Cardio-protective effects of pentraxin 3 produced from bone marrow-derived cells against ischemia/reperfusion injury

AbstractBackgroundInflammation is one of major mechanisms contributing to the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. Pentraxin 3 (PTX3), produced in response to inflammatory signals, acts as a humoral arm of the innate immunity. Here we investigated the role of PTX3 produced from bone marrow-derived cells in myocardial I/R injury using PTX3-deficient (PTX3KO) mice.Methods and resultsPTX3KO mice and wild-type littermate (WT) mice were lethally irradiated and injected with bone marrow (BM) cells, generating four types of mice (WTWT-BM, WTPTX3KO-BM, PTX3KOWT-BM and PTX3KOPTX3KO-BM). Six weeks after BM transplantation, the myocardial I/R procedure (45min of left descending coronary artery ligation followed by 48h of reperfusion) was performed. Infarct size was greater in WT and PTX3KO mice with BM from PTX3KO donor (WTPTX3KO-BM and PTX3KOPTX3KO-BM) compared with WT and PTX3KO mice with BM from WT donor (WTWT-BM and PTX3KOWT-BM). Localization of PTX3 was observed in neutrophils and macrophages in WT and PTX3KO mice with BM from WT donor (WTWT-BM and PTX3KOWT-BM), while only in endothelial cells in WT mice with BM from PTX3KO donor (WTPTX3KO-BM). Infiltration of neutrophils and generation of reactive oxygen species (ROS) at ischemic border zones were greater in PTX3KO mice with BM from PTX3KO donor (PTX3KOPTX3KO-BM) than PTX3KO mice with BM from WT donor (PTX3KOWT-BM). Plasma levels and cardiac expressions of interleukin-6 were higher in PTX3KO mice with BM from PTX3KO donor (PTX3KOPTX3KO-BM) than PTX3KO mice with BM from WT donor (PTX3KOWT-BM). However, no significant differences in infarct size, infiltration of neutrophils, generation of ROS and plasma and cardiac levels of interleukin-6 were observed between WT and PTX3KO mice with BM from WT donor and between WT and PTX3KO mice with BM from PTX3KO donor. These results indicated that the lack of PTX3 produced from BM-derived cells, and not from cardiac resident cells, exacerbated myocardial injury after I/R.ConclusionPTX3 produced from bone marrow-derived cells plays a crucial role in cardiac protection against myocardial I/R injury by attenuating infiltration of neutrophils, generation of ROS and inflammatory cytokine

C188-9, a specific inhibitor of STAT3 signaling, prevents thermal burn-induced skeletal muscle wasting in mice

Burn injury is the leading cause of death and disability worldwide and places a tremendous economic burden on society. Systemic inflammatory responses induced by thermal burn injury can cause muscle wasting, a severe involuntary loss of skeletal muscle that adversely affects the survival and functional outcomes of these patients. Currently, no pharmacological interventions are available for the treatment of thermal burn-induced skeletal muscle wasting. Elevated levels of inflammatory cytokines, such as interleukin-6 (IL-6), are important hallmarks of severe burn injury. The levels of signal transducer and activator of transcription 3 (STAT3)—a downstream component of IL-6 inflammatory signaling—are elevated with muscle wasting in various pro-catabolic conditions, and STAT3 has been implicated in the regulation of skeletal muscle atrophy. Here, we tested the effects of the STAT3-specific signaling inhibitor C188-9 on thermal burn injury-induced skeletal muscle wasting in vivo and on C2C12 myotube atrophy in vitro after the administration of plasma from burn model mice. In mice, thermal burn injury severity dependently increased IL-6 in the plasma and tibialis anterior muscles and activated the STAT3 (increased ratio of phospho-STAT3/STAT3) and ubiquitin-proteasome proteolytic pathways (increased Atrogin-1/MAFbx and MuRF1). These effects resulted in skeletal muscle atrophy and reduced grip strength. In murine C2C12 myotubes, plasma from burn mice activated the same inflammatory and proteolytic pathways, leading to myotube atrophy. In mice with burn injury, the intraperitoneal injection of C188-9 (50 mg/kg) reduced activation of the STAT3 and ubiquitin-proteasome proteolytic pathways, reversed skeletal muscle atrophy, and increased grip strength. Similarly, pretreatment of murine C2C12 myotubes with C188-9 (10 µM) reduced activation of the same inflammatory and proteolytic pathways, and ameliorated myotube atrophy induced by plasma taken from burn model mice. Collectively, these results indicate that pharmacological inhibition of STAT3 signaling may be a novel therapeutic strategy for thermal burn-induced skeletal muscle wasting

Memantine has no effect on KATP channels in pancreatic β cells

Abstract Objective Memantine, a drug for Alzheimer’s disease, is considered to suppress excessive stimulation of N-methyl-d-aspartic acid receptors and to prevent neuronal death. However, a recent report indicated that the neuronal KATP channel also can become a target of memantine. The KATP channel is a key regulator of insulin secretion in pancreatic β cells. Therefore, if memantine could inhibit the KATP channel in pancreatic β cells, it would be an effective drug for both Alzheimer’s disease and diabetes. However, there is no report on the effect of memantine on the KATP channel in pancreatic β cells. Therefore, we investigated whether memantine affect the blood glucose level, insulin secretion and KATP channel activity in pancreatic β cells. Results An intraperitoneal glucose tolerance test was performed with or without memantine (1 mg/kg) injection in intact mice. Insulin secretion from isolated islets was measured under low (2 mM) and high (20 mM) glucose concentrations with or without memantine (1 μM). The effect of memantine (1 μM) on KATP channel currents in isolated pancreatic β cells was recorded using the whole-cell patch-clamp technique. Memantine had no effect on the blood glucose level, insulin secretion from isolated islets or KATP channel current in pancreatic β cells

Inhibitory Effects of Green Tea and (-)-Epigallocatechin Gallate on Transport by OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K and P-Glycoprotein.

Green tea catechins inhibit the function of organic anion transporting polypeptides (OATPs) that mediate the uptake of a diverse group of drugs and endogenous compounds into cells. The present study was aimed at investigating the effect of green tea and its most abundant catechin epigallocatechin gallate (EGCG) on the transport activity of several drug transporters expressed in enterocytes, hepatocytes and renal proximal tubular cells such as OATPs, organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and P-glycoprotein (P-gp). Uptake of the typical substrates metformin for OCTs and MATEs and bromosulphophthalein (BSP) and atorvastatin for OATPs was measured in the absence and presence of a commercially available green tea and EGCG. Transcellular transport of digoxin, a typical substrate of P-gp, was measured over 4 hours in the absence and presence of green tea or EGCG in Caco-2 cell monolayers. OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin uptake was significantly reduced in the presence of green tea and EGCG (P < 0.05). BSP net uptake by OATP1B1 and OATP1B3 was inhibited by green tea [IC50 2.6% (v/v) and 0.39% (v/v), respectively]. Green tea also inhibited OATP1B1- and OATP1B3-mediated atorvastatin net uptake with IC50 values of 1.9% (v/v) and 1.0% (v/v), respectively. Basolateral to apical transport of digoxin was significantly decreased in the presence of green tea and EGCG. These findings indicate that green tea and EGCG inhibit multiple drug transporters in vitro. Further studies are necessary to investigate the effects of green tea on prototoypical substrates of these transporters in humans, in particular on substrates of hepatic uptake transporters (e.g. statins) as well as on P-glycoprotein substrates

Maintenance time of sedative effects after an intravenous infusion of diazepam: A guide for endoscopy using diazepam

AIM: To examine whether the sedative effects assessed by psychomotor tests would depend on the cytochrome P450 (CYP) 2C19 genotypes after an infusion regimen of diazepam commonly used for gastrointestinal endoscopy in Japan

Effect of EGCG on OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin transport.

<p>Data are shown as mean ± S.E.M. VC vector control. *** p< 0.001, * p<0.05 vs. VC, +++ p<0.001 vs. corresponding transport without inhibitor.</p