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Gliflozins are a novel class of oral anti-diabetic drugs, acting as inhibitors of sodium-glucose co-transporters (SGLTs) through the proximal convoluted tubules (PCT) and intestinal epithelium. The sodium-glucose co-transporters 2 (SGLT2) are mainly expressed in S1 and S2 segments of the proximal convoluted tubule in the kidneys. Clinical guidelines recommend their use especially in Type 2 Diabetes mellitus (T2DM) patients with vascular complications and/or heart failure highlighting the importance of sodium-glucose co-transporter 2 inhibitors (SGLT2i) pleiotropic effects. Interestingly, cognitive decline is a widely recognized complication of T2DM and, in addition, to clarify its pathophysiology, there is an urgent need to understand how and if diabetes therapies can control diabetes-related cognitive dysfunction. At the time, although SGLT2 proteins are present in the Central Nervous System (CNS), the SGLT2i effects on cognitive impairments remain partly unknown. In pre-clinical studies, SGLT2i ameliorates cognitive dysfunction in obese and T2DM mice, reducing oxidative stress, neuroinflammation and improving neuronal plasticity and mitochondrial brain pathway. In addition, SGLT2i could bring back mTOR to a physiological state of activation, stopping neurodegenerative diseases' onset or progression. Instead, clinical studies on T2DM-related cognitive dysfunction treated by SGLT2i are much more limited. For these reasons, further studies are needed to better elucidate if SGLT2i therapy can affect T2DM-related cognitive decline. In this scenario, this review aims to summarize the state of knowledge on the role of SGLT2i in T2DM-related cognitive dysfunction and stimulate new clinical trials., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The incidence of heart failure is primarily flat or declining for a presumably reflecting better management of cardiovascular diseases, but that of heart failure with preserved ejection fraction (HFpEF) is probably increasing for the lack of an established effective treatment. Moreover, there is no specific pharmacological treatment for patients with heart failure with mildly reduced ejection fraction (HFmrEF) since no substantial prospective randomized clinical trial has been performed exclusively in such population. According to the recent 2021 European Society of Cardiology (ESC) guidelines, the triad composed of an Angiotensin Converting Enzyme inhibitor or Angiotensin Receptor-Neprilysin Inhibitor (ARNI), a beta-blocker, and a Mineralcorticoid Receptor Antagonist is the cornerstone therapy for all patients with heart failure with reduced ejection fraction (HFrEF) but a substantial gap exists for patients with HFpEF/HFmrEF. Despite the important role of the Renin-Angiotensin-Aldosterone System (RAAS) in heart failure pathophysiology, RAAS blockers were found ineffective for HFpEF patients. Indeed, even the new drug class of ARNI was found effective only in HFrEF patients. In this regard, a therapeutic alternative may be represented by drug stimulating the non-classic RAAS (ACE2 and A1-7) as well as other emerging drug classes (such as SGLT2 inhibitors). Reflecting on this global health burden and the gap in treatments among heart failure phenotypes, we summarize the leading players of heart failure pathophysiology, the available pharmacological treatments for each heart failure phenotype, and that in future development., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In Drosophila, the Heterochromatin Protein 1c (HP1c) forms a transcriptional complex with the zinc-finger proteins WOC and ROW, and the extraproteasomal ubiquitin receptor Dsk2. This complex localizes at promoters of active genes and it is required for transcription. The functions played by the different components of the HP1c complex are not fully understood. In this study we show that WOC and ROW are required for chromatin binding of both Dsk2 and HP1c. However, while impairing chromatin binding strongly destabilizes HP1c, it does not affect Dsk2 stability. We also show that WOC, but not ROW, is required for nuclear localization of Dsk2. Moreover, WOC and Dsk2 co-immunoprecitate upon ROW depletion. These results suggest that WOC and Dsk2 interact to form a subcomplex that mediates nuclear translocation of Dsk2. We also show that ROW mediates chromatin binding of the WOC/Dsk2 subcomplex, as well as of HP1c. Altogether these observations favor a model by which the interaction with WOC recruits Dsk2 to the HP1c complex that, in its turn, binds chromatin in a ROW-dependent manner., Competing Interests: Declaration of competing interest Authors declare no conflict of interests, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Causality assessment is a fundamental biomedical technique for the signal detection performed by Pharmacovigilance centers in a Spontaneous reporting system. Moreover, it is a crucial and important practice for detecting preventable adverse drug reactions. Among different methods for causality assessment, algorithms (such as the Naranjo, or Begaud Methods) seem for their operational procedure and easier applicability one of the most commonly used methods. With the upcoming of the new European Pharmacovigilance legislation including in the definition of the adverse event also effects resulting from abuse, misuse and medication error, all well-known preventable causes of ADRs, there was an emerging need to evaluate whether algorithms could fulfill this new definition. In this review, twenty-two algorithmic methods were identified and none of them seemed to fulfill perfectly the new criteria of adverse event although some of them come close. In fact, several issues were arisen in applying causality assessment algorithms to these new definitions as for example the impossibility to answer the rechallenge question in case of medication error or AEFI (Adverse Event Following Immunization). Moreover, the exact conditions at which events occurred, as for example dosage or mode of administration should be considered to better assess causality in conditions of abuse/overdose, or misuse as well as in conditions of lack of expected efficacy reports for biotechnological drugs and adverse event occurring after mixing of vaccines. Therefore, this review highlights the need of updating algorithmic methods to allow a perfect applicability in all possible clinical scenarios accordingly or not with the terms of marketing authorization., (Copyright © 2017 Elsevier Ltd. All rights reserved.)