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1.
BMJ Open ; 10(9): e040644, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928868

RESUMO

OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Infecções por Coronavirus , Estrogênios/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipoglicemiantes/farmacologia , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral , Anti-Inflamatórios não Esteroides/farmacologia , Betacoronavirus/metabolismo , Regulação para Baixo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Insulina/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Peptidil Dipeptidase A/metabolismo , Tiazolidinedionas/farmacologia , Reino Unido , Regulação para Cima
2.
Life Sci ; 259: 118270, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32814067

RESUMO

AIMS: Partial PPARγ agonists attracted substantially heightened interest as safer thiazolidinediones alternatives. On the other hand, Wnt/ß-catenin antagonists have been highlighted as promising strategy for type 2 diabetes management via up-regulating PPARγ gene expression. We aimed at synthesizing novel partial PPARγ agonists with ß-catenin inhibitory activity which could enhance insulin sensitivity and avoid the side effects of full PPARγ agonists. MAIN METHODS: We synthesized novel series of α-phthlimido-o-toluoyl-2-aminothiazoles hybrids for evaluating their antidiabetic activity and discovering its mechanistic pathway. We assessed effect of the new hybrids on PPARγ activation using a luciferase reporter assay system. Moreover, intracellular triglyceride levels, gene levels of c/EBPα, PPARγ and PPARγ targets including GLUT4, adiponectin, aP2 were measured in 3T3-L1 cells. Uptake of 2-DOG together with PPARγ and ß-catenin protein levels were evaluated in 3T3-L1cells. In addition, molecular docking studies with PPARγ LBD, physicochemical properties and structure activity relationship of the novel hybrids were also studied. KEY FINDINGS: Three of the synthesized hybrids showed partial PPARγ agonistic activity and distinct PPARγ binding pattern. These compounds modulated PPARγ gene expression and PPARγ target genes; and increased glucose uptake in 3T3-L1 and slightly induced adipogenesis compared to rosiglitazone. Moreover, these compounds reduced ß-catenin protein level which reflected in increased both PPARγ gene and protein levels that leads to improved insulin sensitivity and increased GLUT4 and adiponectin gene expression. SIGNIFICANCE: Our synthesized compounds act as novel partial PPARγ agonists and ß-catenin inhibitors that have potent insulin sensitizing activity and mitigate the lipogenic side effects of TZDs.


Assuntos
Resistência à Insulina/fisiologia , Ftalimidas/farmacologia , Tiazóis/farmacologia , Células 3T3-L1 , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Adiponectina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Insulina/metabolismo , Camundongos , Simulação de Acoplamento Molecular , PPAR gama/agonistas , PPAR gama/metabolismo , Rosiglitazona/farmacologia , Tiazolidinedionas/farmacologia , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
3.
PLoS One ; 15(7): e0236603, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706828

RESUMO

BACKGROUND AND OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have pancreatic beta-cell preserving effect according to studies using homeostatic model of assessment for beta-cell function (HOMA-ß). However, whether HOMA-ß is a suitable biomarker for comparisons between hypoglycemic drugs with different mechanisms of action remains unclear. Therefore, we conducted a meta-analysis to compare the effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-ß and proinsulin-to-insulin ratio (PIR). METHODS: We searched MEDLINE, CENTRAL, and Ichushi-web for the period of 1966 to May 2020. We collected randomized, controlled clinical trials in patients with type 2 diabetes mellitus comparing DPP-4 inhibitors and other classes of hypoglycemic agents [α-glucosidase inhibitors (α-GIs), glucagon-like peptide-1 (GLP-1) analogues, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, or thiazolidinediones]. Weighted mean differences and 95% confidence intervals of changes in HOMA-ß or PIR during study periods were calculated for pairwise comparisons. RESULTS: Thirty-seven and 21 relevant trials were retrieved for comparisons of HOMA-ß and PIR, respectively. HOMA-ß and PIR consistently showed superiority of DPP-4 inhibitors compared with α-GIs. Both biomarkers consistently supported inferiority of DPP-4 inhibitors compared with GLP-1 analogues. However, PIR showed inferiority of DPP-4 inhibitors compared with metformin, and superiority compared with SGLT2 inhibitors, whereas HOMA-ß showed no significant differences between DPP-4 inhibitors and the two other agents. CONCLUSION: DPP-4 inhibitors appear to be superior to α-GIs but inferior to GLP-1 analogues in preservation of beta-cell function assessed by either HOMA-ß or PIR. DPP-4 inhibitors seem to be superior to SGLT2 inhibitors but inferior to metformin on islet function assessed only by PIR. Because HOMA-ß and PIR may indicate different aspects of beta-cell function, results of beta-cell function preserving effects of hypoglycemic agents should be interpreted with caution.


Assuntos
Biomarcadores/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Proinsulina/metabolismo , Compostos de Sulfonilureia/farmacologia , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico
4.
Anticancer Res ; 40(6): 3071-3080, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487601

RESUMO

BACKGROUND/AIM: Head and neck squamous cell carcinoma affects nearly 500,000 people annually. Augmenting PPARγ functional activation is linked with multiple anti-carcinogenic processes in aerodigestive cell lines and animal models. PPARγ/RXRα heterodimers may be key partners in this activation. MATERIALS AND METHODS: CA 9-22 and NA cell lines were treated with the PPARγ agonist ciglitazone and/or the RXRα agonist 9-cis-retinoic acid. PPARγ functional activation, cellular proliferation, apoptosis activity, and phenotype were subsequently analyzed. RESULTS: Ciglitazone and 9-cis-retinoic acid independently activated PPARγ and down-regulated the carcinogenic phenotype in vitro. Combination treatment significantly augmented these effects, further decreasing proliferation (p<0.0001), and increasing PPARγ functional activation (p<0.0001), apoptosis (p<0.05), and adipocyte differentiation markers (p<0.0001). CONCLUSION: The efficacy of the combination of ciglitazone and 9-cis-retinoic acid afforded lowering treatment concentrations while maintaining desired therapeutic outcomes, optimistically supporting the feasibility and practicality of this novel treatment option.


Assuntos
Neoplasias Bucais/tratamento farmacológico , PPAR gama/metabolismo , Retinoides/uso terapêutico , Tiazolidinedionas/uso terapêutico , Humanos , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Retinoides/farmacologia , Taxa de Sobrevida , Tiazolidinedionas/farmacologia
5.
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
6.
Molecules ; 25(9)2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32365556

RESUMO

The cytokine storm is an abnormal production of inflammatory cytokines, due to the over-activation of the innate immune response. This mechanism has been recognized as a critical mediator of influenza-induced lung disease, and it could be pivotal for COVID-19 infections. Thus, an immunomodulatory approach targeting the over-production of cytokines could be proposed for viral aggressive pulmonary disease treatment. In this regard, the peroxisome proliferator-activated receptor (PPAR)-γ, a member of the PPAR transcription factor family, could represent a potential target. Beside the well-known regulatory role on lipid and glucose metabolism, PPAR-γ also represses the inflammatory process. Similarly, the PPAR-γ agonist thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorating effects on severe viral pneumonia. In addition to the pharmacological agonists, also nutritional ligands of PPAR-γ, like curcuma, lemongrass, and pomegranate, possess anti-inflammatory properties through PPAR-γ activation. Here, we review the main synthetic and nutritional PPAR-γ ligands, proposing a dual approach based on the strengthening of the immune system using pharmacological and dietary strategies as an attempt to prevent/treat cytokine storm in the case of coronavirus infection.


Assuntos
Infecções por Coronavirus/patologia , PPAR gama/agonistas , Plantas Medicinais/química , Pneumonia Viral/patologia , Tiazolidinedionas/farmacologia , Animais , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Citocinas/antagonistas & inibidores , Óleos de Peixe/farmacologia , Humanos , Ligantes , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Alimentos Marinhos/análise , Especiarias/análise
7.
Metabolism ; 109: 154265, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32446679

RESUMO

BACKGROUND: Dementia is more prevalent among people with type 2 diabetes, but little is known regarding the influence of antidiabetic agents on this association. OBJECTIVE: This study assessed the impact of various antidiabetic agents on the risk of dementia among patients with Type 2 diabetes mellitus. METHODS: Relevant studies were retrieved from the PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases. Nine antidiabetic agents were included in the search. Data were pooled via network meta-analysis and meta-analysis. RESULTS: Nine studies were selected for the network meta-analysis with 530,355 individuals and 17 studies for the meta-analysis with 1,258,879 individuals. The analysis excluded glucagon-like peptide 1 (GLP-1) analogs and sodium-dependent glucose transporter 2 (SGLT-2) inhibitors due to the absence of relevant data. The use of dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, thiazolidinedione, and sulfonylurea was associated with a decreased risk of dementia in comparison to no treatment with antidiabetic agents (hazard ratio [HR] for DPP-4 inhibitors, 0.54; 95% confidence interval [CI], 0.38-0.74, HR for metformin, 0.75; 95% CI, 0.63-0.86; HR for sulfonylurea, 0.85; 95%CI, 0.73-0.98 and HR for thiazolidinedione, 0.70; 95% CI, 0.55-0.89, respectively). However, the node-splitting analysis showed the inconsistency of direct and indirect estimates in sulfonylurea (P = 0.042). DPP-4 inhibitors, metformin, thiazolidinedione, and sulfonylurea exhibited a significant impact on the risk of dementia in diabetics compared with insulin (HR, 0.35; 95%CI, 0.20-0.59, HR, 0.48; 95% CI, 0.30-0.77, HR, 0.45; 95% CI, 0.29-0.73 and HR, 0.55; 95% CI, 0.34-0.88, respectively). DPP-4 inhibitors also exhibited a protective effect on the risk of Alzheimer's dementia compared with the no treatment with antidiabetic agents (HR, 0.48; 95% CI, 0.25-0.92). The meta-analysis demonstrated a protective effect of using metformin and DPP-4 inhibitors on the risk of dementia (HR, 0.86; 95% CI, 0.74-1.00 and HR, 0.65; 95% CI, 0.55-0.76, respectively). Further analysis showed insulin was associated with an increased risk of Alzheimer's dementia (HR, 1.60; 95% CI, 1.13-2.26). Only two case-control studies mentioned GLP-1 analogs and SGLT-2 inhibitors, and the pooled ORs showed no evidence of an association with dementia (GLP-1 analogs: 0.71; 95% CI, 0.46-1.10 and SGLT-2 inhibitors: 0.74; 95% CI, 0.47-1.15). CONCLUSION: This analysis indicated that patients with type 2 diabetes under treatment with DPP-4 inhibitors presented with the lowest risk of dementia, followed by those treated with metformin and thiazolidinedione, while treatment with insulin was associated with the highest risk. For the increasing focus on the protective effect on dementia, further specific clinical studies are needed to evaluate the impact of GLP-1 analogs and SGLT-2 inhibitors on the risk of dementia.


Assuntos
Teorema de Bayes , Demência/etiologia , Hipoglicemiantes/farmacologia , Metanálise em Rede , Demência/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Substâncias Protetoras , Risco , Compostos de Sulfonilureia/farmacologia , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico
8.
Parasitol Res ; 119(7): 2263-2274, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32462293

RESUMO

Leishmaniasis is responsible for approximately 65,000 annual deaths. Despite the mortality data, drugs available for the treatment of patients are insufficient and have moderate therapeutic efficacy in addition to serious adverse effects, which makes the development of new drugs urgent. To achieve this goal, the integration of kinetic and DSF assays against parasitic validated targets, along with phenotypic assays, can help the identification and optimization of bioactive compounds. Pteridine reductase 1 (PTR1), a validated target in Leishmania sp., is responsible for the reduction of folate and biopterin to tetrahydrofolate and tetrahydrobiopterin, respectively, both of which are essential for cell growth. In addition to the in vitro evaluation of 16 thiazolidine-2,4-dione derivatives against Leishmania major PTR1 (LmPTR1), using the differential scanning fluorimetry (ThermoFluor®), phenotypic assays were employed to evaluate the compound effect over Leishmania braziliensis (MHOM/BR/75/M2903) and Leishmania infantum (MHOM/BR/74/PP75) promastigotes viability. The ThermoFluor® results show that thiazolidine-2,4-dione derivatives have micromolar affinity to the target and equivalent activity on Leishmania cells. 2b is the most potent compound against L. infantum (EC50 = 23.45 ± 4.54 µM), whereas 2a is the most potent against L. braziliensis (EC50 = 44.16 ± 5.77 µM). This result suggests that lipophilic substituents on either-meta and/or-para positions of the benzylidene ring increase the potency against L. infantum. On the other hand, compound 2c (CE50 = 49.22 ± 7.71 µM) presented the highest selectivity index.


Assuntos
Antiprotozoários/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Animais , Antiprotozoários/química , Humanos , Leishmania braziliensis/enzimologia , Leishmania infantum/enzimologia , Oxirredutases/antagonistas & inibidores , Testes de Sensibilidade Parasitária , Tiazolidinedionas/química
9.
Eur J Med Chem ; 188: 111955, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31893550

RESUMO

Selective kinase inhibitors development is a cumbersome task because of ATP binding sites similarities across kinases. On contrast, irreversible allosteric covalent inhibition offers opportunity to develop novel selective kinase inhibitors. Previously, we reported thiazolidine-2,4-dione lead compounds eliciting in vitro irreversible allosteric inhibition of IKK-ß. Herein, we address optimization into in vivo active anti-inflammatory agents. We successfully developed potent IKK-ß inhibitors with the most potent compound eliciting IC50 = 0.20 µM. Cellular assay of a set of active compounds using bacterial endotoxin lipopolysaccharide (LPS)-stimulated macrophages elucidated significant in vitro anti-inflammatory activity. In vitro evaluation of microsomal and plasma stabilities showed that the promising compound 7a is more stable than compound 7p. Finally, in vivo evaluation of 7a, which has been conducted in a model of LPS-induced septic shock in mice, showed its ability to protect mice against septic shock induced mortality. Accordingly, this study presents compound 7a as a novel potential irreversible allosteric covalent inhibitor of IKK-ß with verified in vitro and in vivo anti-inflammatory activity.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Tiazolidinedionas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Quinase I-kappa B/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Células RAW 264.7 , Choque Séptico/tratamento farmacológico , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/química
10.
Eur J Med Chem ; 189: 112045, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31951961

RESUMO

The two series of thiazolidine-2,4-dione (TZD) based hybrids with halogenbenzohydrazones and pyridinecarbohydrazones substituents were designed and synthesized. Target hydrazones were evaluated for their antimycobacterial activity by broth microdilution method with resazurin as an indicator of the metabolic activity of mycobacteria. Conducted studies revealed antimycobacterial activity in the concentration range of 1-512 µg/ml for 23 synthesized TZD-based derivatives. The highest antimycobacterial activity (MIC = 1 µg/ml) was demonstrated for the new group of compounds: TZD-based derivatives with pyridine-4-carbohydrazone substituent. Furthermore, all the tested compounds within this group were characterized by low cytotoxicity. On the basis of the results obtained, three compounds with the highest SI were selected. High effectiveness and safety of these synthesized derivatives makes them promising candidates as antimycobacterial agents.


Assuntos
Antituberculosos/farmacologia , Hidrazonas/farmacologia , Tiazolidinedionas/farmacologia , Animais , Antituberculosos/síntese química , Chlorocebus aethiops , Desenho de Fármacos , Hidrazonas/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazolidinedionas/síntese química , Células Vero
11.
Eur J Med Chem ; 185: 111812, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31703818

RESUMO

Zinc metalloprotease 1 (Zmp1) is an extracellular enzyme, which has been found essential for the intracellular survival and pathogenesis of Mycobacterium tuberculosis. In this work, we designed and synthesized a series of novel thiazolidinedione-hydroxamates and evaluated in silico their drug-likeness behavior. Then, their inhibitory properties towards a recombinant Zmp1 from Mycobacterium tuberculosis were analyzed by MALDI-TOF MS. Nine of the tested compounds were found to inhibit the enzymatic reaction more effectively than the generic metalloprotease inhibitor phosphoramidon. Furthermore, the synthesized thiazolidinedione-hydroxamate hybrids were evaluated for their in vitro antimycobacterial activity and acute cytotoxicity using whole-cell assays. Results showed that none of the hybrids exhibited acute cytotoxicity against RAW264.7 macrophages. Whereas extracellular antimycobacterial activity was limited, RAW264.7 macrophage infection results showed that a majority of the hybrids inhibited the intracellular growth of Mycobacterium tuberculosis at a concentration of 100 and 10 µM. The thiazolidinedione-hydroxamate compound 2n was considered to be the best candidate of the evaluated library.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Metaloproteases/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Relação Dose-Resposta a Droga , Humanos , Ácidos Hidroxâmicos/química , Metaloproteases/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/metabolismo , Relação Estrutura-Atividade , Tiazolidinedionas/química
12.
J Mol Biol ; 432(5): 1514-1534, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-31628942

RESUMO

The deleterious effects of chronically elevated free fatty acid (FFA) levels on glucose homeostasis are referred to as lipotoxicity, and the concurrent exposure to high glucose may cause synergistic glucolipotoxicity. Lipo- and glucolipotoxicity have been studied for over 25 years. Here, we review the current evidence supporting the role of pancreatic ß-cell lipo- and glucolipotoxicity in type 2 diabetes (T2D), including lipid-based interventions in humans, prospective epidemiological studies, and human genetic findings. In addition to total FFA quantity, the quality of FFAs (saturation and chain length) is a key determinant of lipotoxicity. We discuss in vitro and in vivo experimental models to investigate lipo- and glucolipotoxicity in ß-cells and describe experimental pitfalls. Lipo- and glucolipotoxicity adversely affect many steps of the insulin production and secretion process. The molecular mechanisms underpinning lipo- and glucolipotoxic ß-cell dysfunction and death comprise endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, impaired autophagy, and inflammation. Crosstalk between these stress pathways exists at multiple levels and may aggravate ß-cell lipo- and glucolipotoxicity. Lipo- and glucolipotoxicity are therapeutic targets as several drugs impact the underlying stress responses in ß-cells, potentially contributing to their glucose-lowering effects in T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Ácidos Graxos não Esterificados/toxicidade , Glucose/toxicidade , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/metabolismo , Animais , Autofagia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Estresse do Retículo Endoplasmático , Ácidos Graxos não Esterificados/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/análise , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Glucose/metabolismo , Humanos , Inflamação , Insulina/biossíntese , Insulina/metabolismo , Metformina/farmacologia , Mitocôndrias/patologia , Estresse Oxidativo , Transdução de Sinais , Tiazolidinedionas/farmacologia
13.
Dev Biol ; 458(1): 12-31, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31605680

RESUMO

The cellular mechanisms underlying the amazing ability of sea cucumbers to regenerate their autotomized intestines have been widely described by us and others. However, the signaling pathways that control these mechanisms are unknown. Previous studies have shown that Wnt homologs are upregulated during early intestinal regenerative stages, suggesting that the Wnt/ß-catenin pathway is active during this process. Here, we used small molecules, putative disruptors of the Wnt pathway, to determine the potential role of the canonical Wnt pathway on intestine regeneration in the sea cucumber Holothuria glaberrima. We evaluated their effects in vivo by using histological analyses for cell dedifferentiation, cell proliferation and apoptosis. We found that iCRT14, an alleged Wnt pathway inhibitor, decreased the size of the regenerating intestine, while LiCl, a presumed Wnt pathway activator, increased its size. The possible cellular mechanisms by which signaling pathway disruptors affect the gut rudiment size were further studied in vitro, using cultures of tissue explants and additional pharmacological agents. Among the tested signaling activators, those that act through GSK-3 inhibition, LiCl, 1-Azakenpaullone, and CHIR99021 were found to increase muscle cell dedifferentiation, while the inhibitor iCRT14 blocked cell dedifferentiation. Differently, cell proliferation was reduced by all GSK-3 inhibitors, as well as by iCRT14 and C59, which interferes with Wnt ligand secretion. The in vivo temporal and spatial pattern of ß-catenin activity was determined using an antibody against phosphorylated ß-catenin and shown to correlate with cell proliferative activity. In vitro treatment using C59 decreased the number of cells immunostained for nuclear phosphorylated ß-catenin. Our results showed that the cell dedifferentiation observed during intestinal regeneration can be decoupled from the cell proliferation event and that these cellular processes can be modulated by particular signaling pathway inhibitors and activators. These results open the door for future studies where the cellular signaling pathways involved at each regeneration stage can be determined.


Assuntos
Holothuria/fisiologia , Intestinos/fisiologia , Regeneração/fisiologia , Via de Sinalização Wnt/fisiologia , Animais , Benzazepinas/farmacologia , Benzenoacetamidas/farmacologia , Desdiferenciação Celular , Núcleo Celular/metabolismo , Proliferação de Células , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Indóis/farmacologia , Cloreto de Lítio/farmacologia , Células Musculares/metabolismo , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Piridinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Tiazolidinedionas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
14.
Am J Respir Cell Mol Biol ; 62(2): 143-156, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31577451

RESUMO

Translational research is essential to the development of reverse-remodeling strategies for the treatment of pulmonary vascular disease, pulmonary hypertension, and heart failure via mechanistic in vivo studies using animal models resembling human pulmonary arterial hypertension (PAH), cardiovascular remodeling, and progressive right heart failure. Since 2007, peroxisome proliferator-activated receptor γ (PPARγ) agonists have emerged as promising novel, antiproliferative, antiinflammatory, insulin-sensitizing, efficient medications for the treatment of PAH. However, early diabetes study results, their subsequent misinterpretations, errors in published review articles, and rumors regarding potential adverse effects in the literature have dampened enthusiasm for considering pharmacological PPARγ activation for the treatment of cardiovascular diseases, including PAH. Most recently, the thiazolidinedione class PPARγ agonist pioglitazone underwent a clinical revival, especially based on the IRIS (Insulin Resistance Intervention After Stroke) study, a randomized controlled trial in 3,876 patients without diabetes status post-transient ischemic attack/ischemic stroke who were clinically followed for 4.8 years. We discuss preclinical basic translational findings and randomized controlled trials related to the beneficial and adverse effects of PPARγ agonists of the thiazolidinedione class, with a particular focus on the last 5 years. The objective is a data-driven approach to set the preclinical and clinical study record straight. The convincing recent clinical trial data on the lack of significant toxicity in high-risk populations justify the timely conduct of clinical studies to achieve "repurposing" or "repositioning" of pioglitazone for the treatment of clinical PAH.


Assuntos
Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , PPAR gama/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Animais , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Tiazolidinedionas/farmacologia
15.
Mini Rev Med Chem ; 20(4): 308-330, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31660809

RESUMO

2,4-Thiazolidinedione (2,4-TZD) is a versatile pharmacophore, a privileged scaffold, and a remarkable sulphur-containing heterocyclic compound with diverse pharmacological activities. The multifarious biological activities, due to different mechanisms of action, low cost, and easy availability of 2,4-TZD impressed medicinal chemists to integrate this moiety to develop various lead compounds with diverse therapeutic actions. This resulted in the swift development in the last decade for generating different new potential molecules bearing 2,4-TZD. In this review, the authors attempt to shape and present the latest investigations (2012 onwards) going on in generating promising 2,4-TZD containing lead compounds. The data has been collected and analyzed to develop the structure-activity relationship (SAR). The SAR and active pharmacophores of various leads accountable for antidiabetic, anticancer, antimicrobial, and antioxidant activities have also been illustrated. This review also highlighted some of the important chemical synthetic routes for the preparation of various 2,4-TZD derivatives. This review will definitely serve as a useful source of structural information to medicinal chemists and may be utilized for the strategic design of potent 2,4-TZD derivatives in the future.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Hipoglicemiantes/farmacologia , Tiazolidinedionas/farmacologia , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/química
16.
Sci Rep ; 9(1): 19085, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836766

RESUMO

Toll-like receptor 9 (TLR9) and Phosphatidylinositol-3-kinase gamma (PI3Kγ) are very important effectors of the immune response, however, the importance of such crosstalk for disease development is still a matter of discussion. Here we show that PI3Kγ is required for immune responses in which TLR9 is a relevant trigger. We demonstrate the requirement of PI3Kγ for TLR9-induced inflammation in a model of CpG-induced pleurisy. Such requirement was further observed in inflammatory models where DNA sensing via TLR9 contributes to disease, such as silicosis and drug-induced liver injury. Using adoptive transfer, we demonstrate that PI3Kγ is important not only in leukocytes but also in parenchymal cells for the progression of inflammation. We demonstrate this crosstalk between TLR9 and PI3Kγ in vitro using human PBMCs. The inhibition of PI3Kγ in CpG-stimulated PBMCs resulted in reduction of both cytokine production and phosphorylated Akt. Therefore, drugs that target PI3Kγ have the potential to treat diseases mediated by excessive TLR9 signalling.


Assuntos
Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Inflamação/patologia , Especificidade de Órgãos , Transdução de Sinais , Receptor Toll-Like 9/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/biossíntese , Feminino , Deleção de Genes , Inflamação/enzimologia , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/patologia , Pulmão/enzimologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/farmacologia , Especificidade de Órgãos/efeitos dos fármacos , Pleura/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Quinoxalinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Dióxido de Silício , Tiazolidinedionas/farmacologia
17.
Int J Mol Sci ; 20(24)2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31835389

RESUMO

Thiazolidinedione is a five-membered heterocycle that is widely used in drug discovery endeavors. In this study, we report the design, synthesis, and biological evaluation of a series of thiazolidinedione-based HDAC6 inhibitors. In particular, compound 6b exerts an excellent inhibitory activity against HDAC6 with an IC50 value of 21 nM, displaying a good HDAC6 selectivity over HDAC1. Compound 6b dose-dependently induces the acetylation level of α-tubulin via inhibition of HDAC6 in human neuroblastoma SH-SY5Y cell line. Moreover, compound 6b efficiently reverses methamphetamine-induced morphology changes of SH-SY5Y cells via regulating acetylation landscape of α-tubulin. Collectively, compound 6b represents a novel HDAC6-isoform selective inhibitor and demonstrates promising therapeutic potential for the treatment of methamphetamine addiction.


Assuntos
Descoberta de Drogas , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases , Tiazolidinedionas , Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Transtornos Relacionados ao Uso de Anfetaminas/enzimologia , Linhagem Celular Tumoral , Desacetilase 6 de Histona/química , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/metabolismo , Tiazolidinedionas/síntese química , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia
18.
Comb Chem High Throughput Screen ; 22(10): 716-727, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31775594

RESUMO

AIMS AND OBJECTIVE: The magic scaffolds rhodanine and thiazolidine are very important heterocyclic compounds in drug design and discovery. Those are important heterocyclic compounds that have attracted a great deal of attention due to the fact that they exhibit a variety of bioactivities including antibacterial, antifungal, antiviral, antimalarial, and anti-inflammatory activities. These agents often exhibit selective toxicity. The goal of this study was molecular docking, green and solvent-free efficient synthesis of a new series of hetero/aromatic substituted rhodanine and thiazolidine analogues and then investigation of their antimicrobial activity. MATERIALS AND METHODS: To a mixture of TZD or rhodanine (1 mmol) in the presence of ionic liquid ChCl/urea, various aldehyde (1 mmol) was added. After completion of the reaction, obtained crude compound was collected by filtration and products were recrystallized from ethanol. The binding-free energy between all synthesized compounds with 3EEJ protein (C. glabrata enzyme) were obtained by molecular docking studies. These compounds were evaluated using microdilution method against (ATCC 6538) and (ATCC 12228) Gram-negative, (ATCC 8739) and (ATCC 9027) as Gram-positive and (ATCC 1012), (ATCC 339), C. (ATCC 1057), (ATCC 503), (ATCC 340) and (ATCC 194) as fungi. RESULTS: All of the acceptable products were determined by 1H NMR, 13C NMR, Mas and FT-IR spectroscopy. The binding-free energy between compounds 10a and 10b with 3EEJ protein were found to be -8.08 kcal/mol and -8.15 kcal/mol, respectively. These compounds having a heteroaromatic ring attached to the TZD or rhodanine core showed excellent antimicrobial activity with MIC values of 0.25-8 µg/mL (compound 10a) and 0.5-16 µg/mL (compound 10b) against the most tested fungi strains, Gram-positive and Gram-negative bacteria. CONCLUSION: A convenient and rapid method has been developed for the synthesis of rhodanine and thiazolidine-2,4-dione (TZD) derivatives as efficient antimicrobial agents using a Deep Eutectic Ionic Liquids (DEILs) choline chloride urea under solvent-free condition. Among the newly synthesized compounds, (Z)-5-((quinoxalin-3-yl) methylene) thiazolidine-2, 4-dione (10a) and (Z)- 5- ((quinoxalin-3-yl) methylene)-2-thioxothiazolidin-one (10b) exerted the promising effect and these compounds can be considered to be further probed as inhibitors of cgDHFR enzyme.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Simulação de Acoplamento Molecular , Rodanina/farmacologia , Tiazolidinedionas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Rodanina/síntese química , Rodanina/química , Tiazolidinedionas/síntese química , Tiazolidinedionas/química
19.
Molecules ; 24(21)2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683749

RESUMO

 In an effort to improve the antimicrobial activity of norfloxacin, a series of hybrid norfloxacin-thiazolidinedione molecules were synthesized and screened for their direct antimicrobial activity and their anti-biofilm properties. The new hybrids were intended to have a new binding mode to DNA gyrase, that will allow for a more potent antibacterial effect, and for activity against current quinolone-resistant bacterial strains. Moreover, the thiazolidinedione moiety aimed to include additional anti-pathogenicity by preventing biofilm formation. The resulting compounds showed promising direct activity against Gram-negative strains, and anti-biofilm activity against Gram-positive strains. Docking studies and ADMET were also used in order to explain the biological properties and revealed some potential advantages over the parent molecule norfloxacin.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Norfloxacino/análogos & derivados , Tiazolidinedionas/química , Tiazolidinedionas/síntese química , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Domínio Catalítico , DNA Girase/metabolismo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Acoplamento Molecular , Solubilidade , Tiazolidinedionas/farmacocinética , Tiazolidinedionas/farmacologia , Água/química
20.
CNS Neurol Disord Drug Targets ; 18(10): 798-807, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31742497

RESUMO

BACKGROUND: Epilepsy is a serious and common neurological disorder threatening the health of humans. Despite enormous progress in epileptic research, the anti-epileptic drugs present many limitations. These limitations prompted the development of more safer and effective AEDs. METHODS: A series of N-substituted (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)- 2-thioxothiazolidin-4- one derivatives and 5-substituted-thioxothiazolidindione derivatives were designed, synthesized and tested for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ). Neurotoxicity was determined by the rotarod test. RESULTS: Among them, the most potent 4e displayed high protection against MES-induced seizures with an ED50 value of 9.7 mg/kg and TD50 value of 263.3 mg/kg, which provided 4e with a high protective index (TD50/ED50) of 27.1 comparable to reference antiepileptic drugs. 4e clearly inhibits the NaV1.1 channel in vitro. The molecular docking study was conducted to exploit the results. CONCLUSION: Stiripentol is a good lead compound for further structural modification. Compound 4e was synthesized, which displayed remarkable anticonvulsant activities, and the NaV1.1 channel inhibition was involved in the mechanism of action of 4e.


Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Convulsões/prevenção & controle , Tiazolidinedionas/síntese química , Tiazolidinedionas/farmacologia , Animais , Anticonvulsivantes/toxicidade , Relação Dose-Resposta a Droga , Eletrochoque , Camundongos , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.1/efeitos dos fármacos , Pentilenotetrazol , Convulsões/induzido quimicamente , Relação Estrutura-Atividade , Tiazolidinedionas/toxicidade
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