Amelioration of non-alcoholic fatty liver disease by targeting adhesion G protein-coupled receptor F1 ().

Background: Recent research has shown that the adhesion G protein-coupled receptor F1 ( also known as ) is an oncogene. The evidence is mainly based on high expression of in numerous cancer types, and knockdown can reduce the cell migration, invasion, and proliferation. is, however, mostly expressed in the liver of healthy individuals.

Virus-Derived Chemokine Modulating Protein Pre-Treatment Blocks Chemokine-Glycosaminoglycan Interactions and Significantly Reduces Transplant Immune Damage.

Immune cell invasion after the transplantation of solid organs is directed by chemokines binding to glycosaminoglycans (GAGs), creating gradients that guide immune cell infiltration. Renal transplant is the preferred treatment for end stage renal failure, but organ supply is limited and allografts are often injured during transport, surgery or by cytokine storm in deceased donors. While treatment for adaptive immune responses during rejection is excellent, treatment for early inflammatory damage is less effective.

Targeted Delivery of Antisense Oligonucleotides Through Angiotensin Type 1 Receptor.

We evaluated the potential of AGTR1, the principal receptor for angiotensin II (Ang II) and a member of the G protein-coupled receptor family, for targeted delivery of antisense oligonucleotides (ASOs) in cells and tissues with abundant AGTR1 expression. Ang II peptide ASO conjugates maintained robust AGTR1 signaling and receptor internalization when ASO was placed at the N-terminus of the peptide, but not at C-terminus. Conjugation of Ang II peptide improved ASO potency up to 12- to 17-fold in AGTR1-expressing cells.

Antisense Therapy Attenuates Phospholamban p.(Arg14del) Cardiomyopathy in Mice and Reverses Protein Aggregation.

Inherited cardiomyopathy caused by the p.(Arg14del) pathogenic variant of the phospholamban () gene is characterized by intracardiomyocyte PLN aggregation and can lead to severe dilated cardiomyopathy. We recently reported that pre-emptive depletion of PLN attenuated heart failure (HF) in several cardiomyopathy models.

Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy.

Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca handling is a key feature of HF pathophysiology. Restoring the Ca regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies.

Different blood pressure responses in hypertensive rats following chemerin mRNA inhibition in dietary high fat compared to dietary high-salt conditions.

Chemerin is a contractile adipokine, produced in liver and fat, and removal of the protein by antisense oligonucleotides (ASO) lowers blood pressure in the normal Sprague Dawley rat. In humans, chemerin is positively associated with blood pressure and obesity so we hypothesized that in a model of hypertension derived from high-fat (HF) feeding, the chemerin ASO would reduce blood pressure more than a high-salt (HS) model. Male Dahl S rats were given a HF (60% kcal fat; age 3-24 wk) or HS diet (4% salt; age 20-24 wk to match age and blood pressure of HF animals).

Fatty acid conjugation enhances potency of antisense oligonucleotides in muscle.

Enhancing the functional uptake of antisense oligonucleotide (ASO) in the muscle will be beneficial for developing ASO therapeutics targeting genes expressed in the muscle. We hypothesized that improving albumin binding will facilitate traversal of ASO from the blood compartment to the interstitium of the muscle tissues to enhance ASO functional uptake. We synthesized structurally diverse saturated and unsaturated fatty acid conjugated ASOs with a range of hydrophobicity.

Endothelial cell CD36 optimizes tissue fatty acid uptake.

Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multiligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown.

Whole-Body but Not Hepatic Knockdown of Chemerin by Antisense Oligonucleotide Decreases Blood Pressure in Rats.

Chemerin is an inflammatory adipokine positively associated with hypertension and obesity. The majority of chemerin derives from the liver and adipose tissue, however, their individual contributions to blood pressure are unknown. We began studying chemerin in the normal rat using antisense oligonucleotides (ASO) with whole-body activity (Gen 2.

Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury.

Uncontrolled hypertension is an important contributor to cardiovascular disease. Despite the armamentarium of antihypertensive treatments, there remains a need for novel agents effective in individuals who cannot reach acceptable blood pressure levels. Inhibitors targeting the renin-angiotensin-aldosterone system (RAAS) are widely used but may not optimally inhibit RAAS and demonstrate an acceptable safety profile.

CD40 Generation 2.5 Antisense Oligonucleotide Treatment Attenuates Doxorubicin-induced Nephropathy and Kidney Inflammation.

Preclinical and clinical data suggest CD40 activation contributes to renal inflammation and injury. We sought to test whether upregulation of CD40 in the kidney is a causative factor of renal pathology and if reduction of renal CD40 expression, using antisense oligonucleotides (ASOs) targeting CD40, would be beneficial in mouse models of glomerular injury and unilateral ureter obstruction. Administration of a Generation 2.

Suppressing angiotensinogen synthesis attenuates kidney cyst formation in a Pkd1 mouse model.

Activation of the intrarenal renin angiotensin system (RAS) is believed to play an important role in the development of hypertension and cystogenesis in autosomal dominant polycystic kidney disease (ADPKD). Results of clinical studies testing RAS inhibitors in slowing the progression of cystic disease in ADPKD are inconclusive, and we hypothesized that current RAS inhibitors do not adequately suppress intrarenal RAS. For this study, we compared a novel Gen 2 antisense oligonucleotide (ASO) that inhibits angiotensinogen (Agt) synthesis to lisinopril in adult conditional Pkd1 systemic-knockout mice, a model of ADPKD.

Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia.

We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of this study was to determine the therapeutic timing and mechanism of action that underlie Bendavia's cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 minutes prior to reperfusion (0.

Sivelestat attenuates myocardial reperfusion injury during brief low flow postischemic infusion.

The neutrophil elastase inhibitor sivelestat (ONO-5046) possesses unknown mechanisms of cardioprotection when infused following global ischemia, even in the absence of neutrophils. Since myocardial ischemia-reperfusion injury is strongly associated with endothelial dysfunction and reactive oxygen species (ROS) generation during reperfusion, we have tested the hypothesis that infusion of sivelestat during postischemic low flow would preserve endothelial and contractile function and reduce infarct size through an ROS-mediated mechanism. Isolated male rat hearts, subjected to global ischemia of 25 minutes, were reperfused with low flow with or without sivelestat followed by a full flow reperfusion.

Hyperoxemic reperfusion after prolonged cardiac arrest in a rat cardiopulmonary bypass resuscitation model.

Background: The effect of hyperoxygenation at reperfusion, particularly in the setting of cardiac arrest, remains unclear. This issue was studied in a prolonged cardiac arrest model consisting of 25 min cardiac arrest in a rat resuscitated with cardiopulmonary bypass (CPB). The objective of this study was to determine the effect of hyperoxygenation following prolonged cardiac arrest resuscitation on mitochondrial and cardiac function.

Biphasic modulation of the mitochondrial electron transport chain in myocardial ischemia and reperfusion.

Mitochondrial electron transport chain (ETC) is the major source of reactive oxygen species during myocardial ischemia-reperfusion (I/R) injury. Ischemic defect and reperfusion-induced injury to ETC are critical in the disease pathogenesis of postischemic heart. The properties of ETC were investigated in an isolated heart model of global I/R.

Post-cardiac arrest hyperoxia and mitochondrial function.

Introduction: Rapid post-ischemic re-oxygenation is necessary to minimize ischemic injury, but itself can induce further reperfusion injury through the induction of reactive oxygen species. Utilization of oxygen within the cell primarily occurs in the mitochondria. The objective of this study was to determine heart mitochondrial function after 1 h of controlled arterial oxygenation following cardiac arrest and restoration of spontaneous circulation (ROSC).

Measurement of hydrogen peroxide and oxidant stress in a recirculating whole blood-perfused rat heart model.

Aim Of Study: Isolated hearts used in the study of ischemia-reperfusion induced myocardial reactive oxygen species (ROS) have typically been perfused with crystalloid buffer. Limitations of crystalloid buffer which may exaggerate the production of ROS, include a requirement for higher oxygen tension and the absence of the intrinsic erythrocyte antioxidant defenses. Using a novel recirculating blood-perfused rat heart model, we measured H(2)O(2) concentration in the blood (as an indicator of ROS formation) and tissue glutathione concentration (an overall measure of oxidant stress) following ischemia and reperfusion.

Simplified method for concentration of mitochondrial membrane protein complexes.

Extracting and concentrating mitochondrial protein complexes from gel strips after blue native PAGE (BN-PAGE) can be daunting tasks using the traditional methods, such as electroelution, passive diffusion and centrifugal concentration. We present a simplified gel electrophoresis method to concentrate mitochondrial protein complexes with excellent recovery rate. Mitochondrial complex I present in a long gel strip from BN-PAGE can be easily concentrated into a 0.

Preservation of mitochondrial function with cardiopulmonary resuscitation in prolonged cardiac arrest in rats.

During cardiac arrest (CA), myocardial perfusion is solely dependent on cardiopulmonary resuscitation (CPR) although closed-chest compressions only provide about 10-20% of normal myocardial perfusion. The study was conducted in a whole animal CPR model to determine whether CPR-generated oxygen delivery preserves or worsens mitochondrial function. Male Sprague-Dawley rats (400-450 g) were randomly divided into four groups: (1) BL (instrumentation only, no cardiac arrest), (2) CA(15) (15 min cardiac arrest without CPR), (3) CA(25) (25 min cardiac arrest without CPR) and (4) CPR (15 min cardiac arrest, followed by 10 min CPR).

Oxygen requirement during cardiopulmonary resuscitation (CPR) to effect return of spontaneous circulation.

Background: Recent scientific evidence has demonstrated the importance of good quality chest compressions without interruption to improve cardiac arrest resuscitation rates, and suggested that a de-emphasis on minute ventilation is needed. However, independent of ventilation, the role of oxygen and the optimal oxygen concentration during CPR is not known. Previous studies have shown that ventilation with high oxygen concentration after CPR is associated with worse neurologic outcome.

Presentations of patients of poisoning and predictors of poisoning-related fatality: findings from a hospital-based prospective study.

Background: Poisoning is a significant public health problem worldwide and is one of the most common reasons for visiting emergency departments (EDs), but factors that help to predict overall poisoning-related fatality have rarely been elucidated. Using 1512 subjects from a hospital-based study, we sought to describe the demographic and clinical characteristics of poisoning patients and to identify predictors for poisoning-related fatality.

Methods: Between January 2001 and December 2002 we prospectively recruited poisoning patients through the EDs of two medical centers in southwest Taiwan.

Protective effects of N-acetylcysteine treatment post acute paraquat intoxication in rats and in human lung epithelial cells.

An animal study in rats and a cell culture study in normal human lung epithelial cells were conducted to evaluate the efficacy of N-acetyl-l-cysteine (NAC) in paraquat intoxication and associated inflammatory and oxidative stress. The effectiveness of post treatment was measured by the change of mortality rates and markers of oxidative stress, including glutathione, malondialdehyde and superoxide anion production. In addition, the levels of nitric oxide were also examined in both animal and cell culture system.

Nonaneurysmal subarachnoid hemorrhage secondary to tuberculous meningitis: report of two cases.

Nontraumatic subarachnoid hemorrhage, one of the life-threatening diseases seen in Emergency Departments, is rarely caused by conditions other than rupture of saccular aneurysms. We report two cases of suspected tuberculous meningitis complicated with nonaneurysmal subarachnoid hemorrhage confirmed by conventional cerebral angiography. Tuberculous meningitis should be considered in the differential diagnoses in cases of nonaneurysmal subarachnoid hemorrhage, especially in tuberculosis endemic areas.