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1.
Ulus Travma Acil Cerrahi Derg ; 30(6): 406-414, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38863295

RESUMO

BACKGROUND: This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing histopathological, immunohistochemical, and biochemical analyses in an experimental adhesion model. METHODS: Fifty Wistar-Albino rats were divided into five groups: Group I (Control), Group II (Sham Treatment), Group III (Hy-aluronic Acid), Group IV (Metformin), and Group V (Pioglitazone). Adhesions were induced in the experimental groups, except for the sham group, using the scraping method. After 10 days, rats were euthanized for evaluation. Macroscopic adhesion degrees were assessed using Nair's scoring system. Immunohistochemical and enzyme-linked immunosorbent assay (ELISA) methods were utilized to assess serum, peritoneal lavage, and intestinal tissue samples. Fructosamine, interleukin-6 (IL-6), transforming growth factor-beta (TGF-ß), and fibronectin levels were measured in serum and peritoneal lavage samples. RESULTS: The groups exhibited similar Nair scores and Type I or Type III Collagen staining scores (all, p>0.05). Pioglitazone significantly reduced serum IL-6 and TGF-ß levels compared to controls (p=0.002 and p=0.008, respectively). Both metformin and pioglitazone groups showed elevated IL-6 in peritoneal lavage relative to controls, while fibronectin levels in the lavage were lower in pioglitazone-treated rats compared to the sham group (all, p<0.005). CONCLUSION: Pioglitazone, but not metformin, demonstrated a positive biochemical impact on preventing PIAA formation in an experimental rat model, although histological impacts were not observed. Further experimental studies employing different dose/duration regimens of pioglitazone are needed to enhance our understanding of its effect on PIAA formation.


Assuntos
Modelos Animais de Doenças , Metformina , Pioglitazona , Ratos Wistar , Animais , Pioglitazona/farmacologia , Metformina/farmacologia , Aderências Teciduais/prevenção & controle , Aderências Teciduais/tratamento farmacológico , Ratos , Hipoglicemiantes/farmacologia , Masculino , Tiazolidinedionas/farmacologia , Complicações Pós-Operatórias/prevenção & controle
2.
Int J Mol Sci ; 25(12)2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38928077

RESUMO

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K-γ pathway. Five days after receiving a single bolus of 0.075 units of bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg of MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-ß1, oxidative loads, Masson's trichrome staining, extracellular collagen levels, positive staining of α-smooth muscle actin, PI3K-γ expression, and myonuclear apoptosis (p < 0.05). Decreased diaphragm contractility and peroxisome proliferator-activated receptor-γ coactivator-1α levels were also observed (p < 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K-γ activity (p < 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated by PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.


Assuntos
Lesão Pulmonar Aguda , Bleomicina , Diafragma , Modelos Animais de Doenças , Fibrose , Camundongos Endogâmicos C57BL , Animais , Bleomicina/efeitos adversos , Diafragma/metabolismo , Diafragma/patologia , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/metabolismo , Masculino , Respiração Artificial/efeitos adversos , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Fator de Crescimento Transformador beta1/metabolismo , Apoptose/efeitos dos fármacos , Quinoxalinas , Tiazolidinedionas
3.
Eur J Med Chem ; 275: 116623, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38943875

RESUMO

A new series of thiazolidine-2,4-dione tethered 1,2,3-triazole derivatives were designed, synthesized and screened for their α-amylase inhibitory potential employing in vitro and in silico approaches. The target compounds were synthesized with the help of Cu (I) catalyzed [3 + 2] cycloaddition of terminal alkyne with numerous azides, followed by unambiguously characterizing the structure by employing various spectroscopic approaches. The synthesized derivatives were assessed for their in vitro α-amylase inhibition and it was found that thiazolidine-2,4-dione derivatives 6e, 6j, 6o, 6u and 6x exhibited comparable inhibition with the standard drug acarbose. The compound 6e with a 7-chloroquinolinyl substituent on the triazole ring exhibited significant inhibition potential with IC50 value of 0.040 µmol mL-1 whereas compound 6c (IC50 = 0.099 µmol mL-1) and 6h (IC50 = 0.098 µmol mL-1) were poor inhibitors. QSAR studies revealed the positively correlating descriptors that aid in the design of novel compounds. Molecular docking was performed to investigate the binding interactions with the active site of the biological receptor and the stability of the complex over a period of 100 ns was examined using molecular dynamics studies. The physiochemical properties and drug-likeliness behavior of the potent derivatives were investigated by carrying out the ADMET studies.


Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Tiazolidinedionas , Triazóis , alfa-Amilases , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , Tiazolidinedionas/química , Tiazolidinedionas/síntese química , Tiazolidinedionas/farmacologia , Estrutura Molecular , Relação Dose-Resposta a Droga , Humanos
4.
Bioorg Med Chem Lett ; 109: 129853, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38909705

RESUMO

Overexpression of Bcl-2 protein is a predominant hallmark of disturbed apoptotic pathway in most of the cancers. Herein, chromone-linked thiazolidinediones were designed and synthesized to target Bcl-2 for regulating anti-apoptotic proteins. The study on in vitro cancer cell lines revealed the presence of compounds 8a, 8k, 8l, and 8n, which were found to have good to moderate anti-proliferative activity (with an IC50 concentration less than 10 µM). Among them, 8l depicted the highest cytotoxicity on the A549 cell line with an IC50 of 6.1 ± 0.02 µM. Aberrantly, the compounds displayed less toxicity towards human embryonic kidney HEK cells underlining its selectivity. The DCFDA study revealed a gradual increase in the ROS generation of 8l, followed by its quantification by flow analysis. Similarly, the studies including DAPI, AO/EtBr and Annexin-V binding clearly elucidated the DNA damage, membrane integrity prospects, and insights for early and late apoptotic phases. Markedly, the Bcl-2-FITC anti-body study revealed that compound 8l reduced the expression of anti-apoptotic proteins by 79.1 % compared to the control at 9 µM concentration. In addition, the molecular docking study provided the impending scope of these hybrids, showing promising interaction with the Mcl-1 target (member of the Bcl-2 family) with comparable binding affinities.


Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Cromonas , Ensaios de Seleção de Medicamentos Antitumorais , Tiazolidinedionas , Humanos , Apoptose/efeitos dos fármacos , Cromonas/farmacologia , Cromonas/química , Cromonas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Tiazolidinedionas/farmacologia , Tiazolidinedionas/química , Tiazolidinedionas/síntese química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Células HEK293 , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linhagem Celular Tumoral
5.
J Diabetes Complications ; 38(7): 108777, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38788522

RESUMO

AIMS: Guidelines emphasize screening high-risk patients for metabolic dysfunction-associated steatotic liver disease (MASLD) with a calculated FIB-4 score for therapy to reverse fibrosis. We aimed to determine whether FIB-4 can effectively screen and monitor changes in steatohepatitis (MASH). METHODS: Data were retrieved from the NIDDK-CR R4R central repository, of the CRN/PIVENS (pioglitazone vs vitamin E vs placebo) trial of adult patients without diabetes mellitus and with MASLD. RESULTS: 220 patients with MASLD had alanine transaminase (ALT), aspartate aminotransferase (AST) and platelet count, to calculate FIB-4, and repeat liver biopsies for histological MASLD activity scores (NAS). Compared to NAS score of 2, Fib-4 was higher at NAS 5) (p = 0.03), and NAS score of 6 (p = 0.02). FIB-4 correlated with cellular ballooning (r = 0.309, p < 0.001). Levels of ALT (ANOVA, p = 0.016) and AST (ANOVA p = 0.0008) were associated with NAS. NAS improved with pioglitazone by 39 %, p < 0.001 and with vitamin E by 36 %, p < 0.001. Pioglitazone and vitamin E both improved histological sub-scores for steatosis, and inflammation, without statistical changes in fibrosis grade. Changes in FIB-4 correlated with changes in NAS (r = 0.237, p < 0.001). CONCLUSIONS: In this post hoc analysis, changes in FIB-4 were associated with changes of steatohepatitis. Medication known to treat steatohepatitis, may be considered, before the onset of advanced fibrosis.


Assuntos
Cirrose Hepática , Pioglitazona , Vitamina E , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Pioglitazona/uso terapêutico , Cirrose Hepática/diagnóstico , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Adulto , Vitamina E/sangue , Vitamina E/uso terapêutico , Aspartato Aminotransferases/sangue , Alanina Transaminase/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/sangue , Fígado/patologia , Tiazolidinedionas/uso terapêutico , Hipoglicemiantes/uso terapêutico , Programas de Rastreamento/métodos , Índice de Gravidade de Doença , Biomarcadores/sangue , Biomarcadores/análise , Contagem de Plaquetas , Biópsia , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/patologia , Fígado Gorduroso/complicações , Progressão da Doença
6.
J Med Chem ; 67(10): 8406-8419, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38723203

RESUMO

Forty-one 1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione derivatives (MY1-41) were designed and synthesized as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity against diabetes mellitus (DM). All synthesized compounds (MY1-41) presented potential PTP1B inhibitory activities, with half-maximal inhibitory concentration (IC50) values ranging from 0.41 ± 0.05 to 4.68 ± 0.61 µM, compared with that of the positive control lithocholic acid (IC50 = 9.62 ± 0.14 µM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 µM), was a reversible, noncompetitive inhibitor of PTP1B. Circular dichroism spectroscopy and molecular docking were employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate palmitic acid (PA)-induced insulin resistance by upregulating the expression of phosphorylated insulin receptor substrate and protein kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose tolerance and dyslipidemia in mice suffering from DM.


Assuntos
Diabetes Mellitus Experimental , Hipoglicemiantes , Simulação de Acoplamento Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Tiazolidinedionas , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Animais , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/síntese química , Hipoglicemiantes/uso terapêutico , Células Hep G2 , Camundongos , Tiazolidinedionas/farmacologia , Tiazolidinedionas/química , Tiazolidinedionas/síntese química , Diabetes Mellitus Experimental/tratamento farmacológico , Relação Estrutura-Atividade , Masculino , Tiadiazóis/farmacologia , Tiadiazóis/química , Tiadiazóis/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Resistência à Insulina , Glicemia/efeitos dos fármacos , Glicemia/análise , Glicemia/metabolismo
7.
Clin Transl Sci ; 17(5): e13834, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38771175

RESUMO

Pioglitazone is class of thiazolidinediones that activates peroxisome proliferator-activated receptors (PPARs) in adipocytes to improve glucose metabolism and insulin sensitivity and has been used as a treatment for type 2 diabetes. However, the underlying mechanisms of associated pioglitazone-induced effects remain unclear. Our study aimed to investigate endogenous metabolite alterations associated with pioglitazone administration in healthy male subjects using an untargeted metabolomics approach. All subjects received 30 mg of pioglitazone once daily in the assigned sequence and period. Urine samples were collected before pioglitazone administration and for 24 h after 7 days of administration. A total of 1465 compounds were detected and filtered using a coefficient of variance below 30% and 108 metabolites were significantly altered upon pioglitazone administration via multivariate statistical analysis. Fourteen significant metabolites were identified using authentic standards and public libraries. Additionally, pathway analysis revealed that metabolites from purine and beta-alanine metabolisms were significantly altered after pioglitazone administration. Further analysis of quantification of metabolites from purine metabolism, revealed that the xanthine/hypoxanthine and uric acid/xanthine ratios were significantly decreased at post-dose. Pioglitazone-dependent endogenous metabolites and metabolic ratio indicated the potential effect of pioglitazone on the activation of PPAR and fatty acid synthesis. Additional studies involving patients are required to validate these findings.


Assuntos
Voluntários Saudáveis , Pioglitazona , Purinas , Tiazolidinedionas , Humanos , Masculino , Pioglitazona/farmacologia , Pioglitazona/administração & dosagem , Purinas/administração & dosagem , Purinas/metabolismo , Adulto , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacologia , Tiazolidinedionas/efeitos adversos , Metabolômica/métodos , Adulto Jovem , Hipoglicemiantes/farmacologia , Hipoglicemiantes/administração & dosagem
8.
Acta Physiol (Oxf) ; 240(8): e14167, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38779820

RESUMO

AIM: To investigate systemic regulators of the cancer-associated cachexia syndrome (CACS) in a pre-clinical model for lung cancer with the goal to identify therapeutic targets for tissue wasting. METHODS: Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-γ agonist, rosiglitazone. RESULTS: Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis. CONCLUSION: Our data suggest that PPAR-γ agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer.


Assuntos
Adiponectina , Caquexia , Neoplasias Pulmonares , Rosiglitazona , Animais , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Caquexia/metabolismo , Caquexia/tratamento farmacológico , Adiponectina/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , PPAR gama/metabolismo , PPAR gama/agonistas , Masculino , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico
9.
J Assoc Physicians India ; 72(1): 32-42, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38736072

RESUMO

BACKGROUND: The efficacy and safety of lobeglitazone sulfate has been reported only in the Korean population, and no study has been conducted in India. MATERIALS AND METHODS: In this 16-week randomized, double-blind, and multicenter study, the efficacy and safety of lobeglitazone sulfate 0.5 mg were evaluated with pioglitazone 15 mg. Type 2 diabetes mellitus (T2DM) patients with ≥7.5% glycated hemoglobin (HbA1c) ≤10.5% and on stable metformin dose were assigned to both treatment arms. The primary outcome was a mean change in HbA1c. Safety assessments included adverse events (AE), home-based glucose monitoring, vital parameters, electrocardiogram (ECG), and laboratory assessments. RESULTS: A total of 328 subjects were randomized equally in two groups. A statistically significant reduction in HbA1c at week 16 in the lobeglitazone group with the least square (LS) mean change: 1.01 [standard error (SE): 0.09] (p < 0.0001) was seen. The LS mean difference between the two groups was 0.05 (SE: 0.12) [95% confidence interval (CI): -0.18, 0.27], which was statistically significant (p = 0.0013). Statistically significant reductions were also observed in fasting and postprandial glucose. Treatment-emergent Aes (TEAE) were comparable between both groups. CONCLUSION: Lobeglitazone 0.5 mg once daily was found to be efficacious and safe in the treatment of T2DM in the Indian population. Lobeglitazone significantly improved glycemic parameters and was noninferior to pioglitazone; hence, it could be a promising insulin sensitizer in T2DM management in India.


Assuntos
Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Hemoglobinas Glicadas , Hipoglicemiantes , Metformina , Pioglitazona , Tiazolidinedionas , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/uso terapêutico , Metformina/administração & dosagem , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Método Duplo-Cego , Feminino , Tiazolidinedionas/uso terapêutico , Tiazolidinedionas/administração & dosagem , Hemoglobinas Glicadas/análise , Índia , Pioglitazona/uso terapêutico , Pioglitazona/administração & dosagem , Glicemia/análise , Glicemia/efeitos dos fármacos , Adulto , Resultado do Tratamento , Idoso , Pirimidinas
10.
Diabetes Obes Metab ; 26(8): 3137-3146, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38699792

RESUMO

AIM: To examine the effects of the thiazolidinedione (TZD) pioglitazone on reducing ketone bodies in non-obese patients with T2DM treated with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin. METHODS: Crossover trials with two periods, each treatment period lasting 4 weeks, with a 4-week washout period, were conducted. Participants were randomly assigned in a 1:1 ratio to receive pioglitazone combined with canagliflozin (PIOG + CANA group) versus canagliflozin monotherapy (CANA group). The primary outcome was change (Δ) in ß-hydroxybutyric acid (ß-HBA) before and after the CANA or PIOG + CANA treatments. The secondary outcomes were Δchanges in serum acetoacetate and acetone, the rate of conversion into urinary ketones, and Δchanges in factors related to SGLT2 inhibitor-induced ketone body production including non-esterified fatty acids (NEFAs), glucagon, glucagon to insulin ratio, and noradrenaline (NA). Analyses were performed in accordance with the intention-to-treat principle. RESULTS: Twenty-five patients with a mean age of 49 ± 7.97 years and a body mass index of 25.35 ± 2.22 kg/m2 were included. One patient discontinued the study during the washout period. Analyses revealed a significant increase in the levels of serum ketone bodies and an elevation in the rate of conversion into urinary ketones after both interventions. However, differernces in levels of ketone bodies (except for acetoacetate) in the PIOG + CANA group were significantly smaller than in the CANA group (219.84 ± 80.21 µmol/L vs. 317.69 ± 83.07 µmol/L, p < 0.001 in ß-HBA; 8.98 ± 4.17 µmol/L vs. 12.29 ± 5.27 µmol/L, p = 0.018 in acetone). NEFA, glucagon, glucagon to insulin ratio, and NA were also significantly increased after both CANA and PIOG + CANA treatments; while only NEFAs demonstrated a significant difference between the two groups. Correlation analyses revealed a significant association between the difference in Δchanges in serum NEFA levels with the differences in Δchanges in ketones of ß-HBA and acetoacetate. CONCLUSION: Supplementation of pioglitazone could alleviate canagliflozin-induced ketone bodies. This benefit may be closely associated with decreased substrate NEFAs rather than other factors including glucagon, fasting insulin and NA.


Assuntos
Canagliflozina , Estudos Cross-Over , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Hipoglicemiantes , Corpos Cetônicos , Pioglitazona , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Masculino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Pessoa de Meia-Idade , Corpos Cetônicos/sangue , Feminino , Pioglitazona/uso terapêutico , Canagliflozina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Ácido 3-Hidroxibutírico/sangue , Acetoacetatos/sangue , Insulina/sangue , Adulto , Glucagon/sangue , Tiazolidinedionas/uso terapêutico , Ácidos Graxos não Esterificados/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo
11.
Domest Anim Endocrinol ; 88: 106848, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38574690

RESUMO

Insulin is a potent adipogenic hormone that triggers a series of transcription factors that regulate the differentiation of preadipocytes into mature adipocytes. Ciglitazone specifically binds to peroxisome proliferator-activated receptor-γ (PPARγ), thereby promoting adipocyte differentiation. As a natural ligand of PPARγ, oleic acid (OA) can promote the translocation of PPARγ into the nucleus, regulate the expression of downstream genes, and promote adipocyte differentiation. We hypothesized that ciglitazone and oleic acid interact with insulin to enhance bovine preadipocyte differentiation. Preadipocytes were cultured 96 h in differentiation medium containing 10 mg/L insulin (I), 10 mg/L insulin + 10 µM cycloglitazone (IC), 10 mg/L insulin + 100 µM oleic acid (IO), or 10 mg/L insulin + 10 µM cycloglitazone+100 µM oleic acid (ICO). Control preadipocytes (CON) were cultured in differentiation medium (containing 5% fetal calf serum). The effects on the differentiation of Yanbian cattle preadipocytes were examined using molecular and transcriptomic techniques, including differentially expressed genes (DEGs) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis. I, IC, IO, and ICO treatments produced higher concentrations of triglycerides (TAG) and lipid droplet accumulation in preadipocytes compared with CON treatment (P < 0.05). Co-treatment of insulin and PPARγ agonists significantly increased the expression of genes involved in regulating adipogenesis and fatty acid synthesis. (P < 0.05). Differential expression analysis identified 1488, 1764, 1974 and 1368 DEGs in the I, IC, IO and ICO groups, respectively. KEGG pathway analysis revealed DEGs mainly enriched in PPAR signalling, FOXO signaling pathway and fatty acid metabolism. These results indicate that OA, as PPARγ agonist, can more effectively promote the expression of bovine lipogenesis genes and the content of TAG and adiponectin when working together with insulin, and stimulate the differentiation of bovine preadipocytes. These findings provide a basis for further screening of relevant genes and transcription factors in intramuscular fat deposition and meat quality to enhance breeding programs.


Assuntos
Adipócitos , Diferenciação Celular , Insulina , Ácido Oleico , PPAR gama , Tiazolidinedionas , Animais , Bovinos , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Insulina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Ácido Oleico/farmacologia , Adipogenia/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos
12.
Diabetes Obes Metab ; 26(7): 2969-2978, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38685616

RESUMO

AIM: The response rate to pioglitazone and the predictive factors for its effects on improving liver biochemistry in patients with steatotic liver disease (SLD) remain elusive, so we aimed to investigate these issues. METHODS: A 3-year prospective cohort study of 126 Taiwanese patients with SLD treated with pioglitazone (15-30 mg/day) was conducted. Phospholipase domain-containing protein 3 I148M rs738409, methylenetetrahydrofolate reductase rs1801133, aldehyde dehydrogenase 2 (ALDH2) rs671 and lipoprotein lipase rs10099160 single nucleotide polymorphisms were assessed in the patients. RESULTS: Of 126 patients, 78 (61.9%) were men, and the mean and median ages were 54.3 and 56.5 years, respectively. Pioglitazone responders were defined as those with decreased alanine aminotransferase (ALT) levels at 6 months post-treatment, and 105 (83.3%) patients were responders. Compared with non-responders, responders were more frequently women and had higher baseline ALT levels. The proportion of patients with the ALDH2 rs671 GG genotype was lower among responders (38.6% vs. 66.6%, p = .028). Female sex [odds ratio (OR): 4.514, p = .023] and baseline ALT level (OR: 1.015, p = .046; cut-off level: ≥82 U/L) were associated with pioglitazone response. Among responders, the liver biochemistry and homeostasis model assessment of insulin resistance improved from 6 to 24 months post-treatment. The total cholesterol levels decreased within 6 months, while increases in high-density lipoprotein cholesterol levels and decreases in triglyceride levels and fibrosis-4 scores were noted only at 24 months post-treatment. The 2-year cumulative incidences of cardiovascular events, cancers and hepatic events were similar between responders and non-responders. CONCLUSIONS: Regarding liver biochemistry, over 80% of Taiwanese patients with SLD had a pioglitazone response, which was positively associated with female sex and baseline ALT levels. Insulin resistance improved as early as 6 months post-treatment, while liver fibrosis improvement was not observed until 24 months post-treatment. The link between the pioglitazone response and the ALDH2 genotype warrants further investigation.


Assuntos
Aldeído-Desidrogenase Mitocondrial , Hipoglicemiantes , Pioglitazona , Polimorfismo de Nucleotídeo Único , Humanos , Pioglitazona/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Hipoglicemiantes/uso terapêutico , Resultado do Tratamento , Aldeído-Desidrogenase Mitocondrial/genética , Taiwan/epidemiologia , Alanina Transaminase/sangue , Tiazolidinedionas/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Idoso , Lipase Lipoproteica/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Genótipo , Adulto
13.
J Appl Toxicol ; 44(8): 1214-1235, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38654465

RESUMO

Thiazolidinediones (TZDs) (e.g. pioglitazone and rosiglitazone), known insulin sensitiser agents for type II diabetes mellitus, exhibit controversial effects on cardiac tissue. Despite consensus on their association with increased heart failure risk, limiting TZD use in diabetes management, the underlying mechanisms remain uncharacterised. Herein, we report a comprehensive in vitro investigation utilising a novel toxicoproteomics pipeline coupled with cytotoxicity assays in human adult cardiomyocytes to elucidate mechanistic insights into TZD cardiotoxicity. The cytotoxicity assay findings showed a significant loss of mitochondrial adenosine triphosphate production upon exposure to either TZD agents, which may underpin TZD cardiotoxicity. Our toxicoproteomics analysis revealed that mitochondrial dysfunction primarily stems from oxidative phosphorylation impairment, with distinct signalling mechanisms observed for both agents. The type of cell death differed strikingly between the two agents, with rosiglitazone exhibiting features of caspase-dependent apoptosis and pioglitazone implicating mitochondrial-mediated necroptosis, as evidenced by the protein upregulation in the phosphoglycerate mutase family 5-dynamin-related protein 1 axis. Furthermore, our analysis revealed additional mechanistic aspects of cardiotoxicity, showcasing drug specificity. The downregulation of various proteins involved in protein machinery and protein processing in the endoplasmic reticulum was observed in rosiglitazone-treated cells, implicating proteostasis in the rosiglitazone cardiotoxicity. Regarding pioglitazone, the findings suggested the potential activation of the interplay between the complement and coagulation systems and the disruption of the cytoskeletal architecture, which was primarily mediated through the integrin-signalling pathways responsible for pioglitazone-induced myocardial contractile failure. Collectively, this study unlocks substantial mechanistic insight into TZD cardiotoxicity, providing the rationale for future optimisation of antidiabetic therapies.


Assuntos
Cardiotoxicidade , Miócitos Cardíacos , Pioglitazona , Proteômica , Rosiglitazona , Tiazolidinedionas , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Tiazolidinedionas/toxicidade , Proteômica/métodos , Rosiglitazona/farmacologia , Hipoglicemiantes/toxicidade , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo
14.
J Gastroenterol Hepatol ; 39(7): 1219-1229, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38627972

RESUMO

BACKGROUND AND AIM: Several agents are under investigation for nonalcoholic fatty liver disease (NAFLD). We assessed the comparative efficacy of pharmacologic interventions for patients with NAFLD focusing on magnetic resonance imaging (MRI) biomarkers. METHODS: We searched Medline, Embase, and CENTRAL. We included randomized controlled trials of more than 12 weeks of intervention that recruited patients with biopsy-confirmed or MRI-confirmed NAFLD and assessed the efficacy of interventions on liver fat content (LFC) and fibrosis by means of MRI. We performed random-effects frequentist network meta-analyses and assessed confidence in our estimates using the CINeMA (Confidence in Network Meta-Analysis) approach. RESULTS: We included 47 trials (8583 patients). Versus placebo, thiazolidinediones were the most efficacious for the absolute change in LFC, followed by vitamin E, fibroblast growth factor (FGF) analogs, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with mean differences ranging from -7.46% (95% confidence interval [-11.0, -3.9]) to -4.36% (-7.2, -1.5). No differences between drug classes were evident. Patients receiving GLP-1 RAs or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs were more likely to achieve ≥30% relative reduction in LFC. Among agents, efruxifermin produced the largest reduction in LFC compared to placebo [-13.5% (-18.5, -8.5)], followed by pioglitazone, while being superior to most interventions. The effect of interventions on magnetic resonance elastography assessed fibrosis was small and insignificant. The confidence in our estimates was low to very low. CONCLUSIONS: Several drug classes may reduce LFC in patients with NAFLD without a significant effect on fibrosis; nevertheless, trial duration was small, and confidence in the effect estimates was low.


Assuntos
Biomarcadores , Imageamento por Ressonância Magnética , Hepatopatia Gordurosa não Alcoólica , Tiazolidinedionas , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Humanos , Tiazolidinedionas/uso terapêutico , Vitamina E/uso terapêutico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Resultado do Tratamento , Fatores de Crescimento de Fibroblastos/sangue , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/diagnóstico por imagem
15.
Hum Genomics ; 18(1): 40, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38650020

RESUMO

BACKGROUND: CYP2C8 is responsible for the metabolism of 5% of clinically prescribed drugs, including antimalarials, anti-cancer and anti-inflammatory drugs. Genetic variability is an important factor that influences CYP2C8 activity and modulates the pharmacokinetics, efficacy and safety of its substrates. RESULTS: We profiled the genetic landscape of CYP2C8 variability using data from 96 original studies and data repositories that included a total of 33,185 unrelated participants across 44 countries and 43 ethnic groups. The reduced function allele CYP2C8*2 was most common in West and Central Africa with frequencies of 16-36.9%, whereas it was rare in Europe and Asia (< 2%). In contrast, CYP2C8*3 and CYP2C8*4 were common throughout Europe and the Americas (6.9-19.8% for *3 and 2.3-7.5% for *4), but rare in African and East Asian populations. Importantly, we observe pronounced differences (> 2.3-fold) between neighboring countries and even between geographically overlapping populations. Overall, we found that 20-60% of individuals in Africa and Europe carry at least one CYP2C8 allele associated with reduced metabolism and increased adverse event risk of the anti-malarial amodiaquine. Furthermore, up to 60% of individuals of West African ancestry harbored variants that reduced the clearance of pioglitazone, repaglinide, paclitaxel and ibuprofen. In contrast, reduced function alleles are only found in < 2% of East Asian and 8.3-12.8% of South and West Asian individuals. CONCLUSIONS: Combined, the presented analyses mapped the genetic and inferred functional variability of CYP2C8 with high ethnogeographic resolution. These results can serve as a valuable resource for CYP2C8 allele frequencies and distribution estimates of CYP2C8 phenotypes that could help identify populations at risk upon treatment with CYP2C8 substrates. The high variability between ethnic groups incentivizes high-resolution pharmacogenetic profiling to guide precision medicine and maximize its socioeconomic benefits, particularly for understudied populations with distinct genetic profiles.


Assuntos
Alelos , Carbamatos , Citocromo P-450 CYP2C8 , Piperidinas , Citocromo P-450 CYP2C8/genética , Humanos , Frequência do Gene/genética , Polimorfismo de Nucleotídeo Único/genética , Europa (Continente) , Tiazolidinedionas/efeitos adversos
16.
Am Fam Physician ; 109(4): 333-342, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38648832

RESUMO

Type 2 diabetes mellitus is a chronic disease that is increasing in global prevalence. An individualized approach to pharmacotherapy should consider costs, benefits beyond glucose control, and adverse events. Metformin is the first-line therapy due to its low cost and effectiveness. Sulfonylureas and thiazolidinediones are additional low-cost oral hypoglycemic classes available in the United States; however, evidence shows variability in weight gain and hypoglycemia. Thiazolidinediones increase fluid retention and are not recommended in patients with New York Heart Association class III or IV heart failure. Newer medications, including glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors, have demonstrated weight loss, reduced cardiovascular events, decreased renal disease, and improved all-cause morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors are recommended for people with known cardiovascular disease, heart failure, and chronic kidney disease but carry an increased risk of urinary tract and mycotic infections. Glucagon-like peptide-1 receptor agonists are contraindicated in patients with active multiple endocrine neoplasia type 2 or a personal or family history of medullary thyroid carcinoma; adverse effects include gastrointestinal upset and pancreatitis. Dipeptidyl-peptidase-4 inhibitors have a low risk of hypoglycemia but may increase the risk of pancreatitis and require a renal dose adjustment. Public and private programs to increase access to newer hypoglycemic medications are increasing; however, there are limitations to access, particularly for uninsured and underinsured people.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Metformina/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Tiazolidinedionas/uso terapêutico
17.
Adv Ther ; 41(6): 2168-2195, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38683294

RESUMO

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a complex endocrine condition affecting women of reproductive age. It is characterised by insulin resistance and is a risk for type 2 diabetes mellitus (T2DM). The aim of this study was to review the literature on the effect of pioglitazone and rosiglitazone in women with PCOS. METHODS: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane Library and the Web of Science in April 2020 and updated in March 2023. Studies were deemed eligible if they were randomised controlled trials (RCTs) reporting the effect of pioglitazone and rosiglitazone in PCOS. The study follows the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers independently extracted data and assessed the risk of bias using the Cochrane risk of bias tool. RESULTS: Out of 814 initially retrieved citations, 24 randomised clinical trials (RCTs) involving 976 participants were deemed eligible. Among women with PCOS, treatment with rosiglitazone compared to metformin resulted in a significant increase in the mean body weight (mean difference (MD) 1.95 kg; 95% CI 0.03-3.87, p = 0.05). Metformin treatment was associated with a reduction in mean body mass index (BMI) compared to pioglitazone (MD 0.85 kg/m2; 95% CI 0.13-1.57, p = 0.02). Both pioglitazone compared to placebo (MD 2.56 kg/m2; 95% CI 1.77-3.34, p < 0.00001) and rosiglitazone compared to metformin (MD 0.74 kg/m2; 95% CI 0.07-1.41, p = 0.03) were associated with a significant increase in BMI. Treatment with pioglitazone compared to placebo showed a significant reduction in triglycerides (MD - 0.20 mmol/L; 95% CI - 0.38 to - 0.03, p = 0.02) and fasting insulin levels (MD - 11.47 mmol/L; 95% CI - 20.20, - 2.27, p = 0.01). Rosiglitazone compared to metformin was marginally significantly associated with a reduction in the luteinising hormone (LH) (MD - 0.62; 95% CI - 1.25-0.00, p = 0.05). CONCLUSION: Both pioglitazone and rosiglitazone were associated with significant increases in body weight and BMI when compared with metformin or placebo. Pioglitazone significantly reduced triglycerides and fasting insulin when compared with placebo while rosiglitazone showed a modest reduction of LH when compared with metformin. PROSPERO REGISTRATION NO: CRD42020178783.


Assuntos
Hipoglicemiantes , Pioglitazona , Síndrome do Ovário Policístico , Ensaios Clínicos Controlados Aleatórios como Assunto , Rosiglitazona , Síndrome do Ovário Policístico/tratamento farmacológico , Humanos , Feminino , Hipoglicemiantes/uso terapêutico , Pioglitazona/uso terapêutico , Rosiglitazona/uso terapêutico , Rosiglitazona/farmacologia , Tiazolidinedionas/uso terapêutico , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Índice de Massa Corporal
18.
Curr Top Med Chem ; 24(14): 1264-1277, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38523516

RESUMO

BACKGROUND: Inflammation is a series of complex defense-related reactions. The inflammation cascade produces various pro-inflammatory mediators. Unregulated production of these pro-inflammatory mediators can lead to a wide range of diseases, including rheumatoid arthritis, sepsis, and inflammatory bowel disease. In the literature, the anti-inflammatory action of quinoline and thiazolidinedione nuclei are well established, alone, and associated with other nuclei. The synthesis of hybrid molecules is a strategy for obtaining more efficient molecules due to the union of pharmacophoric nuclei known to be related to pharmacological activity. OBJECTIVES: Based on this, this work presents the synthesis of thiazolidinedione-quinoline molecular hybrids and their involvement in the modulation of cytokines involved in the inflammatory reaction cascade. METHODS: After synthesis and characterization, the compounds were submitted to cell viability test (MTT), ELISA IFN-γ and TNF-α, adipogenic differentiation, and molecular docking assay with PPARy and COX-2 targets. RESULTS: LPSF/ZKD2 and LPSF/ZKD7 showed a significant decrease in the concentration of IFN- γ and TNF-α, with a dose-dependent behavior. LPSF/ZKD4 at a concentration of 50 µM significantly reduced IL-6 expression. LPSF/ZKD4 demonstrates lipid accumulation with significant differences between the untreated and negative control groups, indicating a relevant agonist action on the PPARγ receptor. Molecular docking showed that all synthesized compounds have good affinity with PPARγ e COX-2, with binding energy close to -10,000 Kcal/mol. CONCLUSION: These results demonstrate that the synthesis of quinoline-thiazolidinedione hybrids may be a useful strategy for obtaining promising candidates for new anti-inflammatory agents.


Assuntos
Simulação de Acoplamento Molecular , Quinolinas , Tiazolidinedionas , Quinolinas/farmacologia , Quinolinas/química , Quinolinas/síntese química , Tiazolidinedionas/farmacologia , Tiazolidinedionas/síntese química , Tiazolidinedionas/química , Estrutura Molecular , Humanos , Sobrevivência Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Animais , PPAR gama/agonistas , PPAR gama/metabolismo , Relação Dose-Resposta a Droga , Camundongos , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Ciclo-Oxigenase 2/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Fator de Necrose Tumoral alfa/metabolismo
19.
Curr Top Med Chem ; 24(10): 885-928, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38500288

RESUMO

BACKGROUND: Thiazolidine-2,4-dione (2,4-TZD) is a flexible pharmacophore and a privileged platform and contains a five-membered ring with a 2-oxygen atom with double bond 2,4- position and one nitrogen atom as well as sulphur containing in the heterocyclic compound. A famous electron-rich nitrogen transporter combines invigorating electronic properties with the prospective for elemental applications. Thiazolidine-2,4-dione analogues have been synthesized using a variety of methods, all of which have shown to have a strong biological effect. OBJECTIVES: The study of the biological activity of Thiazolidine-2,4-dione derivatives has been a fascinating field of pharmaceutical chemistry and has many purposes. This derivative described in the literature between 1995 to 2023 was the focus of this study. Thiazolidine-2,4-diones have been discussed in terms of their introduction, general method, synthetic scheme and antidiabetic significance in the current review. CONCLUSION: Thiazolidine-2,4-diones are well-known heterocyclic compounds. The synthesis of Thiazolidine-2,4-diones has been described using a variety of methods. Antidiabetic activity has been discovered in several Thiazolidine-2,4-dione derivatives, which enhance further research. The use of Thiazolidine-2,4-diones to treat antidiabetics has piqued researchers' interest in learning more about thiazolidine-2,4-diones.


Assuntos
Hipoglicemiantes , Tiazolidinedionas , Tiazolidinedionas/química , Tiazolidinedionas/síntese química , Tiazolidinedionas/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Animais
20.
CPT Pharmacometrics Syst Pharmacol ; 13(6): 982-993, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38549500

RESUMO

Leriglitazone is a unique peroxisome proliferator-activated receptor-gamma (PPARγ) agonist that crosses the blood-brain barrier in humans and clinical trials have shown evidence of efficacy in neurodegenerative diseases. At clinical doses which are well-tolerated, leriglitazone reaches the target central nervous system (CNS) concentrations that are needed for PPARγ engagement and efficacy; PPARγ engagement is also supported by clinical and anti-inflammatory biomarker changes in the Cerebrospinal fluid in the CNS. Plasma pharmacokinetics (PK) of leriglitazone were determined in a phase 1 study in male healthy volunteers comprising a single ascending dose (SAD) and a multiple ascending dose (MAD) at oral doses of 30, 90, and 270 mg and 135 and 270 mg, respectively. Leriglitazone was rapidly absorbed with no food effect on overall exposure and showed a linear PK profile with dose-exposure correlation. A physiologically based pharmacokinetic (PBPK) model was developed for leriglitazone based on phase 1 data (SAD part) and incorporated CYP3A4 (fmCYP3A4 = 24%) and CYP2C8-mediated (fmCYP2C8 = 45%) metabolism, as well as biliary clearance (feBIL = 19.5%) derived from in vitro data, and was verified by comparing the observed versus predicted concentration-time profiles from the MAD part. The PBPK model was prospectively applied to predict the starting pediatric doses and was preliminarily verified with data from five pediatric patients.


Assuntos
Relação Dose-Resposta a Droga , Modelos Biológicos , Tiazolidinedionas , Humanos , Masculino , Criança , Tiazolidinedionas/farmacocinética , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/sangue , Adulto , Adulto Jovem , PPAR gama/agonistas , Adolescente , Administração Oral , Voluntários Saudáveis
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