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1.
Life Sci ; 241: 117108, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31786192

RESUMO

AIMS: Telmisartan (TLM), a highly selective angiotensin II type 1 receptor blocker (ARB) and partial PPAR-γ agonist, has versatile beneficial effects against oxidative stress, apoptosis, inflammatory responses and epithelial-mesenchymal transition (EMT). However, its underlying mechanism of inhibiting oxalate and calcium oxalate (CaOx) crystal-induced EMT by activating the PPAR-γ pathway remains unclear. MAIN METHODS: CCK-8 assays were used to evaluate the effects of TLM on cell viability. In addition, intracellular reactive oxygen species (ROS) levels were measured by the cell-permeable fluorogenic probe 2,7-dichlorofluorescein diacetate (DCFH-DA). Wound-healing and Transwell assays were used to evaluate the migration ability of HK2 cells exposed to oxalate. Moreover, immunofluorescence, immunohistochemistry and western blotting were used to examine the expression of E-cadherin, N-cadherin, vimentin and α-SMA and explore the underlying molecular mechanisms in HK2 cells and a stone-forming rat model. KEY FINDINGS: Our results showed that TLM treatment could protect HK2 cells from oxalate-induced cytotoxicity and oxidative stress injury. Additionally, TLM prevented EMT induction by oxalate and CaOx crystals via the PPAR-γ-AKT/STAT3/p38 MAPK-Snail pathway in vitro and in vivo. However, knockdown of PPAR-γ with small interfering RNA or the PPAR-γ-specific antagonist GW9662 abrogated these protective effects of TLM. SIGNIFICANCE: As a PPAR-γ agonist, TLM can ameliorate oxalate and CaOx crystal-induced EMT by exerting an antioxidant effect through the PPAR-γ-AKT/STAT3/p38 MAPK-Snail signaling pathway. Therefore, TLM can block EMT progression and could be a potential therapeutic agent for preventing and treating calcium oxalate urolithiasis formation and recurrence.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Oxalatos/toxicidade , PPAR gama/metabolismo , Telmisartan/farmacologia , Animais , Oxalato de Cálcio/toxicidade , Linhagem Celular , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Túbulos Renais/citologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta1/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Eur J Med Chem ; 185: 111748, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648125

RESUMO

Recent studies examined the possibility to overcome imatinib resistance in chronic myeloid leukemia (CML) patients by combination therapy with peroxisome proliferator-activated receptor gamma (PPARγ) ligands. Pioglitazone, a full PPARγ agonist, improved the survival of patients by the gradual elimination of the residual CML stem cell pool. To evaluate the importance of the pharmacological profile of PPARγ agonists on the ability to circumvent resistance, the partial PPARγ agonist 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid, derived from telmisartan, and other related derivatives were investigated. The 4-substituted benzimidazole derivatives bearing a [1,1'-biphenyl]-2-carboxamide moiety sensitized K562-resistant cells to imatinib treatment. Especially the derivatives 18a-f, which did not activate PPARγ to more than 40% at 10 µM, retrieved the cytotoxicity of imatinib in these cells. The cell death modulating properties were higher than that of pioglitazone. It is of interest to note that all novel compounds were not cytotoxic neither on non-resistant nor on resistant cells. They exerted antitumor potency only in combination with imatinib.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Telmisartan/farmacologia , Animais , Antineoplásicos/química , Células COS , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Humanos , Mesilato de Imatinib/química , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Estrutura Molecular , PPAR gama/agonistas , Relação Estrutura-Atividade , Telmisartan/análogos & derivados , Telmisartan/química
3.
Life Sci ; 237: 116890, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31606379

RESUMO

AIMS: Telmisartan (TEL), an angiotensin II type I receptor blocker and PPARγ partial agonist, has been used for to treat hypertension. It is known that PPARγ activation induces bone loss. Therefore, we evaluate the effects of telmisartan on PPARγ protein expression, biomechanics, density and bone microarchitecture of femurs and lumbar vertebrae in SHR ovariectomized animals, a model of hypertension in which preexisting bone impairment has been demonstrated. MAIN METHODS: SHR females (3 months old) were distributed into four groups: sham (S), sham + TEL (ST), OVX (C) and OVX + TEL (CT). TEL (5 mg/kg/day) or vehicle were administered according to the groups. After the protocol, blood pressure was measured and density, microarchitecture and biomechanics of bone were analyzed. Western blotting analysis was performed to evaluate PPARγ protein expression in the bones. KEY FINDINGS: Castration induced a deleterious effect on mineral density and trabecular parameters, with telmisartan enhancing such effects. Telmisartan increased PPARγ levels, which were at their highest when the treatment was combined with castration. As to biomechanical properties, telmisartan reduced the stiffness in the castration group (CT vs. S or C group), as well as resilience and failure load in ST group (vs. all others groups). SIGNIFICANCE: These results demonstrated that telmisartan compromised bone density and microarchitecture in animals that shows preexisting osteoporotic bone disorders, probably via mechanisms associated with increased PPARγ. If this translates to humans, a need for greater caution in the use of telmisartan by patients that have preexisting bone problems, as in the postmenopausal period, may be in order.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Doenças Ósseas/tratamento farmacológico , Osso Esponjoso/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Osteoporose/tratamento farmacológico , PPAR gama/metabolismo , Telmisartan/farmacologia , Animais , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas/metabolismo , Doenças Ósseas/fisiopatologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/patologia , Feminino , Osteoporose/metabolismo , Osteoporose/fisiopatologia , PPAR gama/genética , Ratos , Ratos Endogâmicos SHR , Tomografia Computadorizada por Raios X
4.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480330

RESUMO

BACKGROUND: Psoriasis is hallmarked by vascular dysfunction, arterial hypertension, and an increased risk for cardiovascular diseases. We have shown recently that skin-driven interleukin (IL)-17A expression promotes psoriasis-like disease in mice, and this is associated with vascular inflammation, vascular dysfunction, and hypertension. As an intensive risk-factor reduction is recommended for psoriasis patients, we aimed to elucidate the impact of the angiotensin II receptor type 1 (AT1) antagonist telmisartan in a mouse model of severe psoriasis-like skin disease. METHODS AND RESULTS: Elevated blood pressure measured by tail-cuff plethysmography in mice with keratinocyte-specific IL-17A overexpression (K14-IL-17Aind/+ mice) was significantly reduced in response to telmisartan. Importantly, vascular dysfunction, as assessed by isometric tension studies of isolated aortic rings, vascular inflammation measured by flow cytometry analysis of CD45+CD11b+ immune cells, as well as the increased peripheral oxidative stress levels assessed by L-012-enhanced chemiluminescence were not attenuated by telmisartan treatment of K14-IL-17Aind/+ mice, nor was the persisting skin inflammation. CONCLUSION: We provide first evidence for an effective antihypertensive treatment in experimental psoriasis by AT1 blockade, but without any impact on vascular inflammation and dysfunction in our mouse model of severe psoriasis-like skin disease. This suggests that vascular function and inflammation in psoriasis might not be attenuated as long as skin inflammation persists.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Inflamação/patologia , Psoríase/tratamento farmacológico , Psoríase/fisiopatologia , Telmisartan/uso terapêutico , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Telmisartan/farmacologia
5.
Int J Mol Sci ; 20(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261874

RESUMO

Esophageal squamous cell carcinoma (ESCC) is the most common primary esophageal malignancy. Telmisartan, an angiotensin II type 1 (AT1) receptor blocker (ARB) and a widely used antihypertensive, has been shown to inhibit proliferation of various cancer types. This study evaluated the effects of telmisartan on human ESCC cell proliferation in vitro and in vivo and sought to identify the microRNAs (miRNAs) involved in these antitumor effects. We examined the effects of telmisartan on three human ESCC cell lines (KYSE150, KYSE180, and KYSE850). Telmisartan inhibited proliferation of these three cell lines by inducing S-phase arrest, which was accompanied by decreased expression of cyclin A2, cyclin-dependent kinase 2, and other cell cycle-related proteins. Additionally, telmisartan reduced levels of phosphorylated ErbB3 and thrombospondin-1 in KYSE180 cells. Furthermore, expression of miRNAs was remarkably altered by telmisartan in vitro. Telmisartan also inhibited tumor growth in vivo in a xenograft mouse model. In conclusion, telmisartan inhibited cell proliferation and tumor growth in ESCC cells by inducing cell-cycle arrest.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Fase S/efeitos dos fármacos , Telmisartan/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Linhagem Celular Tumoral , Ciclina A2/genética , Ciclina A2/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Telmisartan/uso terapêutico , Trombospondina 1/genética , Trombospondina 1/metabolismo
6.
J Renin Angiotensin Aldosterone Syst ; 20(3): 1470320319862741, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31328615

RESUMO

INTRODUCTION: Telmisartan is an angiotensin-II receptor type-1 blocker and a partial agonist for peroxisome proliferator-activated receptor-γ. The aim of this study was to determine the potential effects of telmisartan on bone metabolism and turnover markers. METHODS: Forty-two patients with newly diagnosed stage I hypertension who were prescribed telmisartan 80 mg/day or losartan 100 mg/day were included. Serum levels of calcium, phosphorus, 25-hydroxy vitamin D, bone-specific alkaline phosphatase, osteocalcin, interleukin 6 and 24-hour urinary N-terminal telopeptide were measured at the beginning and after 12 weeks of treatment. RESULTS: When treatment arms were evaluated together, significantly increased 25-hydroxy vitamin D levels (p=0.01), and decreased parathormone (PTH) (p<0.001), bone-specific alkaline phosphatase (p=0.01), osteocalcin (p=0.045), urinary N-terminal telopeptide (p<0.001) and interleukin 6 levels (p=0.006) were observed. After eliminating the 25-hydroxy vitamin D effect, significant changes were not observed at any of the parameters. None of the levels of parameters were different between groups. CONCLUSIONS: Neither telmisartan, despite its partial peroxisome proliferator-activated receptor-γ agonistic effect, nor losartan treatment had significant effects on bone turnover markers in newly diagnosed stage I hypertensive patients.


Assuntos
Biomarcadores/sangue , Remodelação Óssea , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Losartan/uso terapêutico , Telmisartan/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Feminino , Seguimentos , Humanos , Hipertensão/sangue , Losartan/farmacologia , Masculino , Pessoa de Meia-Idade , Telmisartan/farmacologia
7.
Int Immunopharmacol ; 75: 105750, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31330445

RESUMO

Telmisartan, widely prescribed for the treatment of hypertension, has an anti-inflammatory property in addition to being an angiotensin II type 1 receptor antagonist. This study was carried out to explore the influence of telmisartan upon the elaboration of inflammatory mediators in murine macrophages stimulated with lipopolysaccharide (LPS) prepared from Prevotella intermedia, a periodontal pathogen, as well as its molecular mechanisms. Telmisartan significantly inhibited LPS-induced generation of inducible nitric oxide (NO) synthase-derived NO and interleukin-1ß (IL-1ß) as well as their gene expressions in RAW264.7 cells. Telmisartan treatment of LPS-activated cells significantly up-regulated arginase 1 (Arg-1) and chitinase-like 3 (Ym-1), which are specific markers of M2 macrophages. Telmisartan caused a significant increase in heme oxygenase-1 (HO-1) expression in cells stimulated with LPS, and its inhibitory action against NO production was reversed by treatment with SnPP, an HO-1 inhibitor. Phosphorylation of STAT1 and STAT3 induced by LPS was attenuated by telmisartan. Telmisartan inhibited LPS-induced generation of NO and IL-1ß independently of PPAR-γ activation. In addition, activation of NF-κB as well as JNK and p38 signaling induced by LPS was not modulated by telmisartan. In summary, telmisartan is a potent inhibitor of P. intermedia LPS-induced generation of NO and IL-1ß in RAW264.7 cells and promotes macrophage phenotype switching toward the M2 phenotype. Telmisartan may have potential to be developed into host modulatory agent for inflammatory periodontal disease, although additional studies are needed to confirm the therapeutic effect.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Inflamatórios/farmacologia , Interleucina-1beta/imunologia , Óxido Nítrico/imunologia , Prevotella intermedia , Telmisartan/farmacologia , Animais , Heme Oxigenase-1/genética , Heme Oxigenase-1/imunologia , Interleucina-1beta/genética , Lipopolissacarídeos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Células RAW 264.7
8.
Oxid Med Cell Longev ; 2019: 1302985, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354899

RESUMO

The therapeutic effects of telmisartan, an angiotensin II receptor antagonist and a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, have been demonstrated in several disorders. It has antioxidant and immune response modulator properties and has shown promising results in the treatment of an ischemia/reperfusion (I/R) lesion. In this study, a skeletal muscle (right gastrocnemius muscle) I/R lesion was induced in rats and different reperfusion times (1 h, 24 h, 72 h, 7-day, and 14-day subgroups) were assessed. Furthermore, levels of oxidative markers such as enzymatic scavengers (catalase (CAT) and superoxide dismutase (SOD)) and metabolites (nitrates and 8-oxo-deoxyguanosine) were determined. The degree of tissue injury (total lesioned fibers and inflammatory cell count) was also evaluated. We observed an increase in CAT and SOD expression levels under telmisartan treatment, with a decrease in injury and oxidative biomarker levels in the 72 h, 7-day, and 14-day subgroups. Telmisartan reduced oxidative stress and decreased the damage of the I/R lesion.


Assuntos
Anti-Hipertensivos/uso terapêutico , Isquemia/tratamento farmacológico , Telmisartan/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Humanos , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Traumatismo por Reperfusão , Telmisartan/farmacologia
9.
Cardiology ; 143(1): 1-10, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31307032

RESUMO

The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) in the vascular wall are crucial pathological events involved in cardiovascular impairments including hypertension, heart failure, and atherosclerosis. At the molecular level, the mammalian target of rapamycin (mTOR)-ribosomal protein S6 kinase beta-1 (p70S6K) signaling pathway is essential to potentiate VSMC proliferation and migration. Although angiotensin II receptor type 1 -(AT1-R) antagonists such as valsartan and telmisartan have a significant cardiovascular protective effect, the molecular basis of this class of drugs in VSMC proliferation and migration remains elusive. By using cultured VSMCs, adenosine monophosphate-activated protein kinase (AMPK) α2 knockout mice, and hypertensive rat models, this study investigated whether AT1-R antagonists can inhibit the mTOR-p70S6K signaling pathway in VSMCs and the vascular wall. Valsartan activated AMPK, which in turn suppressed reactive oxygen species production and consequently attenuated VSMC proliferation and migration. In vivo, a clinical dose of telmisartan significantly inhibited the mTOR-p70S6K signaling pathway in the vascular wall of wild-type but not AMPKα2-/- mice. Furthermore, spontaneously hypertensive rats had significantly elevated phosphorylation of mTOR and p70S6K in the aorta compared to Wistar-Kyoto rats, which were reduced by telmisartan administration. These data suggest that AT1-R antagonists inhibit VSMC proliferation and migration via their regulation of AMPK, mTOR, and p70S6K, which contribute to the cardioprotective effects of these drugs.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Músculo Liso Vascular/citologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Ratos Endogâmicos SHR , Ratos Wistar , Proteínas Quinases S6 Ribossômicas 70-kDa , Transdução de Sinais/efeitos dos fármacos , Telmisartan/farmacologia , Valsartana/farmacologia
10.
Biomed Res Int ; 2019: 3851718, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30993112

RESUMO

We examined whether and how uric acid induces epithelial to mesenchymal transition (EMT) in renal tubular cells, along with the mechanism by which telmisartan acts on uric acid-induced renal injury. Rat renal proximal tubular epithelial cells (NRK-52E) were exposed to various concentrations of uric acid in the presence or absence of telmisartan. Treatment with uric acid increased the expression of α-SMA, decreased the expression of E-cadherin, and promoted EMT in NRK-52E cells. Uric acid treatment also led to increased endothelin-1 (ET-1) production, activation of extracellular-regulated protein kinase 1/2 (ERK1/2), and the upregulation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). Use of ET-1 receptor inhibitor (BQ123 or BQ788) could inhibit uric acid-induced EMT in NRK-52E cells. Pretreatment with the ERK inhibitor (U0126 or PD98059) suppressed the release of ET-1 and EMT induced by uric acid. Additionally, pretreatment with a traditional antioxidant (diphenylene iodonium or apocynin) inhibited the activation of ERK1/2, release of ET-1, and uric acid-induced EMT in NRK-52E cells. These findings suggested that uric acid-induced EMT in renal tubular epithelial cells occurs through NADPH oxidase-mediated ERK1/2 activation and the subsequent release of ET-1. Furthermore, telmisartan (102 nmol/L to 104 nmol/L) inhibited the expression of NOX4, intracellular reactive oxygen species (ROS), activation of ERK1/2, and the release of ET-1 in a dose-dependent manner, thereby preventing uric acid-induced EMT in NRK-52E. In conclusion, telmisartan could ameliorate uric acid-induced EMT in NRK-52E cells likely through inhibition of the NADPH oxidase/ERK1/2/ET-1 pathway.


Assuntos
Antioxidantes/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Nefropatias/metabolismo , Túbulos Renais Proximais/metabolismo , Telmisartan/farmacologia , Animais , Caderinas/metabolismo , Linhagem Celular , Nefropatias/induzido quimicamente , Nefropatias/patologia , Túbulos Renais Proximais/patologia , NADPH Oxidase 4/metabolismo , Ratos , Ácido Úrico/toxicidade
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(2): 156-161, 2019 02 28.
Artigo em Chinês | MEDLINE | ID: mdl-30890502

RESUMO

OBJECTIVE: To explore the effect of telmisartan on the expression of metadherin in the kidney of mice with unilateral ureter obstruction. METHODS: Eighteen male C57 mice were randomized into sham-operated group, model group and telmisartan treatment group. In the latter two groups, renal interstitial fibrosis as the result of unilateral ureter obstruction (UUO) was induced by unilateral ureteral ligation with or without telmisartan intervention. Renal pathological changes of the mice were assessed using Masson staining, and immunohistochemistry and Western blotting were used to detect the expression of extracellular matrix proteins and metadherin in the kidney of the mice. In the in vitro experiment, cultured mouse renal tubular epithelial cells (mTECs) were stimulated with transforming growth factor-ß1 (TGF-ß1) and transfected with a siRNA targeting metadherin, and the changes in the expressions of extracellular matrix proteins and metadherin were detected using Western blotting. RESULTS: The expressions of extracellular matrix proteins and metadherin increased significantly in the kidney of mice with UUO (P < 0.05). Intervention with telmisartan significantly lowered the expressions of extracellular matrix proteins and metadherin and alleviated the pathology of renal fibrosis in mice with UUO (P < 0.05). In cultured mTECs, siRNA-mediated knockdown of metadherin obviously reversed TGF-ß1-induced increase in the expressions of extracellular matrix proteins and metadherin. CONCLUSIONS: Telmisartan can suppress the production of extracellular matrix proteins and the expression of metadhein to attenuate UUO-induced renal fibrosis in mice.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Rim/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Telmisartan/farmacologia , Obstrução Ureteral/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Animais , Anti-Hipertensivos , Fibrose , Rim/metabolismo , Rim/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno , Distribuição Aleatória , Fator de Crescimento Transformador beta1/farmacologia , Obstrução Ureteral/complicações
12.
Pharmacol Rep ; 71(2): 330-337, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826574

RESUMO

BACKGROUND: Food allergy (FA) is a worldwide health problem, affecting nearly 10% of all populations, with no prophylactic options or regulatory treatment available until now. Fisetin, a biologically active flavonoid, and telmisartan, the highly selective competitive AT1 receptor antagonist, recently exhibited potent anti-inflammatory and immunomodulatory activities. In the present study, we have evaluated the possible anti-inflammatory and immunomodulatory activities of fisetin and telmisartan each alone or in low-dose combination in a mouse model of FA. METHODS: For induction of FA, eight-week-old BALB/c mice, sensitized by two ip injection of 50 µg ovalbumin (OVA) and 1 mg alum at day 0 and 7. Then, each mouse challenged with 10 mg OVA at days 14, 16, 18, and 21. On the 28th day, the fifth challenge carried out by oral administration of 50 mg OVA. Either fisetin (1 or 3 mg/kg/d), telmisartan (1 or 3 mg/kg/d) or a combination of fisetin 1 mg/kg/d and telmisartan 1 mg/kg/d received orally from the 13th day till 28th day. In challenge days, the treatments received one-hour before the challenge. RESULTS: Our data showed that fisetin and telmisartan each alone or in low-dose combination attenuated the anaphylactic manifestation, decreased blood eosinophilic count, serum OVA-specific IgE, and IL-4 levels, the intestinal total and degranulated mast cells count, and CD4+ immunohistochemical expression. Furthermore, they enhanced the serum IFN-γ level and abrogated the intestinal histopathological changes induced by OVA in mice. CONCLUSION: Either fisetin, telmisartan or their low-dose combination could be promising in the management of FA.


Assuntos
Flavonoides/farmacologia , Hipersensibilidade Alimentar/tratamento farmacológico , Fatores Imunológicos/farmacologia , Telmisartan/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Flavonoides/administração & dosagem , Hipersensibilidade Alimentar/imunologia , Fatores Imunológicos/administração & dosagem , Interferon gama/sangue , Intestinos/imunologia , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Telmisartan/administração & dosagem , Fatores de Tempo
13.
Cell Biochem Funct ; 37(3): 161-168, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30907023

RESUMO

Telmisartan, an angiotensin II receptor blocker, has been widely used for hypertension. It has also been reported to improve insulin sensitivity in animal models of obesity and diabetic patients by targeting to the peroxisome proliferator-activated receptor (PPAR)-γ. High glucose/high lipid (HG/HL)-induced apoptosis of pancreatic ß-cells impairs its function of insulin secretion and is generally believed to be the key factor in the development of diabetes. In this study, we investigated whether telmisartan exerted a protective effect against HG/HL-induced apoptosis and insulin secretion in vitro as well as in vivo; 10-µM telmisartan treatment significantly reduced HG (25 mM) or/and HL (0.4 mM palmitic acid) induced-cell apoptosis and greatly improved insulin secretion in INS-1 pancreatic ß-cells, which is consistent in an obesity rat model induced by HG/HL diets. Furthermore, telmisartan treatment markedly reduced the protein level of GRP78, CHOP, and caspase 12, while increasing anti-apoptotic Bcl-2 protein expression. Moreover, telmisartan treatment significantly reduced intracellular ROS levels. Mechanistically, we demonstrated that PPARγ signaling pathway may be involved in the telmisartan protective effects, which were blocked by a PPARγ blocker, GW9662. In conclusion, the protective effect of telmisartan was mediated by an anti-ER stress-induced apoptotic and anti-oxidative pathway. SIGNIFICANCE OF THIS STUDY: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder worldwide pathologically characterized by hyperglycemia and insulin resistance. Long-term high glucose in the blood has been proposed to induce pancreatic ß-cell loss and is generally believed to be the key factor in the development of diabetes. In the present study, we demonstrated that telmisartan, a common drug used for hypertension treatment, has a protective effect against high glucose/high lipid-induced cell apoptosis and greatly improves the insulin secretion function by inhibiting the oxidative stress and ER stress. Furthermore, this protective effect of telmisartan is mediated by the PPAR-γ signal pathway, which may provide a potential strategy against T2DM.


Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glucose/antagonistas & inibidores , Insulina/metabolismo , Lipídeos/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Telmisartan/farmacologia , Anilidas/farmacologia , Anti-Hipertensivos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Glucose/farmacologia , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Lipídeos/farmacologia , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Telmisartan/antagonistas & inibidores
14.
J Renin Angiotensin Aldosterone Syst ; 20(1): 1470320319827205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30798697

RESUMO

INTRODUCTION:: This study aimed to investigate whether mononucleotide polymorphisms of the angiotensinogen gene at promoter were associated with the blood-pressure-lowering response to telmisartan treatment. MATERIALS AND METHODS:: After a two-week single-blind placebo run-in period, 148 patients with mild-to-moderate primary hypertension received monotherapy with 80 mg/day of telmisartan and then were followed up for eight weeks. The -6A/G and -20A/C polymorphisms of the angiotensinogen gene at promoter were determined through polymerase chain reaction and restriction fragment length polymorphsim analysis. The relationship between these polymorphisms and changes in blood pressure was observed and evaluated after eight weeks of treatment. RESULTS:: There were no significant differences between -6A/G, -20A/C polymorphisms of the angiotensinogen gene and blood pressure reductions after treatment, p>0.05. CONCLUSION:: It is suggested that angiotensinogen-6 A/G and angiotensinogen-20 A/C polymorphisms were not associated with the antihypertensive response to telmisartan treatment in Chinese patients with hypertension.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Angiotensinogênio/genética , Anti-Hipertensivos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Hipertensão/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/genética , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Telmisartan/farmacologia , Telmisartan/uso terapêutico , Adulto Jovem
15.
Life Sci ; 221: 159-167, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769114

RESUMO

AIMS: Renin-angiotensin system (RAS) and natriuretic peptides system (NPS) perturbations govern the development of diabetic nephropathy (DN). Hence, in search of a novel therapy against DN, present study targeted both, NPS and RAS simultaneously using a neprilysin inhibitor (NEPi) in combination with either angiotensin receptor blocker (ARB) or angiotensin-converting enzyme 2 (ACE2) activator. METHODS: We induced diabetes in male Wistar rats by a single dose of streptozotocin (55 mg/kg, i.p.). After four weeks, we treated diabetic rats with thiorphan, telmisartan or diminazene aceturate (Dize) 0.1, 10, 5 mg/kg/day, p.o. alone as monotherapy, or both thiorphan/telmisartan or thiorphan/Dize as combination therapy, for four weeks. Then, plasma and urine biochemistry were performed, and kidneys from all the groups were collected and processed separately for histopathology, ELISA and Western blotting. KEY FINDINGS: Proposed combination therapies attenuated metabolic perturbations, prevented renal functional decline, and normalised adverse alterations in renal ACE, ACE2, Ang-II, Ang-(1-7), neprilysin and cGMP levels in diabetic rats. Histopathological evaluation revealed a significant reduction in glomerular and tubulointerstitial fibrosis by combination therapies. Importantly, combination therapies inhibited inflammatory, profibrotic and apoptotic signalling, way better than respective monotherapies, in preventing DN. CONCLUSION: Renoprotective potential of thiorphan (NEPi)/telmisartan (ARB) and thiorphan/Dize (ACE2 activator) combination therapies against the development of DN is primarily attributed to normalisation of RAS and NPS components and inhibition of pathological signalling related to inflammation, fibrosis, and apoptosis. Hence, we can conclude that NEPi/ARB and NEPi/ACE2 activator combination therapies might be new therapeutic strategies in preventing DN.


Assuntos
Nefropatias Diabéticas/metabolismo , Neprilisina/metabolismo , Sistema Renina-Angiotensina/fisiologia , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/prevenção & controle , Diminazena/análogos & derivados , Diminazena/metabolismo , Diminazena/farmacologia , Fibrose , Inflamação , Rim/patologia , Masculino , Neprilisina/antagonistas & inibidores , Peptidil Dipeptidase A , Ratos , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos , Estreptozocina , Telmisartan/metabolismo , Telmisartan/farmacologia , Tiorfano/metabolismo , Tiorfano/farmacologia
16.
Life Sci ; 221: 109-120, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30699330

RESUMO

AIMS: The heterodimerization of angiotensin II receptors (AT1R and AT2R) with adiponectin receptor AdipoR1 and AdipoR2 may instigate high glucose (HG)-induced renal tubulointerstitial injury. This study examined the effect of telmisartan on diabetic nephropathy (DN) and its underlying mechanism. MAIN METHODS: Diabetes was induced in rats through a single intraperitoneal injection of streptozotocin. Diabetic rats treated with or without the intravenous injection of AdipoR1 siRNA were intragastrically administered with 5 mg/kg/d telmisartan or a vehicle for 12 weeks. The rat proximal tubular epithelial cell line NRK-52E was treated with HG (30 mmol/L) with or without telmisartan (10 µM) for 48 h. KEY FINDINGS: In streptozotocin-induced diabetic rats, telmisartan treatment could decrease the inulin clearance rate, restore the glomerular surface area and mesangial area, alleviate renal fibrosis, and decrease urinary albumin excretion. Furthermore, diabetic rats exhibited increased AT1R-AdipoR1 heterodimers in the renal tubular compartment, which could be attenuated by telmisartan treatment, accompanied by a decrease in the expression level of cytokines MIP-1α, ICAM-1 and MCP-1. In vitro, HG promoted the dimerization formation of AT1R-AdipoR1 in cultured NRK-52E cells, but this effect was not found in NRK-52E cells transfected with the AdipoR1-G269E,G273E mutant. Telmisartan could inhibit HG-induced AT1R-AdipoR1 dimerization, downregulate the expression levels of inflammatory cytokines, and alleviate cell apoptosis in NRK-52E cells. Furthermore, AdipoR1 knockdown could abate the renoprotective benefits of telmisartan. SIGNIFICANCE: The heterodimerization of AT1R-AdipoR1 probably contributes to the renal injury of DN, and provides an additional mechanistic insight into how telmisartan prevents the development and progression of DN.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Telmisartan/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Experimental , Dimerização , Modelos Animais de Doenças , Fibrose , Rim/fisiopatologia , Masculino , RNA Interferente Pequeno , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptores de Adiponectina/efeitos dos fármacos , Estreptozocina/farmacologia , Telmisartan/farmacologia
17.
Heart Vessels ; 34(7): 1230-1239, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30671641

RESUMO

We established a rabbit iliac artery restenosis model to explore the impact of Telmisartan on the expression of Connexin43 (Cx43) and neointimal hyperplasia. Thirty New Zealand white rabbits were randomly divided into three groups: control group (n = 10), restenosis group (n = 10), and Telmisartan group (n = 10). The restenosis model was established by high-cholesterol diet combined with double-balloon injury of iliac arteries. In addition, Telmisartan at 5 mg/(kg day) was administered to the rabbits of Telmisartan group on the second day after the second balloon injury. All rabbits were killed at the end of the experiment followed by institution policy. Before sacrifice, blood samples were obtained to test serum angiotensinII (AngII). Iliac arteries were isolated for morphological analysis and determining the expression of Cx43 by HE staining, immunohistochemical analysis, reverse transcription-polymerase chain reaction (RT-PCR), and Western Blotting analysis. Then, the local AngII levels of arteries were measured by radioimmunoassay. As compared with controls, the expression of Cx43 mRNA (0.98 ± 0.08) vs. (1.27 ± 0.17), P < 0.01), and Cx43 protein [(0.75 ± 0.08) vs. (0.90 ± 0.08), P < 0.05] of restenosis group were increased, which were significantly higher than those of Telmisartan group [Cx43 mRNA: (1.27 ± 0.17) vs. (1.00 ± 0.20), P < 0.01; Cx43 protein: (0.90 ± 0.08) vs. (0.82 ± 0.05), P < 0.05]. Furthermore, The intima thickness [(266.12 ± 70.27) vs. (2.85 ± 0.19) µm, P < 0.01] and the local AngII [(115.6 ± 15.7) vs. (90.1 ± 7.7), P < 0.05] of restenosis group were raised when compared with controls. Telmisartan group exhibited thinner intima compared with restenosis group [(68.22 ± 24.37) vs. (266.12 ± 70.27), P < 0.01]. However, the local AngII levels between these two groups were approximate. In addition, the plasma concentration of AngII was not significantly different among three groups. In conclusion, Telmisartan can inhibit the expression of connexin43 and neointimal hyperplasia in iliac artery restenosis model.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Conexina 43/metabolismo , Artéria Ilíaca/lesões , Telmisartan/farmacologia , Animais , Cateterismo , Proliferação de Células/efeitos dos fármacos , Conexina 43/genética , Hiperplasia/prevenção & controle , Artéria Ilíaca/patologia , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Neointima/prevenção & controle , Coelhos
18.
Clin Exp Hypertens ; 41(1): 75-79, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29589977

RESUMO

OBJECTIVE: The comparison of antihypertensive effects between telmisartan and candesartan in patients with essential hypertension has been investigated in several small studies. The results were not consistent. We performed this meta-analysis determining the antihypertensive effect of telmisartan versus candesartan in these patients. METHODS: We searched Pubmed, Web of Science, and Cochrane Central for all published studies comparing the antihypertensive effects between telmisartan and candesartan in patients with essential hypertension. RESULTS: The antihypertensive effects were assessed in 302 patients included in 4 trials with a mean follow-up of 10 ± 4 weeks. There were no significant differences between telmisartan and candesartan in reduction of systolic blood pressure (SBP) and diastolic BP (DBP) in patients with essential hypertension (weighted mean differences (WMD) for SBP 1.98 mm Hg (95% confidence interval (CI), -0.53, 4.49), p > 0.05; WMD for DBP 0.26 mm Hg (95% CI, -1.65, 2.16), p > 0.05), respectively. In a sub-analysis including 2 randomized studies, there was not a significant difference for the reduction of SBP (WMD 0.90 (95% CI, -2.88, 4.68) mm Hg, p > 0.05) or DBP (WMD -0.80 (95% CI, -3.40, 1.81) mm Hg, p > 0.05) treated with telmisartan or candesartan. CONCLUSIONS: This meta-analysis provides the evidence that the antihypertensive effects of telmisartan and candesartan are similar on SBP and DBP reduction in patients with essential hypertension, suggesting that strict designed randomized controlled trial would be helpful to compare antihypertensive effects of angiotensin II receptor blockers (ARBs) and improve the choice of ARBs in antihypertensive therapy.


Assuntos
Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Hipertensão Essencial/tratamento farmacológico , Telmisartan/uso terapêutico , Tetrazóis/uso terapêutico , Anti-Hipertensivos/farmacologia , Benzimidazóis/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão Essencial/fisiopatologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Telmisartan/farmacologia , Tetrazóis/farmacologia
19.
Mol Neurobiol ; 56(5): 3193-3210, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30105672

RESUMO

The Angiotensin II Receptor Blocker (ARB) Telmisartan reduces inflammation through Angiotensin II AT1 receptor blockade and peroxisome proliferator-activated receptor gamma (PPARγ) activation. However, in a mouse microglia-like BV2 cell line, imitating primary microglia responses with high fidelity and devoid of AT1 receptor gene expression or PPARγ activation, Telmisartan reduced gene expression of pro-injury factors, enhanced that of anti-inflammatory genes, and prevented LPS-induced increase in inflammatory markers. Using global gene expression profiling and pathways analysis, we revealed that Telmisartan normalized the expression of hundreds of genes upregulated by LPS and linked with inflammation, apoptosis and neurodegenerative disorders, while downregulating the expression of genes associated with oncological, neurodegenerative and viral diseases. The PPARγ full agonist Pioglitazone had no neuroprotective effects. Surprisingly, the PPARγ antagonists GW9662 and T0070907 were neuroprotective and enhanced Telmisartan effects. GW9226 alone significantly reduced LPS toxic effects and enhanced Telmisartan neuroprotection, including downregulation of pro-inflammatory TLR2 gene expression. Telmisartan and GW9662 effects on LPS injury negatively correlated with pro-inflammatory factors and upstream regulators, including TLR2, and positively with known neuroprotective factors and upstream regulators. Gene Set Enrichment Analysis (GSEA) of the Telmisartan and GW9662 data revealed negative correlations with sets of genes associated with neurodegenerative and metabolic disorders and toxic treatments in cultured systems, while demonstrating positive correlations with gene sets associated with neuroprotection and kinase inhibition. Our results strongly suggest that novel neuroprotective effects of Telmisartan and GW9662, beyond AT1 receptor blockade or PPARγ activation, include downregulation of the TLR2 signaling pathway, findings that may have translational relevance.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Microglia/patologia , Fármacos Neuroprotetores/farmacologia , PPAR gama/metabolismo , Telmisartan/farmacologia , Anilidas/farmacologia , Animais , Encefalopatias/genética , Encefalopatias/patologia , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , PPAR gama/antagonistas & inibidores , PPAR gama/genética , Pioglitazona/farmacologia , Telmisartan/administração & dosagem , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
20.
Sleep Breath ; 23(1): 341-348, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30219962

RESUMO

PURPOSE: Obstructive sleep apnea (OSA) is associated with renal impairs. As a novel pathophysiological hallmark of OSA, chronic intermittent hypoxia (CIH) enhances apoptosis and autophagy. The present study aims to evaluate the effect of telmisartan on CIH-induced kidney apoptosis and autophagy in a mouse model of OSA. MATERIALS AND METHODS: Mice were randomly allocated to normoxia, CIH, and CIH+telmisartan groups (n = 12 in each group). The CIH exposure duration was 12 weeks. Mice in the CIH+telmisartan group received telmisartan administration. The terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and western blotting of Bax and cleaved caspase-3 were conducted for evaluating apoptosis in kidney tissue. While the autophagy-related proteins, beclin-1 and LC3, were also observed via western blotting. RESULTS: The percentage of apoptotic cell in the CIH group was significantly higher than that of normoxia group; meanwhile, Bax and cleaved caspase-3 protein levels were increased in the CIH group than those of normoxia group (all p < 0.05). Compared with the normoxia group, mice in the CIH group had greater autophagy-related proteins (beclin-1 and LC3) expression. When compared to the CIH group, both the renal apoptosis and autophagy in the CIH+telmisartan group were decreased. CONCLUSION: The CIH accelerates renal apoptosis and autophagy levels. Telmisartan ameliorating those levels suggests that it might prevent renal impairs from the CIH in OSA patients.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/metabolismo , Hipóxia/fisiopatologia , Rim/efeitos dos fármacos , Telmisartan/farmacologia , Angiotensina II/sangue , Animais , Nitrogênio da Ureia Sanguínea , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Modelos Animais de Doenças , Hipóxia/patologia , Marcação In Situ das Extremidades Cortadas , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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