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Ferroptosis plays an important role in ischemia-reperfusion (I/R)-induced cardiac injury and there are many defects in current targeted delivery of miRNAs for the treatment of ferroptosis. We herein report a unique hydrogel (Gel) that can be triggered by a near-infrared-II (NIR-II) light with deep tissue penetration and biocompatible maximum permissible exposure (MPE) value for in situ treatment after I/R. The mir-196c-3p mimic (mimics) and photothermal nanoparticles (BTN) were co-encapsulated in an injectable Gel (mimics + Gel/BTN) with NIR-II light-triggered release. Using 1064 nm light irradiation, local microenvironment photothermal-triggered on-demand noninvasive controllable delivery of miRNA was achieved, aiming to inhibit I/R-induced ferroptosis. Consequently, declined ferroptosis in cardiomyocytes and improved cardiac function, survival rate in rats was achieved through the controlled release of Gel/BTN mimics in I/R model to simultaneously inhibit ferroptosis hub genes NOX4, P53, and LOX expression. Ischemic heart disease is the leading cause of death worldwide. A novel dynamic covalent hydrogel of fructose-containing polymer (PFA) and BOB-containing polymer (PNBA) was successfully constructed, capable of light-triggered release of miRNAs via NIR-II. This work demonstrated that a strategy to noninvasively control release of miRNAs in vivo while providing an effective target for ferroptosis therapy might be a promising treatment for I/R. [Display omitted] • The hydrogel with NIR-II light-triggered release of the mimics is rationally designed as a promising drug delivery system. • The hydrogel can simultaneously regulate the expression of ferroptosis-related genes LOX, NOX4, and P53. • We successfully performed NIR-II-triggered in vivo fluorescence imaging through the chest cavity as deep as 7 mm. [ABSTRACT FROM AUTHOR]

An inverse relationship exists between kallistatin levels and salt-induced oxidative stress in Dahl-salt sensitive rats. We further investigated the role of kallistatin in inhibiting inflammation and fibrosis through antioxidative stress in Dahl-salt sensitive rats and cultured renal cells. High-salt intake in Dahl-salt sensitive rats induced elevation of thiobarbituric acid reactive substances (an indicator of lipid peroxidation), malondialdehyde levels, reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, and superoxide formation, whereas kallistatin gene delivery significantly reduced these oxidative stress parameters. Kallistatin treatment improved renal function and reduced kidney damage as evidenced by diminished proteinuria and serum urea nitrogen levels, glomerular sclerosis, tubular damage, and protein cast formation. Kallistatin significantly decreased interstitial monocyte-macrophage infiltration and the expression of tumor necrosis factor-alpha, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Kallistain also reduced collagen fraction volume and the deposition and expression of collagen types I and III. Renal protection by kallistatin was associated with increased NO levels and endothelial NO synthase expression and decreased p38 mitogen-activated protein kinase, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-beta1 expression. Moreover, kallistatin attenuated tumor necrosis factor-alpha-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression via inhibition of reactive oxygen species formation and p38 mitogen-activated protein kinase and nuclear factor-kappaB activation in cultured proximal tubular cells. Kallistatin inhibited fibronectin and collagen expression by suppressing angiotensin II-induced reactive oxygen species generation and transforming growth factor-beta1 expression in cultured mesangial cells. These combined findings reveal that kallistatin is a novel antioxidant, which prevents salt-induced kidney injury, inflammation, and fibrosis by inhibiting reactive oxygen species-induced proinflammatory cytokine and transforming growth factor-beta1 expression. [ABSTRACT FROM AUTHOR]

Abstract: Background: Tissue kallikrein is a serine proteinase that generates the vasoactive kinin peptide, which produces vasodilatory, angiogenic, and antiapoptotic effects. In this study, we investigated the effect of a stable supply of kallikrein and kinin on ventricular remodeling and blood vessel growth in rats after myocardial infarction. Methods and Results: At 1 week after coronary artery ligation, tissue kallikrein or kinin was infused through a minipump for 4 weeks. At 5 weeks after myocardial infarction, kallikrein and kinin infusion significantly improved cardiac contractility and reduced diastolic dysfunction without affecting systolic blood pressure. Kallikrein and kinin infusion significantly increased capillary density in the noninfarcted region. Kallikrein and kinin infusion also reduced heart weight/body weight ratio, cardiomyocyte size, and atrial natriuretic peptide and brain natriuretic peptide expression in the noninfarcted area. Moreover, kallikrein and kinin infusion inhibited interstitial collagen deposition, collagen fraction volume, and collagen I and collagen III mRNA levels, transforming growth factor (TGF)-β1 and plasminogen activator inhibitor-1 expression, and Smad2 phosphorylation. The effects of kallikrein and kinin on cardiac remodeling were associated with increased nitric oxide levels and reduced NADPH oxidase expression and activity, superoxide formation, and malondialdehyde levels. Furthermore, in cultured cardiac fibroblasts, kinin inhibited angiotensin II-stimulated TGF-β1 production, and the effect was blocked by icatibant. Conclusion: These results indicate that a subdepressor dose of kallikrein or kinin can restore impaired cardiac function in rats with postinfarction heart failure by inhibiting hypertrophy and fibrosis and promoting angiogenesis through increased nitric oxide formation and suppression of oxidative stress and TGF-β1 expression. [Copyright &y& Elsevier]

The progression of renal disease displays several characteristics, including proteinuria, apoptosis, inflammation, and fibrosis. In this study, we investigated the effect of long-term infusion of kinin in protection against salt-induced renal damage in Dahl salt-sensitive rats. Dahl salt-sensitive rats were fed a high-salt diet for 2 weeks and were then infused with bradykinin (500 ng/h) via subcutaneously implanted minipumps for 3 weeks. Kinin infusion attenuated salt-induced impaired renal function as evidenced by reduced proteinuria, serum creatinine, and blood urea nitrogen levels without apparent effect on blood pressure. Morphological analysis indicated that kinin administration reduced salt-induced glomerular sclerosis, tubular dilatation, luminal protein cast formation, and interlobular arterial thickness. Kinin also significantly lowered collagen I, III, and IV deposition and their mRNA levels. Moreover, kinin reduced interstitial monocyte/macrophage accumulation, as well as tubular cell apoptosis and caspase-3 activity. Protection of renal injury by kinin was associated with increased renal NO levels and reduced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate oxidase activities and superoxide generation. Suppression of oxidative stress by kinin was accompanied by reduced transforming growth factor-beta1 protein and mRNA levels, as well as decreased phosphorylation of mitogen-activated protein kinases. This is the first study to demonstrate that kinin infusion can directly protect against salt-induced renal injury without blood pressure reduction by inhibiting apoptosis, inflammation, and fibrosis via suppression of oxidative stress, transforming growth factor-beta1 expression, and mitogen-activated protein kinase activation. [ABSTRACT FROM AUTHOR]