Polyamine–Drug Conjugates: Do They Boost Drug Activity?

Over the past two decades, the strategy of conjugating polyamine tails with bioactive molecules such as anticancer and antimicrobial agents, as well as antioxidant and neuroprotective scaffolds, has been widely exploited to enhance their pharmacological profile. Polyamine transport is elevated in many pathological conditions, suggesting that the polyamine portion could improve cellular and subcellular uptake of the conjugate via the polyamine transporter system. In this review, we have presented a glimpse on the polyamine conjugate scenario, classified by therapeutic area, of the last decade with the aim of highlighting achievements and fostering future developments

A nature‐inspired nrf2 activator protects retinal explants from oxidative stress and neurodegeneration

Oxidative stress (OS) plays a key role in retinal dysfunctions and acts as a major trigger of inflammatory and neurodegenerative processes in several retinal diseases. To prevent OS‐induced retinal damage, approaches based on the use of natural compounds are actively investigated. Recently, structural features from curcumin and diallyl sulfide have been combined in a nature‐inspired hybrid (NIH1), which has been described to activate transcription nuclear factor erythroid‐ 2‐related factor‐2 (Nrf2), the master regulator of the antioxidant response, in different cell lines. We tested the antioxidant properties of NIH1 in mouse retinal explants. NIH1 increased Nrf2 nuclear translocation, Nrf2 expression, and both antioxidant enzyme expression and protein levels after 24 h or six days of incubation. Possible toxic effects of NIH1 were excluded since it did not alter the expression of apoptotic or gliotic markers. In OS‐treated retinal explants, NIH1 strengthened the antioxidant response inducing a massive and persistent expression of antioxidant enzymes up to six days of incubation. These effects resulted in prevention of the accumulation of reactive oxygen species, of apoptotic cell death, and of gliotic reactivity. Together, these data indicate that a strategy based on NIH1 to counteract OS could be effective for the treatment of retinal diseases

From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs

Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2-7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 μM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 μM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity

Contribution of Rare and Low-Frequency Variants to Multiple Sclerosis Susceptibility in the Italian Continental Population

Genome-wide association studies identified over 200 risk loci for multiple sclerosis (MS) focusing on common variants, which account for about 50% of disease heritability. The goal of this study was to investigate whether low-frequency and rare functional variants, located in MS-established associated loci, may contribute to disease risk in a relatively homogeneous population, testing their cumulative effect (burden) with gene-wise tests. We sequenced 98 genes in 588 Italian patients with MS and 408 matched healthy controls (HCs). Variants were selected using different filtering criteria based on allelic frequency and in silico functional impacts. Genes showing a significant burden (n = 17) were sequenced in an independent cohort of 504 MS and 504 HC. The highest signal in both cohorts was observed for the disruptive variants (stop-gain, stop-loss, or splicing variants) located in EFCAB13, a gene coding for a protein of an unknown function (p < 10–4). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (p = 0.0093 and p = 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (p = 0.001) assayed with an SNP array. Real-time PCR on 14 heterozygous individuals for this variant did not evidence the presence of the stop-gain allele, suggesting a transcript degradation by non-sense mediated decay, supported by the evidence that the carriers of the stop-gain variant had a lower expression of this gene (p = 0.0184). In conclusion, we identified a novel low-frequency functional variant associated with MS susceptibility, suggesting the possible role of rare/low-frequency variants in MS as reported for other complex diseases

Distance-Based and Low Energy Adaptive Clustering Protocol for Wireless Sensor Networks

A wireless sensor network (WSN) comprises small sensor nodes with limited energy capabilities. The power constraints of WSNs necessitate efficient energy utilization to extend the overall network lifetime of these networks. We propose a distance-based and low-energy adaptive clustering (DISCPLN) protocol to streamline the green issue of efficient energy utilization in WSNs. We also enhance our proposed protocol into the multi-hop-DISCPLN protocol to increase the lifetime of the network in terms of high throughput with minimum delay time and packet loss. We also propose the mobile-DISCPLN protocol to maintain the stability of the network. The modelling and comparison of these protocols with their corresponding benchmarks exhibit promising results

Internet of Things for Sustainable Community Development: Introduction and Overview

The two-third of the city-dwelling world population by 2050 poses numerous global challenges in the infrastructure and natural resource management domains (e.g., water and food scarcity, increasing global temperatures, and energy issues). The IoT with integrated sensing and communication capabilities has the strong potential for the robust, sustainable, and informed resource management in the urban and rural communities. In this chapter, the vital concepts of sustainable community development are discussed. The IoT and sustainability interactions are explained with emphasis on Sustainable Development Goals (SDGs) and communication technologies. Moreover, IoT opportunities and challenges are discussed in the context of sustainable community development

Intraepithelial and Interstitial Deposition of Pathological Prion Protein in Kidneys of Scrapie-Affected Sheep

Prions have been documented in extra-neuronal and extra-lymphatic tissues of humans and various ruminants affected by Transmissible Spongiform Encephalopathy (TSE). The presence of prion infectivity detected in cervid and ovine blood tempted us to reason that kidney, the organ filtrating blood derived proteins, may accumulate disease associated PrPSc. We collected and screened kidneys of experimentally, naturally scrapie-affected and control sheep for renal deposition of PrPSc from distinct, geographically separated flocks. By performing Western blot, PET blot analysis and immunohistochemistry we found intraepithelial (cortex, medulla and papilla) and occasional interstitial (papilla) deposition of PrPSc in kidneys of scrapie-affected sheep. Interestingly, glomerula lacked detectable signals indicative of PrPSc. PrPSc was also detected in kidneys of subclinical sheep, but to significantly lower degree. Depending on the stage of the disease the incidence of PrPSc in kidney varied from approximately 27% (subclinical) to 73.6% (clinical) in naturally scrapie-affected sheep. Kidneys from flocks without scrapie outbreak were devoid of PrPSc. Here we demonstrate unexpectedly frequent deposition of high levels of PrPSc in ovine kidneys of various flocks. Renal deposition of PrPSc is likely to be a pre-requisite enabling prionuria, a possible co-factor of horizontal prion-transmission in sheep

Urinary α1-Antichymotrypsin: A Biomarker of Prion Infection

The occurrence of blood-borne prion transmission incidents calls for identification of potential prion carriers. However, current methods for intravital diagnosis of prion disease rely on invasive tissue biopsies and are unsuitable for large-scale screening. Sensitive biomarkers may help meeting this need. Here we scanned the genome for transcripts elevated upon prion infection and encoding secreted proteins. We found that α1-antichymotrypsin (α1-ACT) was highly upregulated in brains of scrapie-infected mice. Furthermore, α1-ACT levels were dramatically increased in urine of patients suffering from sporadic Creutzfeldt-Jakob disease, and increased progressively throughout the disease. Increased α1-ACT excretion was also found in cases of natural prion disease of animals. Therefore measurement of urinary α1-ACT levels may be useful for monitoring the efficacy of therapeutic regimens for prion disease, and possibly also for deferring blood and organ donors that may be at risk of transmitting prion infections

Ventilation and outcomes following robotic-assisted abdominal surgery: an international, multicentre observational study

Background: International data on the epidemiology, ventilation practice, and outcomes in patients undergoing abdominal robotic-assisted surgery (RAS) are lacking. The aim of the study was to assess the incidence of postoperative pulmonary complications (PPCs), and to describe ventilator management after abdominal RAS. Methods: This was an international, multicentre, prospective study in 34 centres in nine countries. Patients ≥18 yr of age undergoing abdominal RAS were enrolled between April 2017 and March 2019. The Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) score was used to stratify for higher risk of PPCs (≥26). The primary outcome was the incidence of PPCs. Secondary endpoints included the preoperative risk for PPCs and ventilator management. Results: Of 1167 subjects screened, 905 abdominal RAS patients were included. Overall, 590 (65.2%) patients were at increased risk for PPCs. Meanwhile, 172 (19%) patients sustained PPCs, which occurred more frequently in 132 (22.4%) patients at increased risk, compared with 40 (12.7%) patients at lower risk of PPCs (absolute risk difference: 12.2% [95% confidence intervals (CI), 6.8–17.6%]; P<0.001). Plateau and driving pressures were higher in patients at increased risk, compared with patients at low risk of PPCs, but no ventilatory variables were independently associated with increased occurrence of PPCs. Development of PPCs was associated with a longer hospital stay. Conclusions: One in five patients developed one or more PPCs (chiefly unplanned oxygen requirement), which was associated with a longer hospital stay. No ventilatory variables were independently associated with PPCs. Clinical trial registration: NCT02989415