Candesartan targeting of angiotensin II type 1 receptor demonstrates benefits for hypertension in pregnancy via the NF‑κB signaling pathway

Zhao, Xudong; Wang, Xietong

doi:10.3892/mmr.2018.9070

Cited by 9 publications

(13 citation statements)

References 52 publications

(50 reference statements)

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“…26 More emerging evidence revealed that candesartan could effectively inhibit glial activation, 27 reduce inflammatory response, 28 and block NF-κB activity. 24 However, in the present study, we showed that candesartan inhibited inflammatory response and induced the shift of microglia from pro-inflammatory M1 to anti-inflammatory M2 phenotype, which may be associated with TLR4-mediated NF-κB pathway.…”

Section: Discussioncontrasting

confidence: 59%

Candesartan modulates microglia activation and polarization via NF-κB signaling pathway

Qie

Ran

et al. 2020

Int J Immunopathol Pharmacol

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Microglia are diverse cells that acquire different functional phenotypes in response to microenvironment in which they reside. Several transcriptional regulators have been identified that regulate different microglia phenotypes. They are mainly stimulated into two opposing phenotypes, classically (M1) and alternatively (M2) phenotype. Regulating microglia polarization from M1 to M2 state has been suggested as a potential therapeutic approach in treatment of CNS disorders. Candesartan, an angiotensin II type I receptors antagonist, exerts beneficial effects for antioxidant, anti-inflammation, neurotrophic, and anti-apoptotic function. However, the effect of candesartan on microglia polarization and underlying mechanisms remain unknown. In this study, the resting microglia were stimulated to M1 microglia with lipopolysaccharide (LPS) and interferon-γ (IFN-γ), and then treated with vehicle or candesartan for 24 h. RT-PCR was utilized to detect the mRNA expression of microglia phenotype markers and inflammatory cytokines. Microglia phenotype markers and toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway were determined by western blot. A neuron-microglia co-culture system was used to determine whether candesartan could ameliorate the neurotoxic effect of M1 microglia to oxygen-glucose deprivation (OGD) neuron. Candesartan treatment reduced the expression of M1 markers, and increased M2 markers. Meanwhile, candesartan reduced fluorescence intensity and protein level of M1 marker and enhanced M2 marker. Candesartan also regulated the neuroinflammatory response via reducing the release of pro-inflammatory cytokines and increasing anti-inflammatory cytokines in LPS + IFN-γ stimulated BV2 cells. Candesartan markedly inhibited the protein level of TLR4, the phosphorylation of IKBα and p65, and suppressed nuclear translocation of NF-κB p65. BAY 11-7085, a NF-κB inhibitor, remarkably enlarged the inhibitory effect of candesartan on NF-κB pathway. In addition, M1 phenotype microglia exacerbated post-OGD N2a cells death and LDH release, whereas candesartan reversed such neurotoxic effect. Candesartan treatment may ameliorate stroke-induced neuronal damage through shifting microglia to M2 phenotype in a TLR4/NF-κB-dependent manner.

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Section: Discussioncontrasting

confidence: 59%

Candesartan modulates microglia activation and polarization via NF-κB signaling pathway

Qie

Ran

et al. 2020

Int J Immunopathol Pharmacol

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“…In the human model of forearm blood flow, ET‐1 functions as a vasoconstriction regulator and the application of antagonists of ETAR and ETBR has demonstrated that ETAR lowers blood flow to ET‐1, where ETBR is a vasodilator 35 . Zhao et al reported that the NF‐κB pathway may contribute to candesartan‐induced initiation and progression of PIH 36 . Furthermore, betaine treatment has been shown to attenuate pulmonary arterial hypertension through the inhibition of inflammatory response by inactivating the NF‐κB pathway 37 .…”

Section: Discussionmentioning

confidence: 98%

Long noncoding RNA MALAT1 contributes to pregnancy‐induced hypertension development by enhancing oxidative stress and inflammation through the regulation of the miR‐150‐5p/ET‐1 axis

Zhao

et al. 2020

FASEB j.

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Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified previously in the pathogenesis of hypertension and some gestational diseases. However, the biological functions of MALAT1 in pregnancy-induced hypertension (PIH) are still poorly understood. Herein, we aim to explore the functional relevance of MALAT1 in PIH and to explain the potential underlying mechanisms. We found that the levels of ET-1 and MALAT1 were upregulated and that of miR-150-5p were downregulated in the serum of pregnant women with PIH and the aortic endothelial cells (ECs) of reduced uterine perfusion pressure (RUPP)-induced rat models. In aortic ECs, MALAT1 could competitively bind to miR-150-5p to upregulate the expression of ET-1. The MALAT1/ miR-150-5p/ET-1 axis regulated the expression of endothelin B receptor (ETBR) in aortic ECs leading to oxidative stress imbalance and increased the release of proinflammatory cytokines (IL-18 and IL-1β), which concurrently activated the NF-κB pathway to regulate the ETBR expression and to stimulate smooth muscle cell (SMC) contraction. Furthermore, silencing MALAT1 could alleviate the hypertensive symptoms of RUPP-induced rat models. Taken conjointly, the upregulation of MALAT1 can reduce the expression of ET-1 by competitively binding to miR-150-5p, which enhances the expression of ETBR via the activation of the NF-κB pathway in SMCs, thus exacerbating the hypertensive symptoms in the RUPP-induced rat models. K E Y W O R D Sendothelial cells, endothelin-1, metastasis-associated lung adenocarcinoma transcript 1, microRNA-150-5p, NF-κB pathway, pregnancy-induced hypertension, smooth muscle cells

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“…Recently, it has been shown to ameliorate brain inflammation associated with Alzheimer's disease [16] and to induce neuroprotective effects in patients suffering from Parkinson's disease [17]. Moreover, it has been shown to reduce inflammation and mucin production in patients with allergic asthma [18] and to induce benefits in a gestational hypertension mouse model [19].…”

Section: Introductionmentioning

confidence: 99%

Solid State Stability and Kinetics of Degradation for Candesartan—Pure Compound and Pharmaceutical Formulation

et al. 2020

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The aim of this work was to assess the impact of an excipient in a pharmaceutical formulation containing candesartan cilexetil over the decomposition of the active pharmaceutical ingredient and to comparatively investigate the kinetics of degradation during thermolysis in an oxidative atmosphere under controlled thermal stress. To achieve this, the samples were chosen as follows: pure candesartan cilexetil and a commercial tablet of 32 mg strength. As a first investigational tool, Universal attenuated total reflection Fourier transform infrared (UATR-FTIR) spectroscopy was chosen in order to confirm the purity and identity of the samples, as well as to check if any interactions took place in the tablet between candesartan cilexetil and excipients under ambient conditions. Later on, samples were investigated by thermal analysis, and the elucidation of the decomposition mechanism was achieved solely after performing an in-depth kinetic study, namely the use of the modified non-parametric kinetics (NPK) method, since other kinetic methods (American Society for Testing and Materials—ASTM E698, Friedman and Flynn–Wall–Ozawa) led to inadvertencies. The NPK method suggested that candesartan cilexetil and the tablet were degraded by the contribution of two steps, the main being represented by chemical degradation and the secondary being a physical transformation. The excipients chosen in the formulation seemed to have a stabilizing effect on the decomposition of the candesartan cilexetil that was incorporated into the tablet, relative to pure active pharmaceutical ingredient (API), since the apparent activation energy for the decomposition of the tablet was 192.5 kJ/mol, in comparison to 154.5 kJ/mol for the pure API.

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Candesartan targeting of angiotensin II type 1 receptor demonstrates benefits for hypertension in pregnancy via the NF‑κB signaling pathway

Cited by 9 publications

References 52 publications

Candesartan modulates microglia activation and polarization via NF-κB signaling pathway

Candesartan modulates microglia activation and polarization via NF-κB signaling pathway

Long noncoding RNA MALAT1 contributes to pregnancy‐induced hypertension development by enhancing oxidative stress and inflammation through the regulation of the miR‐150‐5p/ET‐1 axis

Solid State Stability and Kinetics of Degradation for Candesartan—Pure Compound and Pharmaceutical Formulation

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