A Novel Compound C12 Inhibits Inflammatory Cytokine Production and Protects from Inflammatory Injury In Vivo

Inflammation is a hallmark of many diseases. Although steroids and cyclooxygenase inhibitors are main anti-inflammatory therapeutical agents, they may cause serious side effects. Therefore, developing non-steroid anti-inflammatory agents is urgently needed. A novel hydrosoluble compound, C12 (2,6-bis(4-(3-(dimethylamino)-propoxy)benzylidene)cyclohexanone), has been designed and synthesized as an anti-inflammatory agent in our previous study. In the present study, we investigated whether C12 can affect inflammatory processes in vitro and in vivo. In mouse primary peritoneal macrophages, C12 potently inhibited the production of the proinflammatory gene expression including TNF-α, IL-1β, IL-6, iNOS, COX-2 and PGE synthase. The activity of C12 was partly dependent on inhibition of ERK/JNK (but p38) phosphorylation and NF-κB activation. In vivo, C12 suppressed proinflammatory cytokine production in plasma and liver, attenuated lung histopathology, and significantly reduced mortality in endotoxemic mice. In addition, the pre-treatment with C12 reduced the inflammatory pain in the acetic acid and formalin models and reduced the carrageenan-induced paw oedema and acetic acid-increased vascular permeability. Taken together, C12 has multiple anti-inflammatory effects. These findings, coupled with the low toxicity and hydrosolubility of C12, suggests that this agent may be useful in the treatment of inflammatory diseases

Injectable Materials for the Treatment of Myocardial Infarction and Heart Failure: The Promise of Decellularized Matrices

Cardiovascular disease continues to be the leading cause of death, suggesting that new therapies are needed to treat the progression of heart failure post-myocardial infarction. As cardiac tissue has a limited ability to regenerate itself, experimental biomaterial therapies have focused on the replacement of necrotic cardiomyocytes and repair of the damaged extracellular matrix. While acellular and cellular cardiac patches are applied surgically to the epicardial surface of the heart, injectable materials offer the prospective advantage of minimally invasive delivery directly into the myocardium to either replace the damaged extracellular matrix or to act as a scaffold for cell delivery. Cardiac-specific decellularized matrices offer the further advantage of being biomimetic of the native biochemical and structural matrix composition, as well as the potential to be autologous therapies. This review will focus on the requirements of an ideal scaffold for catheter-based delivery as well as highlight the promise of decellularized matrices as injectable materials for cardiac repair

Assessment of microvascular dysfunction in acute limb ischemia-reperfusion injury

This is the peer reviewed version of the following article: Ganesh, T., Zakher, E., Estrada, M. and Cheng, H.‐L.M. (2019), Assessment of microvascular dysfunction in acute limb ischemia‐reperfusion injury. J. Magn. Reson. Imaging, 49: 1174-1185. doi:10.1002/jmri.26308, which has been published in final form at https://doi.org/10.1002/jmri.26308. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Background Ischemia‐reperfusion (I/R) injury involves damage to the microvessel structure (eg, increased permeability) and function (blunted vasomodulation). While microstructural damage can be detected with dynamic contrast‐enhanced (DCE) MRI, there is no diagnostic to detect deficits in microvascular function. Purpose To apply a novel MRI method for evaluating dynamic vasomodulation to assess microvascular dysfunction in skeletal muscle following I/R injury. Study Type Prospective, longitudinal. Animal Model Twenty‐three healthy male adult Sprague–Dawley rats. Field Strength/Sequence Dynamic T1 fast field echo imaging at 3.0T with preinjection T1 mapping. Assessment Injury in the left hindlimb was induced using a 3‐hour I/R procedure. Longitudinal MRI scanning was performed up to 74 days, with animals completing assessment at different intervals for histological and laser Doppler perfusion validation. Pharmacokinetic parameters Ktrans and ve were determined following i.v. injection of gadovist (0.1 mmol/kg). Vasomodulatory response was probed on gadofosveset (0.3 mmol/kg) using hypercapnic gases delivered through a controlled gas‐mixing circuit to induce vasoconstriction and vasodilation in ventilated rats. Heart rate and blood oxygen saturation were monitored. Statistical Tests Two‐way analysis of variance with Tukey–Kramer post‐hoc analysis was used to determine significant changes in vasomodulatory response, Ktrans, and ve. Results This new MRI technique revealed impaired vasomodulation in the injured hindlimb. Vasoconstriction was maintained, but vasodilation was blunted up to 21 days postinjury (P < 0.05). However, DCE‐MRI measured Ktrans and ve were significantly (P < 0.05) different from baseline only during acute inflammation (Day 3), with severe inflammation noted on histology. Data Conclusion While conventional DCE‐MRI shows normalization after the acute phase, our new approach reveals sustained functional impairment in muscle microvasculature following I/R injury, with compromised response in vasomotor tone present for at least 21 days. Level of Evidence: 4 Technical Efficacy: Stage