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The search of new therapeutic tools for the treatment of cancer is being a challenge for medicinal chemists. Due to their role in different pathological conditions, histone deacetylase (HDAC) enzymes are considered valuable therapeutic targets. HDAC6 is a well-investigated HDAC-class IIb enzyme mainly characterized by a cytoplasmic localization; HDAC8 is an epigenetic eraser, unique HDAC-class I member that displays some aminoacidic similarity to HDAC6. New polypharmacological agents for cancer treatment, based on a dual hHDAC6/hHDAC8 inhibition profile were developed. The dual inhibitor design investigated the diphenyl-azetidin-2-one scaffold, typified in three different structural families, that, combined to a slender benzyl linker (6c, 6i, and 6j), displays nanomolar inhibition potency against hHDAC6 and hHDAC8 isoforms. Notably, their selective action was also corroborated by measuring their low inhibitory potency towards hHDAC1 and hHDAC10. Selectivity of these compounds was further demonstrated in human cell-based western blots experiments, by testing the acetylation of the non-histone substrates alpha-tubulin and SMC3. Furthermore, the compounds reduced the proliferation of colorectal HCT116 and leukemia U937 cells, after 48 h of treatment. The toxicity of the compounds was evaluated in rat perfused heart and in zebrafish embryos. In this latter model we also validated the efficacy of the dual hHDAC6/hHDAC8 inhibitors against their common target acetylated-alpha tubulin. Finally, the metabolic stability was verified in rat, mouse, and human liver microsomes., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: The COVID-19 pandemic has significantly impacted the management of solid organ transplant recipients and on clinical evolution in post-transplantation. Little is known on the impact of SARS-CoV-2 infection in these patients. The severity and lethality of this disease in solid organ transplant patients are higher thanin the general population. This study aims to describe clinical characteristics of SARS-CoV-2 infection in solid organ transplant recipients followed in our center., Methods: In this observational study, we enrolled all kidney transplant recipientsattending the A.O.U. Federico II of Naples from March 2020 to January 2021. For each patient we evaluated the epidemiological and clinical characteristics as well as outcome., Results: We enrolled 369 kidney transplant patients (229, male, 62%). Of these, 51 (13.8%) acquired SARS-CoV-2 infection and 29 showed symptomatic disease. Of the 51 patients with the infection, 48 (94.11%) had at least one comorbidity and such comorbidities did not constitute a risk factor for a more severe disease. Hospitalization was necessary for 7 (13.7%) patients. Of these, 2 required low-flow oxygen supplementation, 3 non-invasive/high flow ventilation and 2 invasive ventilation. Finally, 2 patients died., Conclusions: Our study shows a lower mortality and hospitalization rate compared to figures available in the literature (4% vs. 13-30% and 14% vs. 32-100%, respectively). Furthermore, the comorbidities examined (hypertension, dyslipidemia, and diabetes) did not constitute a risk factor for a more severe disease condition in this patient category. Further studies with larger sample size are necessary to confirm these data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pinchera, Spirito, Ferreri, Rocca, Celentano, Buonomo, Foggia, Scotto, Federico, Gentile, Carrano and “Federico II” COVID-19 Team.)

Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking endocannabinoid catabolism would elicit antiepileptic effects, devoid of psychotropic effects. We herein report the discovery of selective anandamide catabolic enzyme fatty acid amide hydrolase (FAAH) inhibitors with promising antiepileptic efficacy, starting from a further investigation of our prototypical inhibitor 2a . When tested in two rodent models of epilepsy, 2a reduced the severity of the pilocarpine-induced status epilepticus and the elongation of the hippocampal maximal dentate activation. Notably, 2a did not affect hippocampal dentate gyrus long-term synaptic plasticity. These data prompted our further endeavor aiming at discovering new antiepileptic agents, developing a new set of FAAH inhibitors ( 3a - m ). Biological studies highlighted 3h and 3m as the best performing analogues to be further investigated. In cell-based studies, using a neuroblastoma cell line, 3h and 3m could reduce the oxinflammation state by decreasing DNA-binding activity of NF-kB p65, devoid of cytotoxic effect. Unwanted cardiac effects were excluded for 3h (Langendorff perfused rat heart). Finally, the new analogue 3h reduced the severity of the pilocarpine-induced status epilepticus as observed for 2a .

Due to the surge in resistance to common therapies, malaria remains a significant concern to human health worldwide. In chloroquine (CQ)-resistant (CQ-R) strains of Plasmodium falciparum, CQ and related drugs are effluxed from the parasite's digestive vacuole (DV). This process is mediated by mutant isoforms of a protein called CQ resistance transporter (PfCRT). CQ-R strains can be partially re-sensitized to CQ by verapamil (VP), primaquine (PQ) and other compounds, and this has been shown to be due to the ability of these molecules to inhibit drug transport via PfCRT. We have previously developed a series of clotrimazole (CLT)-based antimalarial agents that possess inhibitory activity against PfCRT (4a,b). In our endeavor to develop novel PfCRT inhibitors, and to perform a structure-activity relationship analysis, we synthesized a new library of analogues. When the benzhydryl system was linked to a 4-aminoquinoline group (5a-f) the resulting compounds exhibited good cytotoxicity against both CQ-R and CQ-S strains of P. falciparum. The most potent inhibitory activity against the PfCRT-mediated transport of CQ was obtained with compound 5k. When compared to the reference compound, benzhydryl analogues of PQ (5i,j) showed a similar activity against blood-stage parasites, and a stronger in vitro potency against liver-stage parasites. Unfortunately, in the in vivo transmission blocking assays, 5i,j were inactive against gametocytes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Toll-like receptors (TLRs) are a class of proteins that recognize pathogen-associated molecular patterns (PAMPs) and damaged-associated molecular patterns (DAMPs), and they are involved in the regulation of innate immune system. These transmembrane receptors, localized at the cellular or endosomal membrane, trigger inflammatory processes through either myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling pathways. In the last decades, extensive research has been performed on TLR modulators and their therapeutic implication under several pathological conditions, spanning from infections to cancer, from metabolic disorders to neurodegeneration and autoimmune diseases. This Perspective will highlight the recent discoveries in this field, emphasizing the role of TLRs in different diseases and the therapeutic effect of their natural and synthetic modulators, and it will discuss insights for the future exploitation of TLR modulators in human health.

Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit 6a . We identified compound 6j as the most potent and selective h HDAC6 inhibitor of the series. Biological investigation of compounds 6b , 6h , and 6j demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. 6j induced HDAC6-dependent pSTAT3 inhibition., Competing Interests: The authors declare no competing financial interest.

Inherited retinal diseases (IRDs) are a group of retinopathies generally caused by genetic mutations. Retinitis pigmentosa (RP) represents one of the most studied IRDs. RP leads to intense vision loss or blindness resulting from the degeneration of photoreceptor cells. To date, RP is mainly treated with palliative supplementation of vitamin A and retinoids, gene therapies, or surgical interventions. Therefore, a pharmacologically based therapy is an urgent need requiring a medicinal chemistry approach, to validate molecular targets able to deal with retinal degeneration. This Review aims at outlining the recent research efforts in identifying new drug targets for RP, especially focusing on the neuroprotective role of the Wnt/β-catenin/GSK3β pathway and apoptosis modulators (in particular PARP-1) but also on growth factors such as VEGF and BDNF. Furthermore, the role of spatiotemporally expressed G protein-coupled receptors (GPR124) in the retina and the emerging function of histone deacetylase inhibitors in promoting retinal neuroprotection will be discussed.

Telomeres are protective chromosomal ends that shield the chromosomes from DNA damage, exonucleolytic degradation, recombination, and end-to-end fusion. Telomerase is a ribonucleoprotein that adds TTAGGG tandem repeats to the telomeric ends. It has been observed that 85 to 90% of human tumors express high levels of telomerase, playing a crucial role in the development of cancers. Interestingly, the telomerase activity is generally absent in normal somatic cells. This selective telomerase expression has driven scientists to develop novel anti-cancer therapeutics with high specificity and potency. Several advancements have been made in this area, which is reflected by the enormous success of the anticancer agent Imetelstat. Since the discovery of Imetelstat, several research groups have contributed to enrich the therapeutic arsenal against cancer. Such contributions include the application of new classes of small molecules, peptides, and hTERT-based immunotherapeutic agents (p540, GV1001, GRNVAC1 or combinations of these such as Vx-001). Many of these therapeutic tools are under different stages of clinical trials and have shown promising outcomes. In this review, we highlight the current status of telomerase-based cancer therapeutics and the outcome of these investigations., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Tacrolimus (TCR) is an immunosuppressive drug used by oral administration. Intravenous (IV) TCR administration is required under conditions of gastrointestinal diseases or abdominal surgery at the onset of paralytic ileus. The infusion formulation needs a large dilution and therefore a careful technical management during continuous infusion by 24 h and may determine anaphylaxis, cardiac arrhythmia, QT prolongation and torsades de pointes. Sublingual (SL) TCR administration was suggested as an alternative route., Design: The aim of this study was to compare in the same kidney transplanted patients the TCR pharmacokinetic profiles by both the routes coupled with the pharmacoeconomic analysis. The study enrolled eight subjects undergoing renal transplantation and treated with TCR and methylprednisolone. TCR was administered by oral route at the scheduled dosage while the 50% of oral dosage was used by SL route, taking into account the absence of liver first pass., Results: Except for AUC, which resulted significantly increased after oral administration, all exposure parameters were not significantly different between the two routes of administration. Analysis of dose-adjusted exposure parameters showed significant increases in AUC and Cmin after SL administration confirming a better bioavailability of the SL route compared with oral route. Cost saving was obtained using the SL rather than the IV route of TCR delivery., Conclusion: When oral administration of TCR is not advised, SL delivery represents an attractive option to IV administration., (© 2016 Stichting European Society for Clinical Investigation Journal Foundation.)

The Home Hemodialysis (HHD) is an uncommon dialytic option that can offer better clinical outcomes and a more satisfactory quality of life. The Health Plan of the Region Campania 2011-2013 states that" the system of home care for regional planning is particularly important". From August 2014 to March 2015 two patients, on standard dialysis (HD) as inpatients at Dialysis Centre of the University "Federico II" of Naples, started Short Daily Home Hemodialysis (SDHD) (4-6 dialysis treatments%week, 2.5 hours per session) using the portable cycler NxStage System One). The data collected showed that the clinical benefits described in the literature were confirmed in patients enrolled in this HHD program. Shorter and more frequent hemodialysis sessions allowed a significant reduction in interdialytic weight gain and greater intradialytic hemodynamic stability. A significant reduction in blood pressure and anti-hypertensive drugs were obtained. The control of phosphorus appeared better and hemoglobin was to target with a lower dose of weekly erythropoetin. The patients reported a greater well-being and a reduction in post-dialytic asthenia. No problem has been reported in using the vascular access (CVC and FAV) by the patient%caregiver. The dialysis adequacy and efficiency were comparable between SDHD and HD. The experience with the HHD is encouraging as the patients achieved an adequate dialysis dose without any complications reporting an improving sense of well-being and a better quality of life., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

To activate a program of home hemodialysis (HHD) and to ensure its sustainability and success, it is essential to provide a structured path with the realization of a programmatic document detailing the technological requirements and the type of organization and assistance in line with the regulations currently in force. The path must consider the following: (a) eligibility clinical criteria of the patient and the caregiver, (b) analysis of the most recent HHD literature and the reasons of the choice of the latest technology, (c) accurate information of the patient and the caregiver with their approval, (d) care coverage and hospital admission modalities (e) suitability of the rooms where the patient will perform the HHD treatment, (f) training program of the patient and the caregiver, home treatment start and patient follow-up. The implementation of this structured process has allowed us to launch a successful HHD program: this modus operandi has preventively defined the pathway care and analyzed the priorities of risk. We have analyzed the HHD process to identify the possible problems and predictable critical situations in home health care. The experience with the HHD is promising: the patients did not show any clinical problems and reported a better quality of life; this dialysis method can be considered as further treatment option to selected patients, according to the eligibility criteria., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Introduction: Kidney transplantation is frequently complicated by delayed graft function (DGF). DGF is associated with more frequent rejection episodes, increased need of post-transplantation biopsies, dialysis sessions and prolonged hospitalization. These complications may have negative impact on long-term survival of transplanted kidney.Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is regarded as acute kidney injury marker.This preliminary study aimed at evaluating whether uNGAL may be early predictor of DGF in kidney transplanted patients., Subjects and Methods: Urine samples were collected from renal transplant recipients on day 1 post-transplantation to determine 24/h urinary NGAL and creatinine excretion. On same day, routine blood chemistry was assessed., Results: N. 20 renal transplant recipients were evaluated. DGF was observed in n. 6 patients (DGF-patients). In DGF-patients compared to NO-DGF-patients, mean age was higher (586 Vs 5111, p=0.001), while 24/h urine output (5735 Vs 4150 2230 ml/24h; p=0.001) and urinary creatinine excretion (191184 Vs 683660 mg/24h; p=0.001) were lower. No difference was found between DGF- and NO-DGF-patients in 24/h urinary NGAL excretion (1,202,20 Vs 2,444,0 mg/24h; p<0.20). In univariate analysis, DGF was inversely associated to 24/h urine output (r2=-0.795, p=0.001) and urinary creatinine excretion (r2=-0.480, p=0.037) and positively to age (r2=0.446, p=0.049). In multivariate analysis 24/h urine output (p=0.014) and 24/h urinary creatinine excretion (p=0.039) were associated to DGF., Conclusion: This preliminary study suggests that 24/h urinary NGAL excretion, measured 1 day after kidney transplantation, is not a reliable predictor of DGF. Larger study with longer observation period is mandatory.

Both experimental and clinical studies have suggested that any potential treatment of polycystic kidney disease (PKD) should start early and last for a long time to be effective, with unavoidable side reactions and considerable costs. The aim of the present study was to test how low doses of rapamycin (RAPA; 0.15 mg/kg ip for 4 days/wk), tolvaptan (TOLV; 0.005% in diet), or AEZ-131 (AEZ; a novel ERK inhibitor, 30 mg/kg for 3 days/wk by gavage), alone and in association, affect the progression of polycystic renal disease in PCK rats. Rats were treated for 8 wk starting at 4-6 wk of age. The efficacy of low doses of such drugs in inhibiting their respective targets was confirmed by immunoblot experiments. Compared with rats in the control (CON) group, RAPA treatment caused a significant reduction in cyst volume density (CVD; -19% vs. the CON group) and was numerically similar to that in TOLV-treated rats (-18%, not significiant), whereas AEZ treatment was not effective. RAPA + TOLV treatment resulted in a significantly lower CVD (-49% vs. the CON group) and was associated with a striking decrease in cAMP response element-binding protein phosphorylation, and similar data were detected in RAPA + AEZ-treated rats (-42%), whereas TOLV + AEZ treatment had virtually no effect. RAPA administration significantly lessened body weight gain, whereas TOLV administration resulted a mild increase in diuresis and a significant increase in cAMP urinary excretion. Histological data of tubular proliferation were in full agreement with CVD data. In conclusion, this study demonstrates that the association of low doses of RAPA, TOLV, and AEZ slows the progression of PKD with limited side effects, suggesting the use of combined therapies also in clinical trials., (Copyright © 2014 the American Physiological Society.)

Objectives: Several donor and recipient factors are known to be associated with graft loss in a kidney transplant. In this retrospective single-center study, we analyzed the effect of clinical and immunologic factors on kidney transplant outcomes in our region in Italy., Materials and Methods: The study included 245 transplanted recipients from deceased donors at Federico II University of Naples, Kidney Transplant Centre, between the years 2000 and 2006. Age, cause of death, history of hypertension, hypotension or cardiac arrest, length of time spent in the intensive care unit, serum creatinine levels and human leukocyte antigen typing all were evaluated in the donors. Age, time spent on the wait list, human leukocyte antigen typing, antibody sensitization, and allocation were evaluated in the recipients. Age, donor/recipient matching, and human leukocyte antigen mismatches also were evaluated., Results: Cox regression analysis showed that in recipients, time spent on the wait list increased the risk of restarting dialysis (OR 1.019, 95% CI: 1.000-1.038; P = .050) and dying (OR 1.017, 95% CI: 1.000-1.038; P = .032). Patients who received a kidney from a donor with a history of hypertension presented a major risk of death (OR 3.212, 95% CI: 1.190-8.668; P = .021), while human leukocyte antigen-A mismatch increased the risk of restarting dialysis (OR 3.137, 95% CI: 1.255-7.842; P = .014)., Conclusions: In our study, in recipients, time spent on the wait list, and a history of hypertension were associated with a greater risk of death. Human leukocyte antigen-A mismatch is associated with a greater risk of restarting dialysis.

Background: In these last years, several traditional risk factors for cardiovascular disease, like obesity, dyslipidaemia, hypertension and post-transplant diabetes mellitus have been also identified as important non-immunological risk factors leading to the development of chronic allograft nephropathy, the first cause of graft loss in transplanted patients. The aim of the present study was to determine the effects of a 12-month dietary regimen on the nutritional status and metabolic outcome of renal transplant recipients in the first post-transplant year., Methods: Forty-six cadaver-donor renal transplant recipients (mean age 40.8 +/- 10.1-years), enrolled during the first post-transplant year (4.8 +/- 3.3 months) and followed prospectively for a 12 month period. Biochemical and nutritional markers, anthropometric measurements, body composition (by conventional bioelectrical impedance analysis) and dietary records (using a detailed food-frequency questionnaire) at baseline and after 12 months., Results: Compliance to the diet was related to sex (male better than female) and was associated with weight loss primarily due to a decrease in fat mass, with decrease in total cholesterol and glucose plasma levels and with a concomitant rise in serum albumin., Conclusion: After renal transplantation, health benefits of proper metabolic balance that include reduced body fat, weight loss, lower cholesterol and triglycerides levels and an improvement, fasting glucose levels can be obtained when dietary intervention occurred.

Background: Posttransplant erythrocytosis (PTE; i.e., hematocrit [Ht] >=51%) may be responsible for cardiovascular events. Angiotensin-converting enzyme inhibitors (ACEIs) are increasingly employed in PTE treatment. Diverse ACEIs have been administered at variable doses and with erratic follow-up. In addition, guidelines recommend the administration of ACEIs as first-line therapy for PTE but do not give information on dosage. In this study the dose-response of a single ACEI was assessed, and patients were followed up for 1 year. The role of ACE gene polymorphism in both prevalence of PTE and successful response to ACEI therapy was also tested., Methods: At study entry, blood chemistry and ACE-gene polymorphism were measured. ACEI (ramipril) was initiated at 1.25 mg/day; if Ht was still >=51%, ramipril was increased every 6 weeks to ensuing greater dosages. Scheduled dosages were 1.25, 2.5, 5.0, 7.5 and 10 mg/day. Blood chemistry was repeated every 6 weeks. Serum erythropoietin (EPO) concentration was assayed at the start and end of the study. Follow-up was extended for 1 year., Results: PTE developed 12.6 +/- 16.0 months after transplantation in 40 out of 400 patients; 27 patients completed the study. Initial Ht was not correlated with any variable. Final Ht appeared normalized in 26 out of 27 patients. Mean dose (+/- SD) of ramipril was 4.6 +/- 3.6 mg. Mean time for correction of PTE was 135 days, and was not dependent on baseline Ht, hemoglobin or EPO. PTE relapsed in 4 patients. Prevalence of PTE and successful response to ramipril was not dependent on ACE-gene polymorphism., Conclusion: Ramipril was effective in PTE; low doses normalized Ht in most patients. No clinical characteristics or biochemical variables predicted the response to ramipril. PTE may relapse; thus long-term follow-up is mandatory.

Purpose: Sonographic measurement of renal volume is one of the parameters used in the diagnosis of renal transplant dysfunction and in follow-up of patients with renal transplant. The aim of this study was to compare the prolate ellipsoid formula with a new formula in calculating the volume of a transplanted kidney., Methods: The renal volumes in 24 patients with a stable renal transplant were determined sonographically with the ellipsoid formula and via helical CT with the voxel-count method, which is the gold standard. A new formula that uses renal length and the cross-sectional area at the maximum transverse section has been evaluated in a small series of transplanted kidneys., Results: Renal volume was underestimated with the sonographic ellipsoid formula and the new formula. The new formula yielded the lowest underestimation of the mean renal volume, and the measurements obtained with it were not significantly different from those obtained with CT., Conclusions: The use of sonography is appropriate for accurate calculation of renal volume, and the new formula that uses only 2 ultrasound parameters best represents the volume of a renal transplant., (Copyright 2006 Wiley Periodicals, Inc.)

Background and Objective: Bacterial infections are common complications after organ transplantation. Fluoroquinolones are frequently used for treatment because of their broad spectrum of activity; but some of them, such as ciprofloxacin and norfloxacin, are reported to increase blood concentration of ciclosporin because they are metabolised by the liver through the same enzymatic pathway, the cytochrome P450 system. This study was performed to establish whether levofloxacin, a more recent fluoroquinolone that undergoes limited hepatic metabolism, interferes with metabolism and excretion of either ciclosporin microemulsion or tacrolimus., Methods: Pharmacokinetic studies were carried out in two groups of renal transplant patients, on either ciclosporin or tacrolimus treatment, before and at the sixth day of treatment with levofloxacin., Results: Levofloxacin significantly increased the mean area under the blood concentration-time curve (AUC) and the other pharmacokinetic parameters of ciclosporin and tacrolimus by about 25%. The interference of levofloxacin on the hepatic metabolism of these drugs was demonstrated by the concomitant decrease by 5% of polyclonal ciclosporin concentration, which is the expression of parent drug and its metabolites. Both before and during levofloxacin treatment we observed trough concentrations of monoclonal and polyclonal ciclosporin significantly lower in the evening (C(12)) than in the morning (C(0)); this observation suggests a circadian variation in the metabolism of this drug. However, no difference between C(0) and C(12) was observed with tacrolimus, confirming its more predictable bioavailability., Conclusion: Our data demonstrate that levofloxacin partially inhibits the metabolism of both ciclosporin microemulsion and tacrolimus, and therefore close therapeutic monitoring of these two drugs should be recommended during levofloxacin therapy.

Background: Despite the great prevalence of sleep disorders and the low quality of sleep in patients with renal diseases, to date no study has evaluated these problems in renal transplant patients., Methods: The aim of the study was to assess sleep quality (SQ) in 301 kidney graft recipients by the Pittsburgh Sleep Quality Index (PSQI, range 0-21, with higher scores indicating worse SQ), in comparison with PSQI of both patients on haemodialysis (HD) (n = 245) and normal control subjects (n = 169)., Results: PSQI of renal transplant patients averaged 6.46+/-3.71, a value significantly lower than in HD patients (8.52+/-3.81, P<0.001), but higher than in control subjects (3.54+/-1.61, P<0.0001 vs both transplant and dialysis patients). No correlation was found between PSQI and the main biochemical parameters of transplant patients. When the patients were divided into 'good' (PSQI<5) or 'poor' (PSQI>5) sleepers, a significant risk of psychological problems was associated with the condition of 'poor sleeper' (OR: 2.3; P<0.02), with no further correlation detected in either of the two groups., Conclusions: These data demonstrate that SQ in renal transplant patients is surprisingly low, despite a well preserved renal function, and that poor sleep in these patients is also secondary to psychological problems. The use of PSQI in such patients represents a useful tool for the investigation of SQ and quality of life.