , PPAR gama/genética , Pioglitazona/uso terapêutico , Polimorfismo de Nucleotídeo Único
7.
Int J Pharm ; 607: 120985, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34389418

RESUMO

In this paper, graft-copolymerization of N-vinylcaprolactam and allylamine onto tungsten disulfide (WS2) in the presence of AIBN as initiator has been carried out to prepare the WS2@ (NVCL-co-AAm). Subsequent fifth-generation dendrimer was attached to their surface, and used as a nanocarrier for the pioglitazone (PG) drug delivery. The resulting polymer was characterized by FTIR, XRD, TEM, EDX, and TGA. We loaded PG onto polymer and evaluated the drug loading and release patterns in simulated human blood fluid (pH 7.4) for the treatment of diabetes in vitro. The thermosensitive nanocarrier indicated a maximum of 98 % PG release in the simulated human blood fluid at 50 °C within 6 h, and about 18 % of total PG was released from the nanocarrier within 6 h at 37 °C. Herein, we studied near-infrared (NIR) radiation as an irritant for inducing PG release from nanocarrier. Also, PG releasing was 100 % under NIR laser irradiation within 15 min, which was roughly four times of that without laser irradiation. NIR laser light heated the nanocarrier, causing shrinkage of the polymer, which increased the penetrability of the membrane and resulted in PG release. Following four adsorption isotherm models, the Langmuir model excellently explained the adsorption isotherm.


Assuntos
Dendrímeros , Sistemas de Liberação de Medicamentos , Humanos , Raios Infravermelhos , Pioglitazona , Polímeros
8.
Liver Int ; 41(11): 2534-2546, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34328687

RESUMO

Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum ranging from simple steatosis to histologically defined hepatocyte injury and inflammatory changes that define steatohepatitis (NASH), and increase risk for fibrosis. Although zonal differences in NASH have not been systematically studied, periportal involvement has been associated with worse metabolic outcomes and more hepatic fibrosis as compared to pericentral disease. These data suggest that hepatic zonation of disease may influence the diversity of clinical presentations. Similarly, several randomized clinical trials suggest a differential response based on zonation of disease, with preferential effects on periportal (cysteamine) or pericentral disease (obeticholic acid, pioglitazone). Intriguingly, morphogenic pathways known to affect zonal development and maintenance - WNT/ß-Catenin, Hedgehog, HIPPO/Yap/TAZ and Notch - have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient-specific activation of these pathways may explain the variability in clinical presentation, and the zone-specific response observed in clinical trials.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Hepatócitos , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Pioglitazona
9.
J Immunol ; 207(2): 483-492, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34193599

RESUMO

Alcohol use disorders (AUD) increase susceptibility to respiratory infections by 2- to 4-fold in part because of impaired alveolar macrophage (AM) immune function. Alcohol causes AM oxidative stress, diminishing AM phagocytic capacity and clearance of microbes from the alveolar space. Alcohol increases AM NADPH oxidases (Noxes), primary sources of AM oxidative stress, and reduces peroxisome proliferator-activated receptor γ (PPARγ) expression, a critical regulator of AM immune function. To investigate the underlying mechanisms of these alcohol-induced AM derangements, we hypothesized that alcohol stimulates CCAAT/enhancer-binding protein ß (C/EBPß) to suppress Nox-related microRNAs (miRs), thereby enhancing AM Nox expression, oxidative stress, and phagocytic dysfunction. Furthermore, we postulated that pharmacologic PPARγ activation with pioglitazone would inhibit C/EBPß and attenuate alcohol-induced AM dysfunction. AM isolated from human AUD subjects or otherwise healthy control subjects were examined. Compared with control AM, alcohol activated AM C/EBPß, decreased Nox1-related miR-1264 and Nox2-related miR-107, and increased Nox1, Nox2, and Nox4 expression and activity. These alcohol-induced AM derangements were abrogated by inhibition of C/EBPß, overexpression of miR-1264 or miR-107, or pioglitazone treatment. These findings define novel molecular mechanisms of alcohol-induced AM dysfunction mediated by C/EBPß and Nox-related miRs that are amenable to therapeutic targeting with PPARγ ligands. These results demonstrate that PPARγ ligands provide a novel and rapidly translatable strategy to mitigate susceptibility to respiratory infections and related morbidity in individuals with AUD.


Assuntos
Alcoolismo/tratamento farmacológico , Alcoolismo/metabolismo , Etanol/efeitos adversos , Macrófagos Alveolares/efeitos dos fármacos , Fagócitos/efeitos dos fármacos , Pioglitazona/farmacologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Linhagem Celular , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Masculino , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Fagócitos/metabolismo
10.
Exp Cell Res ; 406(1): 112736, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34273404

RESUMO

Electric field (EF) directed cell migration (electrotaxis) is known to occur in glioblastoma multiforme (GBM) and neural stem cells, with key signalling pathways frequently dysregulated in GBM. One such pathway is EGFR/PI3K/Akt, which is down-regulated by peroxisome proliferator activated receptor gamma (PPARγ) agonists. We investigated the effect of electric fields on primary differentiated and glioma stem cell (GSCs) migration, finding opposing preferences for anodal and cathodal migration, respectively. We next sought to determine whether chemically disrupting Akt through PTEN upregulation with the PPARγ agonist, pioglitazone, would modulate electrotaxis of these cells. We found that directed cell migration was significantly inhibited with the addition of pioglitazone in both differentiated GBM and GSCs subtypes. Western blot analysis did not demonstrate any change in PPARγ expression with and without exposure to EF. In summary we demonstrate opposing EF responses in primary GBM differentiated cells and GSCs can be inhibited chemically by pioglitazone, implicating GBM EF modulation as a potential target in preventing tumour recurrence.


Assuntos
Movimento Celular/genética , Células-Tronco Neoplásicas/metabolismo , Neuroglia/metabolismo , PPAR gama/genética , Resposta Táctica , Anilidas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Eletricidade , Eletrodos , Campos Eletromagnéticos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , PPAR gama/agonistas , PPAR gama/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Pioglitazona/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
12.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208374

RESUMO

Previous studies have demonstrated that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. The present study was conducted to examine whether pioglitazone can reduce impairment of behavioral deficits mediated by inflammatory-induced brain white matter injury in neonatal rats. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 2 mg/kg) was administered to Sprague-Dawley rat pups on postnatal day 5 (P5), and i.p. administration of pioglitazone (20 mg/kg) or vehicle was performed 5 min after LPS injection. Sensorimotor behavioral tests were performed 24 h after LPS exposure, and changes in biochemistry of the brain was examined after these tests. The results show that systemic LPS exposure resulted in impaired sensorimotor behavioral performance, reduction of oligodendrocytes and mitochondrial activity, and increases in lipid peroxidation and brain inflammation, as indicated by the increment of interleukin-1ß (IL-1ß) levels and number of activated microglia in the neonatal rat brain. Pioglitazone treatment significantly improved LPS-induced neurobehavioral and physiological disturbances including the loss of body weight, hypothermia, righting reflex, wire-hanging maneuver, negative geotaxis, and hind-limb suspension in neonatal rats. The neuroprotective effect of pioglitazone against the loss of oligodendrocytes and mitochondrial activity was associated with attenuation of LPS-induced increment of thiobarbituric acid reactive substances (TBARS) content, IL-1ß levels and number of activated microglia in neonatal rats. Our results show that pioglitazone prevents neurobehavioral disturbances induced by systemic LPS exposure in neonatal rats, and its neuroprotective effects are associated with its impact on microglial activation, IL-1ß induction, lipid peroxidation, oligodendrocyte production and mitochondrial activity.


Assuntos
Comportamento Animal , Encefalite/tratamento farmacológico , Mitocôndrias/patologia , Pioglitazona/uso terapêutico , Substância Branca/patologia , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Encefalite/patologia , Feminino , Hipotermia Induzida , Lipopolissacarídeos , Microglia/efeitos dos fármacos , Microglia/patologia , Mitocôndrias/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Pioglitazona/farmacologia , Gravidez , Ratos Sprague-Dawley , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Perda de Peso/efeitos dos fármacos , Substância Branca/efeitos dos fármacos
13.
Biomed Pharmacother ; 139: 111684, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243632

RESUMO

PPARγ regulate the expression of genes involved in peripheral insulin sensitivity, adipogenesis, and glucose homeostasis. Moreover, PPARγ agonists, such as pioglitazone and rosiglitazone, are used in the treatment of various diseases, e.g. diabetes (type II), atherosclerosis, inflammatory skin disease, and some types of cancers. PPARγ agonists have also been found to reduce oxidative-stress (OS) and OS-induced apoptosis. Therefore, the aim of the present study was to evaluate the impact of 4-thiazolidinone-based derivatives Les-2194, Les-3377, and Les-3640 on the expression of antioxidant enzymes in human squamous cell carcinoma (SCC-15), lung carcinoma (A549), colon adenocarcinoma (CACO-2), and skin fibroblast (BJ) cell lines. After 24 h of exposure, Les-2194 caused an increase in ROS production in the SCC-15 and CACO-2 cell lines; however, no changes in caspase-3 activity and metabolic activity were observed. Nevertheless, the Ki67 level was significantly decreased. Les-3377 was able to increase ROS production in all tested cell lines, but no impact on metabolic activity and caspase-3 activity were noticed. In turn, Les-3640 was able to induce ROS overproduction in BJ, SCC-15, and CACO-2 and did not affect metabolic activity. However, an increase in caspase-3 activity was observed at the 10 µM concentration in all tested cell lines. All tested compounds were able to influence CAT and SOD1 expression and decreased (Les-2194 in the BJ cells) or increased (Les-3640 in the SCC-15 and CACO-2 cells) PPARγ expression.


Assuntos
Antioxidantes/metabolismo , Pioglitazona/farmacologia , Rosiglitazona/farmacologia , Tiazolidinas/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Células CACO-2 , Caspase 3/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Espécies Reativas de Oxigênio/metabolismo
14.
J Drugs Dermatol ; 20(7): 779-782, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34232001

RESUMO

IMPORTANCE: Pediatric lichen planopilaris (LPP) is a clinical variant of lichen planus (LP) that can lead to scarring hair loss without prompt intervention. While various therapies exist, intralesional and topical corticosteroids remain the mainstay of treatment in pediatric LPP. Refractory cases may require systemic therapies, selection of which may prove challenging due to the lack of data regarding pediatric disease and effective treatment regimens. The objective of this case study is to present a new instance of pediatric LPP and identify all reported cases of pediatric LPP with an emphasis on treatment and response. J Drugs Dermatol. 2021;20(7):779-782. doi:10.36849/JDD.5729.


Assuntos
Líquen Plano , Alopecia , Criança , Humanos , Líquen Plano/diagnóstico , Líquen Plano/tratamento farmacológico , Pioglitazona , Resultado do Tratamento
15.
Liver Int ; 41 Suppl 1: 105-111, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34155798

RESUMO

Individuals with obesity or type 2 diabetes (T2D) have an increased risk of developing non-alcoholic fatty liver disease (NAFLD). In insulin-resistant states, altered adipose tissue function may be the initial abnormality underlying NAFLD. Hepatic lipid oversupply interferes with insulin signalling and mitochondrial function. In obese individuals, adaptation of hepatic mitochondrial respiration fails with the progression of NAFLD and can activate pro-inflammatory pathways. T2D as well as type 1 diabetes are associated with altered hepatic mitochondrial function. Screening for NAFLD remains challenging especially in those with diabetes because liver enzymes are often in the normal range and the performance of NAFLD scores is limited. Patients with T2D and severe insulin-resistant diabetes (SIRD) have the highest prevalence of NAFLD at diagnosis and the greatest risk of progression. In this subgroup, the single-nucleotide-polymorphism (SNP) rs738409(G) of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with high liver fat content and adipose tissue insulin resistance. This frequent SNP is also known to be associated with lean NAFLD so that genetic testing for this and other SNPs could improve future screening strategies to identify high-risk individuals. Although lifestyle modifications are effective, this approach is limited owing to difficulties with compliance and several classes of drugs are being tested to treat NAFLD. Antihyperglycaemic drugs such as glucagon-like peptide 1 receptor agonists (GLP-1 RA), sodium-glucose cotransporter 2 inhibitors (SGLT2i) and pioglitazone are promising and halt the progression of NAFLD. In conclusion, although NAFLD in diabetes may not be a separate entity, there are specific features to its pathogenesis and clinical management.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hipoglicemiantes/uso terapêutico , Fígado , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/terapia , Pioglitazona
17.
Lancet Neurol ; 20(7): 537-547, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34146512

RESUMO

BACKGROUND: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. METHODS: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65-83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. FINDINGS: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85-12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45-1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. INTERPRETATION: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. FUNDING: Takeda and Zinfandel.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Pioglitazona/uso terapêutico , Medição de Risco/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Biomarcadores Farmacológicos , Disfunção Cognitiva/metabolismo , Método Duplo-Cego , Feminino , Humanos , Masculino , Pioglitazona/metabolismo , Prognóstico , Fatores de Risco , Resultado do Tratamento
18.
Redox Biol ; 45: 102029, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107382

RESUMO

Prolonged hyperglycemia plays a major role in the progression of ß-cell loss in diabetes mellitus. Here we report an insulin sensitizer thiazolidinedione Pioglitazone selectively preserves the beta cells against high glucose-induced dysfunction by activation of AMPK and Glutaminase 1 (GLS1) axis. AMPK activation increases the stability of Glutaminase 1 by HSP90 family mitochondrial heat shock protein 75 (HSP75/TRAP1). This is associated with an elevation of GSH/GSSG ratio which leads to inhibition of mitochondrial dysfunction by induction of BCL2/BCL-XL in high glucose conditions. Pioglitazone was able to also protect against high glucose-induced elevations in maladaptive ER stress markers and increase the adaptive unfolded protein response (UPR) by inhibiting mTORC1-eEF2 protein translation machinery. Moreover, the pioglitazone effect on AMPK activation was not dependent on the PPARγ pathway. Strikingly, chemical inhibition of AMPK signaling or glutaminase-1 inhibition abrogates the pioglitazone effect on the TRAP1-GLS1 axis and GSH/GSSG ratio linked to mitochondrial dysfunction. Finally, inhibition of AMPK signaling enhanced maladaptive ER stress markers by mTORC1-eEF2 activation. Altogether, these results support the proposal that pioglitazone induced AMPK activation stabilizes a novel interaction of TRAP1/HSP75-GLS1 and its downstream signaling leads to improved ß-cell function and survival under high glucose conditions.


Assuntos
Proteínas Quinases Ativadas por AMP , Glutaminase , Proteínas Quinases Ativadas por AMP/genética , Antioxidantes , Glucose , Glutationa , Pioglitazona
19.
Life Sci ; 280: 119706, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102190

RESUMO

AIMS: Cigarette smoking (CS) is the main cause of chronic obstructive pulmonary disease (COPD). Endothelial dysfunction is related to the severity of pulmonary disease in COPD. This study aimed to evaluate the effectiveness of single and combined administration of pioglitazone (Pio) and irbesartan (Irb) against COPD-induced endothelial dysfunction in mice and the involvement of NO and H2S in their effects. MATERIALS AND METHODS: Adult male Swiss mice (n = 40, weighing 25-30 g) were assigned into 5 groups. The normal control group received 1% carboxy methyl cellulose (CMC). The CS group was exposed to CS and administered 1% CMC for 3 months. The CS + Pio, CS + Irb, and CS + Pio/Irb groups were subjected to CS and received Pio (60 mg/kg), Irb (50 mg/kg), and their combination respectively, daily orally for 3 months. Body weight gain, mean blood pressure, urinary albumin, serum NO and ET-1 levels with TNF-α and IL-2 levels in lung tissue and bronchoalveolar lavage were measured. Lung H2S and ET-1 levels, protein expression of PPARγ in lung and VEGF in lung and aortic tissues with histological changes were assessed. KEY FINDINGS: Our results illustrated that CS induced a model of COPD with endothelial dysfunction in mice. Pio/Irb singly and in combination elicited protective effects against the pathophysiology of the disease with more improvement in the combined group. There is a strong correlation between NO and H2S as well as the other measured parameters. SIGNIFICANCE: Collectively, both drugs performed these effects via their anti-inflammatory potential and increasing H2S and NO levels.


Assuntos
Anti-Hipertensivos/uso terapêutico , Fumar Cigarros/efeitos adversos , Hipoglicemiantes/uso terapêutico , Irbesartana/uso terapêutico , Pioglitazona/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Endotélio/efeitos dos fármacos , Endotélio/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Fumaça/efeitos adversos
20.
Pharmacology ; 106(7-8): 409-417, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34082428

RESUMO

INTRODUCTION: Pioglitazone is a thiazolidinedione oral antidiabetic agent. This study aimed to investigate the effects of pioglitazone as insulin sensitizer on ß-arrestin2 signaling in classical insulin target tissues. METHODS: Experiments involved three groups of mice; the first one involved mice fed standard chow diet for 16 weeks; the second one involved mice fed high-fructose, high-fat diet (HFrHFD) for 16 weeks; and the third one involved mice fed HFrHFD for 16 weeks and received pioglitazone (30 mg/kg/day, orally) in the last four weeks of feeding HFrHFD. RESULTS: The results showed significant improvement in the insulin sensitivity of pioglitazone-treated mice as manifested by significant reduction in the insulin resistance index. This improvement in insulin sensitivity was associated with significant increases in the ß-arrestin2 levels in the adipose tissue, liver, and skeletal muscle. Moreover, pioglitazone significantly increased ß-arrestin2 signaling in all the examined tissues as estimated from significant increases in phosphatidylinositol 4,5 bisphosphate and phosphorylation of Akt at serine 473 and significant decrease in diacylglycerol level. CONCLUSION: To the best of our knowledge, our work reports a new mechanism of action for pioglitazone through which it can enhance the insulin sensitivity. Pioglitazone increases ß-arrestin2 signaling in the adipose tissue, liver, and skeletal muscle of HFrHFD-fed mice.


Assuntos
Resistência à Insulina , Insulina/metabolismo , Pioglitazona/farmacologia , beta-Arrestina 2/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Frutose , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Transdução de Sinais/efeitos dos fármacos
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