GRK2 as a therapeutic target for heart failure

Introduction: G protein-coupled receptor (GPCR) kinase-2 (GRK2) is a regulator of GPCRs, in particular β-adrenergic receptors (ARs), and as demonstrated by decades of investigation, it has a pivotal role in the development and progression of cardiovascular disease, like heart failure (HF). Indeed elevated levels and activity of this kinase are able to promote the dysfunction of both cardiac and adrenal α- and β-ARs and to dysregulate other protective signaling pathway, such as sphingosine 1-phospate and insulin. Moreover, recent discoveries suggest that GRK2 can signal independently from GPCRs, in a ‘non-canonical’ manner, via interaction with non-GPCR molecule or via its mitochondrial localization.

Areas covered: Based on this premise, GRK2 inhibition or its genetic deletion has been tested in several disparate animal models of cardiovascular disease, showing to protect the heart from adverse remodeling and dysfunction.

Expert opinion: HF is one of the leading cause of death worldwide with enormous health care costs. For this reason, the identification of new therapeutic targets like GRK2 and strategies such as its inhibition represents a new hope in the fight against HF development and progression. Herein, we will update the readers about the ‘state-of-art’ of GRK2 inhibition as a potent therapeutic strategy in HF.     

Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of α-Fe2O3 nanoparticles

Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. α-Fe₂O₃ NPs were synthesized, characterized and tested in a model for toxicity utilizing human whole blood without added anticoagulant. MALDI-TOF of the corona was performed and activation markers for plasma cascade systems (complement, contact and coagulation systems), platelet consumption and release of growth factors, MPO, and chemokine/cytokines from blood cells were analyzed. The coronas formed on the pristine α-Fe₂O₃ NPs contained contact system proteins and they induced massive activation of the contact (kinin/kallikrein) system, as well as thrombin generation, platelet activation, and release of two pro-angiogeneic growth factors: platelet-derived growth factor and vascular endothelial growth factor, whereas complement activation was unaffected. The α-Fe₂O₃ NPs exhibited a noticeable toxicity, with kinin/kallikrein activation, which may be associated with hypotension and long-term angiogenesis in vivo, with implications for cancer, arteriosclerosis and pulmonary disease.     

Neuroprotective effect of gold nanoparticles composites in Parkinson's disease model

Parkinson’s disease (PD) is second most common neurodegenerative disorder worldwide. Although drugs and surgery can relieve the symptoms of PD, these therapies are incapable of fundamentally treating the disease. For PD patients, over-expression of α-synuclein (SNCA) leads to the death of dopaminergic neurons. This process can be prevented by suppressing SNCA over-expression through RNA interference. Here, we successfully synthesized gold nanoparticles (GNP) composites (CTS@GNP-pDNA-NGF) via the combination of electrostatic adsorption and photochemical immobilization, which could load plasmid DNA (pDNA) and target specific cell types. GNP was transfected into cells via endocytosis to inhibiting the apoptosis of PC12 cells and dopaminergic neurons. Simultaneously, GNP composites are also used in PD models in vivo, and it can successfully cross the blood-brain barrier by contents of GNP in the mice brain. In general, all the works demonstrated that GNP composites have good therapeutic effects for PD models in vitro and in vivo.     

Nano in nano: Biosynthesized gold and iron nanoclusters cargo neoplastic exosomes for cancer status biomarking

Timely detection is crucial for successful treatment of cancer. The current study describes a new approach that involves utilization of the tumor cell environment for bioimaging with in-situ biosynthesized nanoscale gold and iron probes and subsequent dissemination of Au-Fe nanoclusters from cargo exosomes within the circulatory system. We have isolated the Au-Fe cargo exosomes from the blood of the treated murine models after in situ biosyntheses from their respective pre-ionic solutions (HAuCl₄, FeCl₂), whereas Na₂SeO₃ supplementation added into Au lethal effect. The microarray data of various differentially expressed genes revealed the up-regulated tumor ablation and metal binding genes in SGC-7901 cell lines after treatment with Au-Fe-Se triplet ionic solution. The isolation of Au-Fe nanoclusters cargo exosomes (nano in nano) after secretion from deeply seated tumors may help in early diagnosis and reveal the tumor ablation status during and after the relevant treatment like radio-chemo therapies et al.     

Protective effects of melatonin and memantine in human retinal pigment epithelium (ARPE-19) cells against 2-ethylpyridine-induced oxidative stress: implications for age-related macular degeneration

Purpose: To investigate the possible protective effects of melatonin and memantine (MMT) against 2-ethylpyridine (2-EP)-induced oxidative stress and mitochondrial dysfunction in human RPE (ARPE-19) cells in vitro.

Materials and methods: The ARPE-19 cells were divided into seven groups. Oxidative stress was triggered by incubating the ARPE-19 cells with 30?μM of 2-EP for 24?h. Then, 200?μM of melatonin was administered over three days and 20?μM of MMT over six hours prior to the experiment. The effects of melatonin and MMT on the intracellular calcium release mechanism, reactive oxygen species production, caspase-3 and caspase-9 activities, as well as vascular endothelial growth factor levels were measured.

Results: Melatonin and MMT were found to significantly decrease apoptosis levels. The intracellular calcium release was regulated by both melatonin and MMT. Further, melatonin and MMT significantly decreased both caspase-3 and caspase-9 activities, as well as pro-caspase and poly(ADP-ribose) polymerase expression, in ARPE-19 cells. Moreover, melatonin significantly increased the protective effect of MMT. The combination of melatonin and MMT significantly decreased 2-EP-induced oxidative toxicity and apoptosis by inhibiting the intracellular reactive oxygen species production and mitochondrial depolarization levels.

Conclusions: These notable findings are the first to demonstrate the synergistic protective effects of melatonin and MMT against 2-EP-induced oxidative stress in ARPE-19 cells.     

Invasive mold infections in acute leukemia patients undergoing allogeneic hematopoietic stem cell transplantation

Background/purposePatients with acute leukemia undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are exposed to high risk of developing invasive fungal infections, and the invasive mold infections (IMIs) are becoming more and more common after transplantation. Here, we conducted a retrospective study to analyze demographics, microbiology, and risk factors for IMIs development in adult acute leukemia patients undergoing allo-HSCT.MethodsWe reviewed 245 adult acute leukemia patients undergoing allo-HSCT from January 2003 to December 2014. Clinical characteristics including age, sex, conditioning regimens, European Group for Blood and Bone marrow Transplantation (EBMT) risk score, and presence of acute graft-versus-host disease (aGVHD) or chronic GVHD (cGVHD) were collected and analyzed. Cox proportional hazard model was adopted to explore the independent risk factors for IMIs developments.ResultsSeventeen of 245 patients developed IMIs during the study period. The cumulative incidence of IMIs in this cohort was 8.7% and 16.8% at 6 and 12 months, respectively, with Aspergillus species being the most common pathogen. The significant risk factors predicting IMIs were unrelated donor transplantation (hazard ratio [HR] 5.11), smoking (HR 3.55), EBMT risk score > 2 (HR 4.22), and moderate to severe cGVHD (HR 3.76).ConclusionsWe identified four risk factors-unrelated donor transplantation, smoking, EBMT risk score >2 and moderate to severe cGVHD to predict IMIs among acute leukemia patients undergoing allo-HSCT. This cohort study suggests early identification of high-risk patients and to provide better prevention strategies would reduce the incidence and severity of IMIs in these patients.     

Distribution of virulence genes in bacteremic methicillin-resistant Staphylococcus aureus isolates from various sources

Background/purposeMethicillin-resistant Staphylococcus aureus (MRSA) can encode proteins which directly bind bacteria to many tissues and medical devices or catheters to trigger pathogenesis. However, the relationship between genetic backgrounds and virulent factors in MRSA isolates remained incompletely understood yet.MethodsMRSA isolates were collected from blood cultures of patients with infective endocarditis, bone/joint infection, skin/soft tissue infection, or catheter-related bacteremia in hemodialysis at a tertiary medical center between 2005 and 2011. MRSA isolates were characterized by the methods of spa, multilocus sequence, and staphylococcal cassette chromosome mec (SCCmec) typing. Identification of virulence gene expression was measured by Power SYBR Green PCR Master Mix.ResultsOverall collected were 136 MRSA bacteremic isolates, including those from the cases of infective endocarditis (n = 23), bone/joint infection (n = 49), skin/soft tissue infection (n = 20), or catheter-related bacteremia in patients with acute kidney injury or end-stage renal stage receiving hemodialysis (n = 54). CC8-ST239-MRSA-SCCmec type III-spa type t037 was the most prevalent type observed in all of 136 MRSA bacteremic isolates. The prevalent genes in the group of infective endocarditis were clfA, clfB, fnbA, ebpS, eap, emp, sae, and eno; bone/joint infections clfA, emp, sae, and eno; skin/soft tissue infection eno; hemodialysis catheter-related bacteremia clfA and sae. The distribution of each gene was not statically different among four groups.ConclusionsA major MRSA lineage, CC8-ST239-MRSA-SCCmec type III-spa type t037, is noted among bacteremic MRSA isolates. No disease-specific virulent genes can be identified.