Potential therapeutic benefits stemming from the thermal nature of irreversible electropora tion of solid cancers

To the Editor：Irreversible electroporation （IRE） is a CE- and FDA- approved treatment modality for pancreatic and liver tumors that is based on the site-confined destruction of tumor tissue by multiple short, high-intensity electrical pulses.

Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is today considered the most common form of chronic liver disease, affecting a high proportion of the population worldwide. NAFLD encompasses a large spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. Obesity, hyperglycemia, type 2 diabetes and hypertriglyceridemia are the most important risk factors. The pathogenesis of NAFLD and its progression to fibrosis and chronic liver disease is still unknown. Accumulating evidence indicates that mitochondrial dysfunction plays a key role in the physiopathology of NAFLD, although the mechanisms underlying this dysfunction are still unclear. Oxidative stress is considered an important factor in producing lethal hepatocyte injury associated with NAFLD. Mitochondrial respiratory chain is the main subcellular source of reactive oxygen species(ROS), which may damage mitochondrial proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid located at the level of the inner mitochondrial membrane, plays an important role in several reactions and processes involved in mitochondrial bioenergetics as well as in mitochondrial dependent steps of apoptosis. This phospholipid is particularly susceptible to ROS attack. Cardiolipin peroxidation has been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including NAFLD. In this review, we focus on the potential roles played by oxidative stress and cardiolipin alterations in mitochondrial dysfunction associated with NAFLD.

SARS-CoV-2 induced myocarditis:Current knowledge about its molecular and pathophysiological mechanisms

The existence of an inflammatory process in the heart muscle,related to a progressive worsening of myocardial function,different etiopathogenetic mechanisms concur and often overlap,thus making the diagnosis and the therapeutic approach complex.As the COVID-19 pandemic progresses,the effects of the disease on the organ systems and in particular on the cardiovascular system are becoming more and more profound.Cardiac involvement is a well-known event with a high percentage of findings in the heart’s magnetic field,even in asymptomatic areas.There are numerous uncertainties regarding their evolution,in the long and short term,due not only to a difficult to determine the varied clinical expression and the rarely performed intramyocardial biopsy which additionally presents diagnostic problems but also in part to different clinical prognosis.Today,the new SARS-CoV-2 virus that uses the angiotensin converting enzyme 2(ACE2)which is present at high levels in myocardial cells as its entrance it can create even severe heart injury.The pathophysiology in all of these cases can involve multiple immune and non-immune mechanisms within organs and vessels and can be occur in the clinical phases.Possible mechanisms of direct and indirect myocardial infarction in patients with COVID-19 include additional lesion and oxygen-rich and generalized inflammation response with myocardial immune hyperactivity(myocarditis).Therefore,these can occur through the excessive release of cytokines,the presence of thrombocytopenia,endocrine damage,heart failure,arrhythmias and more.Patients can show average signs of myocardial damage,and some develop spontaneous cardiac complications,such as heart failure,arrhythmias and,rarely,rare cardiogenic disorders.Pathophysiology in all of these may involve multiple mechanisms within the cytokine cephalic membrane,endocrine damage and thrombogenicity.The diagnosis of this myocardial injuri is mainly based on the myocardial enzyme troponin.This viewpoint paper explains today’s knowledge on viral myocarditis,in particular that from SARS-CoV-2 infection,if there is a connection with other possible biomolecular pathogenetic factors that can influence its natural course.In fact,it is for this reason that the pathogenetic mechanisms are analyzed and described.At the same time,its possible interaction with other parameters that are documented risk factors for cardiovascular disease was examined.Although these biomolecular findings were mainly related to necrotic parts of the myocardium,it is important to recognize that myocardial damage early for a better approach and prognosis.

Characterization of the molecular dysfunctions occurring in Aicardi-Goutieres syndrome patients with mutations in ADAR1

Aicardi-Goutieres syndrome(AGS)is a systemic inflammatory disorder caused by mutations in any one of the nine different genes,whose deficiency provokes a type I(interferon)IFN response probably central to pathogenesis.^(1) ADAR1,one of the genes mutated in AGS(AGS6),encodes for an enzyme that belongs to the ADAR family(ADAR1,ADAR2,and ADAR3)that catalyzes the conversion of adenosine to inosine within double-stranded RNAs(dsRNAs)(RNA editing A-to-1).

An update on the role of RANKL-RANK/osteoprotegerin and WNT-β-catenin signaling pathways in pediatric diseases

Background Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs),the bone-reabsorbing cells,and osteoblasts (OBs),and the bone-forming cells.This equilibrium is regulated by numerous cytokines,but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/β-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis,respectively.The pro-osteoblastogenic activity of the Wnt/β-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1).RANKL,sclerostin and DKKs-1 are often up-regulated in bone diseases,and they are the target of new monoclonal antibodies.Data sources The authors performed a systematic literature search in PubMed and EMBASE to June 2018,reviewed and selected articles,based on pre-determined selection criteria.Results We re-evaluated the role of RANKL,osteoprotegerin,sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases,such as type 1 diabetes mellitus (T1DM),alkaptonuria (AKU),hemophilia A,osteogenesis imperfecta (OI),21-hydroxylase deficiency (21 OH-D) and Prader-Willi syndrome (PWS).To do so,we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-β-catenin signaling pathways have been investigated,and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed.Conclusions The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases.Furthermore,for some of them,bone damage began in childhood but only manifested with age.The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children,although further studies need to be carried out.

Natural products,PGC-1α,and Duchenne muscular dystrophy

Peroxisome proliferator-activated receptorγ(PPARγ)is a transcriptional coactivator that binds to a diverse range of transcription factors.PPARγcoactivator 1(PGC-1)coactivators possess an extensive range of biological effects in different tissues,and play a key part in the regulation of the oxidative metabolism,consequently modulating the production of reactive oxygen species,autophagy,and mitochondrial biogenesis.Owing to these findings,a large body of studies,aiming to establish the role of PGC-1 in the neuromuscular system,has shown that PGC-1 could be a promising target for therapies targeting neuromuscular diseases.Among these,some evidence has shown that various signaling pathways linked to PGC-1αare deregulated in muscular dystrophy,leading to a reduced capacity for mitochondrial oxidative phosphorylation and increased reactive oxygen species(ROS)production.In the light of these results,any intervention aimed at activating PGC-1 could contribute towards ameliorating the progression of muscular dystrophies.PGC-1αis influenced by different patho-physiological/pharmacological stimuli.Natural products have been reported to display modulatory effects on PPARγactivation with fewer side effects in comparison to synthetic drugs.Taken together,this review summarizes the current knowledge on Duchenne muscular dystrophy,focusing on the potential effects of natural compounds,acting as regulators of PGC-1α.