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Epigenetic modulation of the immune response entails modifiable and inheritable modifications that do not modify the DNA sequence. While there have been many studies on epigenetic changes in tumor cells, there is now a growing focus on epigenetically mediated changes in immune cells of both the innate and adaptive systems. These changes have significant implications for both the body's response to tumors and the development of potential therapeutic vaccines. This study primarily discusses the key epigenetic alterations, with a specific emphasis on pseudouridination, as well as non-coding RNAs and their transportation, which can lead to the development of cancer and the acquisition of new phenotypic traits by immune cells. Furthermore, the advancement of therapeutic vaccinations targeting the tumor will be outlined., 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 © 2024. Published by Elsevier Ltd.)

Highly mutable influenza is successfully countered based on individual susceptibility and similar precision-like medicine approach should be effective against SARS-COV-2. Among predictive markers to bring precision medicine to COVID-19, circulating ACE2 has potential features being upregulated in both severe COVID-19 and predisposing comorbidities. Spike SARS-CoVs were shown to induce ADAM17-mediated shedding of enzymatic active ACE2, thus accounting for its increased activity that has also been suggested to induce positive feedback loops leading to COVID-19-like manifestations. For this reason, pre-existing ACE2 activity and inhibition of ACE2/ADAM17 zinc-metalloproteases through zinc chelating agents have been proposed to predict COVID-19 outcome before infection and to protect from COVID-19, respectively. Since most diagnostic laboratories are not equipped for enzymatic activity determination, other potential predictive markers of disease progression exploitable by diagnostic laboratories were explored. Concentrations of circulating albumin, zinc, ACE2 protein and its activity were investigated in healthy, diabetic (COVID-19-susceptible) and SARS-CoV-2-negative COVID-19 individuals. ACE2 both protein levels and activity significantly increased in COVID-19 and diabetic patients. Abnormal high levels of ACE2 characterised a subgroup (16-19%) of diabetics, while COVID-19 patients were characterised by significantly higher zinc/albumin ratios, pointing to a relative increase of albumin-unbound zinc species, such as free zinc ones. Data on circulating ACE2 levels are in line with the hypothesis that they can drive susceptibility to COVID-19 and elevated zinc/albumin ratios support the therapeutic use of zinc chelating inhibitors of ACE2/ADAM17 zinc-metalloproteases in a targeted therapy for COVID-19., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Ltd.)

The article describes the possible pathophysiological origin of COVID-19 and the crucial role of renin-angiotensin system (RAS), providing several "converging" evidence in support of this hypothesis. SARS-CoV-2 has been shown to initially upregulate ACE2 systemic activity (early phase), which can subsequently induce compensatory responses leading to upregulation of both arms of the RAS (late phase) and consequently to critical, advanced and untreatable stages of COVID-19 disease. The main and initial actors of the process are ACE2 and ADAM17 zinc-metalloproteases, which, initially triggered by SARS-CoV-2 spike proteins, work together in increasing circulating Ang 1-7 and Ang 1-9 peptides and downstream (Mas and Angiotensin type 2 receptors) pathways with anti-inflammatory, hypotensive and antithrombotic activities. During the late phase of severe COVID-19, compensatory secretion of renin and ACE enzymes are subsequently upregulated, leading to inflammation, hypertension and thrombosis, which further sustain ACE2 and ADAM17 upregulation. Based on this hypothesis, COVID-19-phase-specific inhibition of different RAS enzymes is proposed as a pharmacological strategy against COVID-19 and vaccine-induced adverse effects. The aim is to prevent the establishment of positive feedback-loops, which can sustain hyperactivity of both arms of the RAS independently of viral trigger and, in some cases, may lead to Long-COVID syndrome., (Copyright © 2021. Published by Elsevier Ltd.)

Cellular prion protein (PrP(c)), the normal isoform of the pathogenic peptide (PrP(sc)) responsible of the transmissible spongiform encephalopaties (TSEs), is present in many neural tissues, including neuromuscular junctions (NMJ). To analyze if this protein could influence the synaptic transmission, we performed an electrophysiological approach to study the effect of cellular prion protein on a mammalian neuromuscular junction. The loose patch clamp (LPC) technique enables the study of the whole preparation including the pre- and the post-synaptic domains. In a mouse phrenic-diaphragm preparation, nanomolar concentrations of cellular prion protein were able to induce a very striking potentiation of the acetylcholine (ACh) release. The effect was mainly pre-synaptic with an increase of the amplitude of the miniature end-plate currents, probably calcium dependent. Moreover, an apparent facilitation of the synaptic transmission was noted. The results clearly indicate that cellular prion protein may play a key role in the function of the neuromuscular junction.

Linalool is a monoterpene compound reported to be a major component of essential oils in various aromatic species. Several linalool-producing species are used in traditional medical systems. Among these is Aeolanthus suaveolens G. Dom (Labiatae) which is used as an anticonvulsant in the Brazilian Amazon. Psychopharmacological in vivo evaluation of linalool showed that this compound has dose-dependent marked sedative effects at the central nervous system (CNS), including hypnotic, anticonvulsant and hypothermic properties. It has been suggested that these neurochemical effects might be ascribed to the local anaesthetic activity of linalool. The present study reports an inhibitory effect of linalool on the acetylcholine (ACh) release and on the channel open time in the mouse neuromuscular junction. These findings could provide a rational basis to confirm the traditional medical use of linalool-producing plant species. Indeed, our data demonstrate some interactions in the modulation of the ACh release at the mouse neuromuscular junction, which are well correlated with the suggested molecular mechanisms. Linalool induced a reduction of the ACh-evoked release. The possibility that this effect could be ascribed to some interaction with pre-synaptic function is noteworthy. Moreover, the inhibitory effect induced on the kinetics of the miniature end-plate current decay demonstrates a local anaesthetic action, either on the voltage or on the receptor-activated channels., (Copyright 2000 Academic Press.)

Natural extracts have been proved to be useful in different human pathological conditions. The scientific consideration of the therapeutic potential of plant extracts is still inappropriate due to the lack of both pharmacological and epidemiological basic studies. Here, we started from an electrophysiological point of view, a study on the effects of two extracts on the acetylcholine (ACh) release at the neuromuscular junction. The extracts purified from Sugar cane (policosanol) and Psidium guajava (quercetin) have been submitted to this study. The wide epidemiology of these agents suggests therapeutic potentials not yet well outlined at the basic level. Our data demonstrate some interactions in the modulation of the ACh release at the mouse neuro-muscular junction, which are well correlated with the suggested molecular mechanisms. Policosanol enhances to a small extent either the spontaneous or the evoked ACh release. Furthermore, an increase of the rate of the conformational change induced at the nicotinic receptor-channel complex by ACh is also observed. Quercetin induced a reduction of the ACh evoked release. The possibility that this effect could be ascribed to some interaction with presynaptic calcium channel is noteworthy. The results are discussed in terms of a possible interference with acetylcholinesterase by policosanol and of a presynaptic molecular action of quercetin modulating the cytosolic calcium concentration., (Copyright 1999 The Italian Pharmacological Society.)

Background: Prolonged antihypertensive therapy might be less effective in reversing the left ventricular hypertrophy (LVH) in uremics bearing the deleted (DD) allele of the angiotensin converting enzyme (ACE) gene than in patients with the inserted (II) allele or in those heterozygous (ID) for the gene., Methods: Thirteen DD and 17 II + ID hemodialyzed uremics were followed-up with yearly echocardiography and 24-hour blood pressure (BP) monitoring over five years while on an antihypertensive therapy that included ACE inhibitors as first line drugs., Results: In the II + ID group there were significant decreases of the left ventricular mass index (LVMi) and of both systolic and diastolic BPs. These changes were less pronounced in the DD group, but the difference was not statistically significant given the wide overlap between the two groups. Further analysis of the data revealed that the only factor associated to a decreased LVMi was the decrease of the systolic BP irrespective of the ACE gene genotype of each individual patient., Conclusions: The ACE-gene genotype does not necessarily predict the extent to which LVMi will be lowered by ACE-inhibitors therapy. The LVH of hypertensive uremics is amenable by long-term antihypertensive therapy provided that it results in significantly decreased systolic blood pressure.

Lymphocytes from different donors may be frozen in Terasaki trays by a simple procedure. This method provides the tissue typing laboratory with a readily available panel that can be routinely used to test for lymphocytotoxic antibodies sera from patients waiting for kidney transplant, transplanted patients and polytransfused individuals. The advantage of this procedure is that expensive programmed freezing apparatus is not required.