Clinical and experimental pharmacology & physiology
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Clin. Exp. Pharmacol. Physiol. · Feb 2017
Mycophenolate mofetil improves renal haemodynamics, microvascular oxygenation, and inflammation in a rat model of supra-renal aortic clamping-mediated renal ischaemia reperfusion injury.
Ischaemia/reperfusion (I/R) is one of the main causes of acute kidney injury (AKI), which is characterized by sterile inflammation and oxidative stress. Immune cell activation can provoke overproduction of inflammatory mediators and reactive oxygen species (ROS), leading to perturbation of the microcirculation and tissue oxygenation associated with local and remote tissue injury. This study investigated whether the clinically employed immunosuppressant mycophenolate mofetil (MMF) was able to reduce I/R-induced renal oxygenation defects and oxidative stress by preventing sterile inflammation. ⋯ Oral MMF administration prior to insult restored renal cortical oxygenation (P<.05) and iNOS, renal injury markers, and inflammation parameters (P<.001) to near-baseline levels without affecting renal function. MMF exerted a prophylactic effect on renal microvascular oxygenation and abrogated tissue inflammation and renal injury following lower body I/R-induced AKI. These findings may have clinical implications during major vascular or renal transplant surgery.
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Clin. Exp. Pharmacol. Physiol. · Jan 2017
Pulmonary vascular inflammation: effect of TLR signalling on angiopoietin/TIE regulation.
Increased pulmonary vascular resistance is a critical complication in sepsis. Toll-like receptor (TLR) as well as angiopoietin (ANG) signalling both contribute to the emergence of pulmonary arterial hypertension. We hypothesized that TLR stimulation by bacterial ligands directly affects expression and secretion of ligands and receptors of the angiopoietin/TIE axis. ⋯ Furthermore, enhanced ANG2 activity increased endothelial permeability, as demonstrated in an in vitro transwell assay. We conclude that sole TLR stimulation by bacterial ligands plays no significant role for altered expression and secretion of ANG1, -2 and TIE2 in human pulmonary vascular cells. The interplay between various stimuli is required to induce imbalances between ANG1 and -2.
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Clin. Exp. Pharmacol. Physiol. · Oct 2016
Daphnetin inhibits TNF-α and VEGF-induced angiogenesis through inhibition of the IKKs/IκBα/NF-κB, Src/FAK/ERK1/2 and Akt signalling pathways.
Coumarins, identified as plant secondary metabolites possess diverse biological activities including anti-angiogenic properties. Daphnetin (DAP), a plant derived dihydroxylated derivative of coumarin has shown significant pharmacological properties such as anticancer, anti-arthritic and anti-inflammatory. The present study was performed to investigate the anti-angiogenic potential of DAP, focusing on the mechanism of action. ⋯ Furthermore, western blotting revealed that DAP significantly down-regulated the VEGF-induced signalling such as c-Src, FAK, ERK1/2 and the related phosphorylation of protein kinase B (Akt) and VEGFR2 expressions. DAP reduced the elevated mRNA expression of iNOS, MMP2 and also, induced apoptosis in VEGF-stimulated HUVECs by the caspase-3 dependent pathway. Taken together, this study reveals that DAP may have novel prospective as a new multi-targeted medication for the anti-angiogenesis and cancer therapy.
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Clin. Exp. Pharmacol. Physiol. · Sep 2016
Hyperoxia-mediated LC3B activation contributes to the impaired transdifferentiation of type II alveolar epithelial cells (AECIIs) to type I cells (AECIs).
Life-saving mechanical ventilation can also cause lung injury through the overproduction of reactive oxygen species (ROS), leading to bronchopulmonary dysplasia (BPD)-like symptoms in preterm infants. It is reported that the autophagic protein microtubule-associated protein-1 light chain (LC)-3B can confer protection against hyperoxia-induced DNA damage in lung alveolar epithelium. However, its role in the transdifferentiation of type II alveolar epithelial cells (AECIIs) to type I cells (AECIs) is unclear and requires further investigation. ⋯ Both the LC3B expression and the conversion from LC3BI to LC3BII were enhanced in hyperoxic AECs. Interestingly, inhibition of LC3B either by ROS inhibitor N-acetyl-l-cysteine (NAC) or adenovirus-mediated LC3B shRNA could partly restore AECII transdifferentiation under hyperoxia condition. In summary, the current study reveals a novel role of activated LC3B induced by hyperoxia in AECII transdifferentiation.
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Clin. Exp. Pharmacol. Physiol. · Jun 2016
miR-410 suppresses the expression of interleukin-6 as well as renal fibrosis in the pathogenesis of lupus nephritis.
Lupus nephritis (LN) is a highly complex autoimmune disease caused by systemic lupus erythematosus (SLE). MicroRNAs (miRNAs) play a vital role in the pathogenesis of SLE. Previously, a total of 29 miRNAs were identified to be down-regulated in SLE patients, in which miR-410 was likely to be involved in the signalling transduction pathways in regulating the pathogenesis of SLE. ⋯ Moreover, overexpression of miR-410 significantly reduced the expression levels of fibrosis factors such as transforming growth factor-β1 (TGF-β1) and collagen I/III in SV40MES13 cells; Inhibition of the expression of miR-410 with miR-410 inhibitor resulted in increased levels of IL-6 as well as fibrosis factors. The results identify that miR-410, as a novel and critical factor in the pathogenesis of LN, decreases IL-6 expression by binding directly to the 3'UTR and suppresses fibrosis through down-regulation of TGF-β1 in SV40MES13 cells. Our study brings new insight into understanding the complex mechanisms involved in the pathogenesis of lupus disease.