Organophosphorus (OP) compounds are highly toxic molecules mainly used as pesticides. OP compounds also include nerve gases used in the past as chemical warfare agents and collectively OP pesticides and nerve gases are referred to as nerve agents (NA). An intensive, widespread use of pesticides since the 20th century has resulted in the emergence of an urgent global issue concerning both environment and human health. In addition, past terroristic acts and the recent dramatic events in Syria highlighted more than ever the need to explore applicable strategies for the sensing, decontamination and detoxification of these compounds in stored bulks, on critical surfaces and media (food, water and air) and for in vivo prophylaxes and therapies.OP compounds, act as covalent inhibitors of acetylcholinesterase (AChE) in the nerve system of vertebrates, thus posing a substantial threat to the ecosystem. In order to address a strong demand for the establishment of an environmental monitoring system and remediation process for NA, an increasing number of studies have been focused on the enzymatic degradation in vitro. Use of enzymes for detoxification and decontamination of toxic NA could provide a long‐term benefit as it is environmentally friendly compared with conventional methods such as chemical treatments and incineration. This review presents an overview of the current state of enzymatic detoxification research against NA. This includes the detailed characterization and protein engineering for the improvement in NA‐degrading activities of such enzymes. Research on biosensors for NA detection and identification, although important in the field, has not been treated in this review. Instead special attention has been paid to the Phosphotriesterase‐Like‐Lactonase (PLL) enzyme family. Several PLL enzymes have been isolated from hyperthermophilic Archaea or thermophilic/extremophilic Bacteria, and exhibit exceptional thermal stability. Extremophilic PLLs therefore hold promise for potential industrial application towards NA detoxification. © 2018 Society of Chemical Industry

Nephrogenic diabetes insipidus (NDI) is a rare tubulopathy characterized by urinary concentration defect due to renal resistance to vasopressin. Loss-of-function mutations of vasopressin V2 receptor (V2R) gene (AVPR2) is the most common cause of the disease. We have identified five novel mutations L86P, R113Q, C192S, M272R, and W323_I324insR from NDI-affected patients. Functional characterization of these mutants revealed that R113Q and C192S were normally localized at the basolateral membrane of polarized Madin-Darby Canine Kidney (MDCK) cells and presented proper glycosylation maturation. On the other side, L86P, M272R, and W323_I324insR mutants were retained in endoplasmic reticulum and exhibited immature glycosylation and considerably reduced stability. All five mutants were resistant to administration of vasopressin analogues as evaluated by defective response in cAMP release. In order to rescue the function of the mutated V2R, we tested VX-809, sildenafil citrate, ibuprofen and tolvaptan in MDCK cells. Among these, tolvaptan was effective in rescuing the function of M272R mutation, by both allowing proper glycosylation maturation, membrane sorting and response to dDAVP. These results show an important proof of concept for the use of tolvaptan in patients affected by M272R mutation of V2R causing NDI.

Mitogen-activated protein kinases (MAPKs) are intracellular molecules regulating a wide range of cellular functions, including proliferation, differentiation, apoptosis, cytoskeleton remodeling and cytokine production. MAPK activity has been shown in normal kidney, and its over-activation has been demonstrated in several renal diseases. The extracellular signal-regulated protein kinases (ERK 1,2) signalling pathway is the first described MAPK signaling. Intensive investigations have demonstrated that it participates in the regulation of ureteric bud branching, a fundamental process in establishing final nephron number; in addition, it is also involved in the differentiation of the nephrogenic mesenchyme, indicating a key role in mammalian kidney embryonic development. In the present manuscript, we show that ERK1,2 signalling mediates several cellular functions also in mature kidney, describing its role along the nephron and demonstrating whether it contributes to the regulation of ion channels and transporters implicated in acid-base and electrolytes homeostasis.

Introduction. Since the pandemic of Coronavirus Disease 2019 (COVID-19) started from December 2019, remarkable numbers of infections and deaths associated with COVID-19 have been recorded worldwide. End-Stage Renal Disease (ESRD) patients on dialysis are particularly at high risk of infections due to impairments in the innate and adaptive immune system. Vaccination on dialysis patients (DP) still remains challenging, because of the variable response and low seroconversion rate compared with healthy controls (HC). Therefore, it is urgently necessary to establish a different vaccination strategy for DP, in terms of dose and administration time. Methods. Here, we report an observational prospective cohort study in which the immunogenic efficacies of SARS-CoV-2 vaccine BNT162b2 on DP and HC were evaluated by absolute quantification of IgG levels in the blood. Results. DP showed a delayed seroconversion after two vaccine doses, with a low absolute IgG levels compared to HC. While healthy populations reached complete seroconversion within 10 days from the administration of second dose, only 76% of DP were seropositive. After booster dose, DP strongly improved seroconversion rate as well as antibody levels, reaching 97% seropositivity and 50 times enhancement on antibody levels. Discussion/Conclusion. These results prompt to suggest an additional vaccine dose in DP, reducing the interval of time from the second dose. Since few data are available on immune response in DP overtime after three vaccine doses currently, our study is among the first reports demonstrating the improved seropositivity and IgG levels in DP after booster vaccine dose.