Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Regulated necrosis (RN) may result from cyclophilin (Cyp)D-mediated mitochondrial permeability transition (MPT) and receptor-interacting protein kinase (RIPK)1-mediated necroptosis, but it is currently unclear whether there is one common pathway in which CypD and RIPK1 act in or whether separate RN pathways exist. Here, we demonstrate that necroptosis in ischemia–reperfusion injury (IRI) in mice occurs as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI. Protection of RIPK3-knockout mice was significantly stronger than of CypD-deficient mice. Mechanistically, in vivo analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. We, therefore, generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI, which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 and the MPT inhibitor sanglifehrin A confirmed the results with mutant mice. The data demonstrate the pathophysiological coexistence and corelevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury.     

Safety and tolerability of injectable lipid-lowering drugs: an update of clinical data

Introduction: Cardiovascular (CV) diseases are the leading cause of death and disability in the developed countries. Lipid-lowering therapy is a cornerstone of the CV risk modification strategy. The first line treatment for hyperlipidemia is statins, which decrease low-density lipoprotein cholesterol (LDL-C) by 30–50% and proportionally reduce the CV events. However, they are not always enough to achieve LDL-C goals in many patients, and some patients are statin intolerant. For this reason, new powerful injectable lipid-lowering drugs have been developed.

Areas covered: The aim of this narrative review was to summarize the more recent clinical data on safety and tolerability of injectable lipid-lowering drugs. After an attentive literature search, the authors resumed here information on proprotein convertase subtilisin/kexin 9 inhibitors (evolocumab and alirocumab), small interfering RNA molecule inclisiran, antisense oligonucleotides (mipomersen, volanesorsen, ISIS 681257), and drugs targeting angiopoietin-like protein 3 (evinacumab, IONIS-ANGPTL3_Rx).

Expert opinion: Injectable lipid-lowering therapy for patients at high risk for CV disease complications or with severe inherited hypercholesterolemias can be an important element of the available therapeutic armamentarium. Clinical data prove the favorable risk-benefit profile of evolocumab, alirocumab, and inclisiran. Mipomersen, volanesorsen, ISIS 681257, evinacumab, and IONIS-ANGPTL3_Rx safety is currently less extensively studied, especially in patients with comorbidities and polypharmacotherapy.     

Exploring the link between diabetes and pancreatic cancer

Introduction: Epidemiological studies indicate an association between type 2 diabetes and pancreatic cancer but the complex and multidirectional relationship between them remains unclear.

Areas covered: We summarized epidemiological evidence on diabetes and pancreatic cancer exploring the time–risk relationship. We described mechanisms linking long-standing diabetes to pancreatic cancer. We discussed pancreatic cancer-associated diabetes and its implication in the early detection of pancreatic cancer.

Expert opinion: The markedly increased risk of pancreatic cancer in patients with new-onset diabetes compared with long-standing diabetes observed in several epidemiological studies indicates a complex and bidirectional connection, with long-standing diabetes being a predisposing factor for pancreatic cancer (increasing the risk of the malignancy 1.5- to 2-fold) and new-onset diabetes an early manifestation of the tumor. Identifying clinical features and biomarkers to distinguish pancreatic cancer-associated diabetes from type 2 diabetes is an important goal to improve management and survival of this cancer. Imaging (MRI) for middle-age patients with new-onset diabetes may be considered.     

Do the socioeconomic context and the European geographical area modify parental influences on smoking experimentation among adolescents?

Adolescent smoking is a major public health problem. While the socioeconomic status (SES) of the neighbourhood and that of the family are known to play a role in smoking onset and progression, it is not clear whether it modifies the association between parental influences and adolescent behaviour. The purpose of this study is to investigate family correlates of adolescent smoking experimentation and to explore the modifying role of socioeconomic context and European geographical area in a sample of European adolescents. This is a secondary analysis of the baseline survey of the European Drug Addiction Prevention (EU-Dap) trial which took place in seven European countries and involved 7079 students. School SES was used as indicator of socioeconomic context. European countries were aggregated in two geographical areas: North-Central and South. The associations between parental, family factors, and adolescents smoking experimentation were analysed through multilevel mixed-effect logistic regression models, stratified by school SES and European geographical area. Parental smoking, permissiveness towards tobacco, family conflicts, problematic relationships, low connectedness, and low parental control were significantly associated with adolescent smoking experimentation. Paternal smoking was a stronger correlate of adolescent smoking in low SES schools, while maternal smoking in high SES schools. Parental permissiveness was a stronger correlate in low SES schools. Family conflicts and low parental control were correlates only in low SES schools. The associations did not substantially differ between European geographical areas, with the exception of parental smoking that was a stronger correlate in the North, and parental control that was a correlate only in the South of Europe. To reduce inequalities in tobacco-related outcomes, prevention efforts in low socioeconomic contexts appear to be a public health priority. Parental smoking, permissiveness, family relationships, and connectedness should be addressed in preventive programs.