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Competing Interests: None

Obesity is linked to neurodegeneration, which is mainly caused by inflammation and oxidative stress. We analyzed whether the long-term intake of honey and/or D-limonene, which are known for their antioxidant and anti-inflammatory actions, when ingested separately or in combination, can counteract the neurodegeneration occurring in high fat diet (HFD)-induced obesity. After 10 weeks of HFD, mice were divided into: HFD-, HFD + honey (HFD-H)-, HFD + D-limonene (HFD-L)-, HFD + honey + D-limonene (HFD-H + L)-fed groups, for another 10 weeks. Another group was fed a standard diet (STD). We analyzed the brain neurodegeneration, inflammation, oxidative stress, and gene expression of Alzheimer's disease (AD) markers. The HFD animals showed higher neuronal apoptosis, upregulation of pro-apoptotic genes Fas-L, Bim P27 and downregulation of anti-apoptotic factors BDNF and BCL2; increased gene expression of the pro-inflammatory IL-1β, IL-6 and TNF-α and elevated oxidative stress markers COX-2, iNOS, ROS and nitrite. The honey and D-limonene intake counteracted these alterations; however, they did so in a stronger manner when in combination. Genes involved in amyloid plaque processing (APP and TAU), synaptic function (Ache) and AD-related hyperphosphorylation were higher in HFD brains, and significantly downregulated in HFD-H, HFD-L and HFD-H + L. These results suggest that honey and limonene ingestion counteract obesity-related neurodegeneration and that joint consumption is more efficacious than a single administration.

COronaVIrus Disease 2019 (COVID-19) is a newly emerging infectious disease that spread across the world, caused by the novel coronavirus Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). Despite the advancements in science that led to the creation of the vaccine, there is still an urgent need for new antiviral drugs effective against SARS-CoV-2. This study aimed to investigate the antiviral effect of Paulownia tomentosa Steud extract against SARS-CoV-2 and to evaluate its antioxidant properties, including respiratory smooth muscle relaxant effects. Our results showed that P. tomentosa extract can inhibit viral replication by directly interacting with both the 3-chymotrypsin-like protease and spike protein. In addition, the phyto complex does not reduce lung epithelial cell viability and exerts a protective action in those cells damaged by tert-butyl hydroperoxide , a toxic agent able to alter cells' functions via increased oxidative stress. These data suggest the potential role of P. tomentosa extract in COVID-19 treatment, since this extract is able to act both as an antiviral and a cytoprotective agent in vitro., (Copyright © 2022. Published by Elsevier Masson SAS.)

The aim of the present work is the evaluation of biological effects of natural stilbenoids found in Vitis vinifera, with a focus on their activity as epigenetic modulators. In the present study, resveratrol, pterostilbene and for the first time their dimers (±)-trans-δ-viniferin, (±)-trans-pterostilbene dehydrodimer were evaluated in Caco-2 and HepG-2 cell lines as potential epigenetic modulators. Stilbenoids were added in a Caco-2 cell culture as a model of the intestinal epithelial barrier and in the HepG-2 as a model of hepatic environment, to verify their dose-dependent toxicity, ability to interact with DNA, and epigenomic action. Resveratrol, pterostilbene, and (±)-trans-pterostilbene dehydrodimer were found to have no toxic effects at tested concentration and were effective in reversing arsenic damage in Caco-2 cell lines. (±)-trans-δ-viniferin showed epigenomic activity, but further studies are needed to clarify its mode of action., (© 2023. The Author(s).)

Obesity, type 2 diabetes (T2DM), hypertension (HTN), and Cardiovascular Disease (CVD) often cluster together as "Cardiometabolic Disease" (CMD). Just under 50% of patients with CMD increased the risk of morbidity and mortality right from the beginning of the COVID-19 pandemic as it has been reported in most countries affected by the SARS-CoV2 virus. One of the pathophysiological hallmarks of COVID-19 is the overactivation of the immune system with a prominent IL-6 response, resulting in severe and systemic damage involving also cytokines such as IL2, IL4, IL8, IL10, and interferon-gamma were considered strong predictors of COVID-19 severity. Thus, in this mini-review, we try to describe the inflammatory state, the alteration of the adipokine profile, and cytokine production in the obese state of infected and not infected patients by SARS-CoV2 with the final aim to find possible influences of COVID-19 on CMD and CVD. The immunological-based discussion of the molecular processes could inspire the study of promising targets for managing CMD patients and its complications during COVID-19., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: None reports was provided by none. None reports a relationship with none that includes: None has patent pending to none. None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A series of phenolic derivatives designed to selectively target mitochondria were synthesized under flow conditions starting from natural phenolic acids. The two-step continuous flow protocol, performed in Cyrene, a bioavailable dipolar aprotic solvent, allowed the isolation of the MITO compounds in moderate to good yields. The MITO compounds obtained, as a first step, were tested for their safety by cell viability analysis. The cytocompatible dose, in human neuronal cell line SH-SH5Y, depends on the type of compound and the non-toxic dose is between 3.5 and 125 µM. Among the seven MITO compounds synthesized, two of them have shown interesting performances, being able to protect mitochondria from oxidative insult.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly. The two cardinal neuropathological hallmarks of AD are the senile plaques, which are extracellular deposits mainly constituted by beta-amyloids, and neurofibrillary tangles formed by abnormally phosphorylated Tau ( p -Tau) located in the cytoplasm of neurons. Although the research has made relevant progress in the management of the disease, the treatment is still lacking. Only symptomatic medications exist for the disease, and, in the meantime, laboratories worldwide are investigating disease-modifying treatments for AD. In the present review, results centered on the use of peptides of different sizes involved in AD are presented.

It is estimated that one-third of the world's population lives in areas where iodine (I) is scarce and its deficiency is responsible for many related disorders, such as goiter, reproductive failure, hearing loss, growth impairment, congenital I deficiency syndrome, and numerous kinds of brain injury. Mineral deficiencies can be overcome via dietary diversification and mineral supplementation. An alternative or even complementary way is represented by the intake of biofortified foods, which can tackle this lack of micronutrients. In this short-term double-arm nutritional intervention study, a cohort of ten people was supplemented with curly endive leaf biofortified with I and ten people with curly endive without biofortification (Intervention Study on Iodine Biofortification Vegetables (Nutri-I-Food - Full-Text View - ClinicalTrials.gov). The effects on whole-body homeostasis and specifically on I, glucose, lipid, and hepatic, iron metabolism was investigated. Blood samples were obtained at baseline and after 12 days of supplementation with curly endive and compared with controls. Hematochemical and urinary parameters were analyzed at baseline and after 12 days. The results showed that short-term I curly endive intervention did not affect the whole body homeostasis in healthy people and revealed an increase in I concentration in urine samples and an increase in vitamin D, calcium, and potassium concentration in blood samples only in the biofortified cohort respect to controls. This study suggests that short-term consumption of I curly endive crops is safe and could positively impact body health., 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 Baldassano, Di Gaudio, Sabatino, Caldarella, De Pasquale, Di Rosa, Nuzzo, Picone and Vasto.)

The aim of the present work is the characterization of biscuit doughs enriched with pomegranate peel powder (PPP) at 3 (PPP3) and 5 (PPP5) wt% in the prospect of developing a fortified aliment as a support of the therapy of chronic inflammatory diseases of the intestinal tract. The total phenolic content of the powder was preliminarily evaluated. Then, the main compounds present in the PPP were identified by HPLC-ESI-TOF-MS analysis, being mainly hydrolysable tannins. The PPP was then treated at 180 °C for 20 min to mimic the baking treatment, and its water-soluble fraction (PPPwsf) was then added in the Caco-2 cell culture as a model of the intestinal epithelial barrier to verify its dose-dependent toxicity, ability in counteracting the oxidative stress, and anti-inflammatory action. Rheological experiments were performed to predict the macroscopic behavior of the PPP-added doughs during lamination and biscuit baking. SEM investigations gave their contribution to the microscopic comprehension of the dough structure. Finally, a consumer panel composed by thirty volunteers was enrolled to express its opinion on the sensory agreeableness of the biscuits prepared with two different concentrations of PPP compared with the reference dough. The discussion is focused on the biological effects of the main components found in the PPP.

In recent years, several studies have examined the multifaceted role of mitochondria in Multiple Sclerosis (MS), suggesting that, besides inflammation and demyelination, mitochondrial aberration is a crucial factor in mediating axonal degeneration, the latter being responsible for persistent disabilities in MS patients. Therefore, mitochondria have been recognized as a possible multiple sclerosis therapeutic target. Recently, mitochondrial transplantation has become a new term for the transfer of live mitochondria into damaged cells for the treatment of various diseases, including neurodegenerative diseases. In this hypothesis, we propose mitochondrial transplantation as a new, potentially applicable approach to counteract axonal degeneration in multiple sclerosis.

The purpose of the present study was to evaluate the impact of long-term honey ingestion on metabolic disorders and neurodegeneration in mice fed a high-fat diet (HFD). Three groups of mice were fed with a standard diet (STD), HFD or HFD supplemented with honey (HFD-H) for 16 weeks. Biochemical, histological, Western blotting, RT-PCR and Profiler PCR array were performed to assess metabolic parameters, peripheral and central insulin resistance and neurodegeneration. Daily honey intake prevented the HFD-induced glucose dysmetabolism. In fact, it reduced plasma fasting glucose, insulin and leptin concentrations and increased adiponectin levels. It improved glucose tolerance, insulin sensitivity and HOMA index without affecting plasma lipid concentration. HFD mice showed a significantly higher number of apoptotic nuclei in the superficial and deep cerebral cortex, upregulation of Fas-L , Bim and P27 (neuronal pro-apoptotic markers) and downregulation of Bcl-2 and BDNF (anti-apoptotic factors) in comparison with STD- and HFD-H mice, providing evidence for honey neuroprotective effects. PCR-array analysis showed that long-term honey intake increased the expression of genes involved in insulin sensitivity and decreased genes involved in neuroinflammation or lipogenesis, suggesting improvement of central insulin resistance. The expressions of p-AKT and p-GSK3 in HFD-H mice, which were decreased and increased, respectively, in HFD mouse brain, index of central insulin resistance, were similar to STD animals supporting the ability of regular honey intake to protect brain neurons from insulin resistance. In conclusion, the present results provide evidence for the beneficial preventative impact of regular honey ingestion on neuronal damage caused by HFD.

Background: The COVID-19 pandemic, induced by the worldwide spreading of the SARS-CoV-2, is well known for its clinical picture consistent with respiratory symptoms. If pulmonary complications are the most common manifestation of the disease, neurological problems are also significantly present, with complications including acute cerebrovascular events, encephalitis, Guillain-Barré and Miller Fisher syndromes, acute necrotizing hemorrhagic encephalopathy and hemophagocytic lymphohistiocytosis. These medical signs can be considered direct effects of the virus on the nervous system, para-infectious or post-infectious immune-mediated diseases, and neurological complications of the systemic effects of the SARS-CoV-2., Case: In the present article, the encephalitis case in a 5-year-old girl positive for COVID-19 admitted to the emergency department complaining of fever and swelling in the neck is described. At this time, her neurological examination was unremarkable. Over the next few days, the fever went down and she experienced acute behavioral changes, mild confusion, and drowsiness. The brain MRI and electroencephalography (EEG) showed CNS involvement, suggestive of encephalitis., Conclusion: The dramatic improvement of the symptoms after immunotherapy with corticosteroids reinforced the hypothesis of an immune-related mechanism., (© 2021. Fondazione Società Italiana di Neurologia.)

1,2,4-Oxadiazole is a heterocycle with wide reactivity and many useful applications. The reactive O-N bond is usually reduced using molecular hydrogen to obtain amidine derivatives. NH 4 CO 2 H-Pd/C is here demonstrated as a new system for the O-N reduction, allowing us to obtain differently substituted acylamidine, acylguanidine and diacylguanidine derivatives. The proposed system is also effective for the achievement of a reductive rearrangement of 5-(2'-aminophenyl)-1,2,4-oxadiazoles into 1-alkylquinazolin-4(1 H )-ones. The alkaloid glycosine was also obtained with this method. The obtained compounds were preliminarily tested for their biological activity in terms of their cytotoxicity, induced oxidative stress, α-glucosidase and DPP4 inhibition, showing potential application as anti-diabetics.

The COVID-19 pandemic represents an unprecedented global emergency. Despite all efforts, COVID-19 remains a threat to public health, due to the complexity of mass vaccination programs, the lack of effective drugs, and the emergence of new variants. A link has recently been found between the risk of developing a severe COVID-19 infection and a high level of oxidative stress. In this context, we have focused our attention on natural compounds with the aim of finding molecules capable of acting through a dual virucidal-antioxidant mechanism. In particular, we studied the potential of grapefruit seed extracts (GSE) and their main components, belonging to the class of limonoids. Using chemical and biological approaches including isolation and purification of GSE, antioxidant and virucidal assays, we have shown that grapefruit seed constituents, belonging to the class of limonoids, are endowed with remarkable virucidal, antioxidant and mitoprotective activity.

Neurodegenerative diseases affect millions of people worldwide and the presence of various physiological barriers limits the accessibility to the brain and reduces the efficacy of various therapies. Moreover, new carriers having targeting properties to specific brain regions and cells are needed in order to improve therapies for the brain disorder treatment. In this study, for the first time, Myelin nanoVesicles (hereafter defined MyVes) from brain-extracted myelin were produced. The MyVes have an average diameter of 100-150 ​nm, negative zeta potential, spheroidal morphology, and contain lipids and the key proteins of the myelin sheath. Furthermore, they exhibit good cytocompatibility. The MyVes were able to target the white matter and interact mainly with the microglia cells. The preliminary results here presented allow us to suppose the employment of MyVes as potential carrier to target the white matter and microglia in order to counteract white matter microglia-related diseases., Competing Interests: 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., (© 2021 The Authors.)

Altered insulin signaling and insulin resistance are considered the link between Alzheimer's disease (AD) and metabolic syndrome. Here, by using an in vitro and an in vivo model, we investigated the relationship between these disorders focusing on neuronal mitochondrial dysfunction and mitophagy. In vitro Aβ insult induced the opening of mitochondrial permeability transition pore (mPTP), mitochondrial membrane potential (ΔΨm) loss, and apoptosis while insulin addition ameliorated these dysfunctions. The same alterations were detected in a 16 weeks of age mouse model of diet-induced obesity and insulin resistance. In addition, we detected an increase of fission related proteins and activation of mitophagy, proved by the rise of PINK1 and Parkin proteins. Nevertheless, in vitro, the increase of p62 and LC3 indicated an alteration in autophagy, while, in vivo decreased expression of p62 and increase of LC3 suggested removing of damaged mitochondria. Finally, in aged mice (28 and 48 weeks), the data indicated impairment of mitophagy and suggested the accumulation of damaged mitochondria. Taken together these outcomes indicate that alteration of the insulin pathway affects mitochondrial integrity, and effective mitophagy is age-dependent., (Copyright © 2021 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Background: Mitochondrial dysfunction is a critical factor in the onset and progression of neurodegenerative diseases. Recently, mitochondrial transplantation has been advised as an innovative and attractive strategy to transfer and replace damaged mitochondria. Here we propose, for the first time, to use rat brain extracted synaptosomes, a subcellular fraction of isolated synaptic terminal that contains mitochondria, as mitochondrial delivery systems., Results: Synaptosome preparation was validated by the presence of Synaptophysin and PSD95. Synaptosomes were characterized in terms of dimension, zeta potential, polydispersity index and number of particles/ml. Nile Red or CTX-FITCH labeled synaptosomes were internalized in LAN5 recipient cells by a mechanism involving specific protein-protein interaction, as demonstrated by loss of fusion ability after trypsin treatment and using different cell lines. The loading and release ability of the synaptosomes was proved by the presence of curcumin both into synaptosomes and LAN5 cells. The vitality of mitochondria transferred by Synaptosomes was demonstrated by the presence of Opa1, Fis1 and TOM40 mitochondrial proteins and JC-1 measurements. Further, synaptosomes deliver vital mitochondria into the cytoplasm of neuronal cells as demonstrated by microscopic images, increase of TOM 40, cytochrome c, Hexokinase II mitochondrial proteins, and presence of rat mitochondrial DNA. Finally, by using synaptosomes as a vehicle, healthy mitochondria restored mitochondrial function in cells containing rotenone or CCCp damaged mitochondria., Conclusions: Taken together these results suggest that synaptosomes can be a natural vehicle for the delivery of molecules and organelles to neuronal cells. Further, the replacement of affected mitochondria with healthy ones could be a potential therapy for treating neuronal mitochondrial dysfunction-related diseases.

Alzheimer's disease (AD) is the most widespread form of dementia, characterized by memory loss and reduction of cognitive functions that strongly interfere with normal daily life. Numerous evidences show that aggregates of the amyloid beta peptide, formed by 39 to 42 amino acid residues (Aβ39-43), from soluble small oligomers to large fibrils are characteristic markers of this pathology. However, AD is a complex disease and its neurodegenerative molecular mechanism is not yet fully understood. Growing evidence suggests a link between Aβ polymorphic nature, oligomers and fibrils, and specific mechanisms of neurodegeneration. The Aβ variable nature and its multiplicity of interactions with different proteins and organelles reflect the complexity of this pathology. In this review, we analyze the effects of the interaction between Aβ peptide and different cellular compartments in relation to the different kinds and sizes of amyloid aggregates. In particular, Aβ interaction with different cell structures such as the plasma membrane, mitochondria, lysosomes, nucleus, and endoplasmic reticulum is discussed. Further, we analyze the Aβ peptide ability to modify the structure and function of the target organelle, inducing alteration of its physiological role thus contributing to the pathological event. Dysfunction of cellular components terminating with the activation of the cellular death mechanism and subsequent neurodegeneration is also taken into consideration.

Angiotensin II, the main effector of renin angiotensin system, plays an important role in the inflammatory process and most of its effects are mediated through the AT1 receptor activation. However, the knowledge about the AT2 receptor involvement in this process is still evolving. We previously found that in an experimental model of colitis, AT2 receptor activation can contribute to the impairment of the muscle contractility in vitro in the course of inflammation. Here, we investigated the potential alleviating effects of the in vivo treatment of PD123319 (1-[[4-(Dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate), AT2 receptor antagonist, in 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat model of colitis. The effects of i.p PD123319 (0.3, 3 and 10 mg/kg) administration to rats subjected to intra-rectal DNBS instillation were investigated. The study revealed that the colon injury and the inflammatory signs were ameliorated by PD123319 when visualized by the histopathological examination. The colon shortening, myeloperoxidase activity, and colonic expression of IL-1β, IL-6 and iNOS were downregulated in a dose-dependent manner in DNBS-induced colitis rats treated with PD123319 and the anti-oxidant defense machinery was also improved. The mechanism of these beneficial effects was found in the ability of PD123319 to inhibit NF-κB activation induced by DNBS. The colonic contractility in inflamed tissues was also improved by PD123319 treatment. In conclusion, our data have demonstrated previously that undescribed proinflammatory effects for the AT2 receptors in DNBS-induced colitis in rats in which they are mediated likely by NF-κB activation and reactive oxygen species generation. Moreover, when the inflammatory process is mitigated by the AT2 receptor antagonist treatment, the smooth muscle is able to recover its functionality.

Recently we found that acute treatment with Oxotremorine (Oxo), a non-selective mAChRs agonist, up-regulates heat shock proteins and activates their transcription factor heat shock factor 1 in the rat hippocampus. Here we aimed to investigate: a) if acute treatment with Oxo may regulate pro-inflammatory or anti-inflammatory cytokines and oxidative stress in the rat hippocampus; b) if chronic restraint stress (CRS) induces inflammatory or oxidative alterations in the hippocampus and whether such alterations may be affected by chronic treatment with Oxo. In the acute experiment, rats were injected with single dose of Oxo (0.4 mg/kg) and sacrificed at 24 h, 48 h and 72 h. In the CRS experiment, the rats were exposed for 21 days to the CRS and then were treated with Oxo (0.2 mg/kg) for further 10 days. The acute Oxo treatment showed an ability to significantly reduce reactive oxygen species (ROS), singlet oxygen ( 1 O 2 ), pro-inflammatory cytokines levels (IL-1β and IL-6) and phosphorylated NF-κB-p65. Acute Oxo treatment also increased superoxide dismutase (SOD)-2 protein levels and stimulated SOD activity. No differences were detected in the anti-inflammatory cytokine levels, including IL-10 and TGF-β1. In the group of rats exposed to the CRS were found increased hippocampal IL-1β and IL-6 levels, together with a reduction of SOD activity level. These changes produced by CRS were counteracted by chronic Oxo treatment. In contrast, the upregulation of ROS and 1 O 2 levels in the CRS group was not counteracted by chronic Oxo treatment. The results revealed a hippocampal anti-inflammatory and antioxidant effect of Oxo treatment in both basal conditions and anti-inflammatory in the CRS rat model.

Background: Guanosine, a guanine-based purine, is an extracellular signaling molecule exerting anti-inflammatory and antioxidative effects in several in vivo and in vitro injury models. We aimed to investigate its protective effects on 2, 4-dinitrobenzene sulfonic acid (DNBS)-induced colitis in rat., Methods: Rats were divided into five groups and colitis was induced by intracolonic instillation of DNBS (15 mg/rat). Guanosine (4 or 8 mg/kg) was administered for 6 days i.p. starting the day of the colitis induction. Body weight loss, stool consistency, colon weight/length, histological analysis, myeloperoxidase activity (MPO) and pro-inflammatory cytokine levels were assessed. Immunoblotting of nuclear factor-κB (NF-κB) p65 protein levels and detection of oxidative and nitrosative stress markers were also performed., Results: Guanosine, in a dose-dependent manner, significantly ameliorated the severity of DNBS-induced colitis, reducing body weight loss and diarrhea incidence, preventing the DNBS-induced macroscopic and microscopic damage to the colonic mucosa, and the MPO increase. Guanosine treatment also lowered interleukin-1β, interleukin-6, and tumor necrosis factor-α mRNA levels. Importantly, guanosine in DNBS rats down-regulated the expression of NF-κB p65 and the levels of reactive oxygen species and nitrite., Conclusions: In conclusion, guanosine exerts beneficial effects in DNBS-induced colitis in rats, through modulation of colonic inflammation, downregulating of NFκB-mediated signaling.

Background: Aβ 1-42 peptide abnormal production is associated with the development and maintenance of neuroinflammation and oxidative stress in brains from Alzheimer disease (AD) patients. Suppression of neuroinflammation may then represent a suitable therapeutic target in AD. We evaluated the efficacy of IFNβ1a in attenuating cognitive impairment and inflammation in an animal model of AD., Methods: A rat model of AD was obtained by intra-hippocampal injection of Aβ 1-42 peptide (23 μg/2 μl). After 6 days, 3.6 μg of IFNβ1a was given subcutaneously (s.c.) for 12 days. Using the novel object recognition (NOR) test, we evaluated changes in cognitive function. Measurement of pro-inflammatory or anti-inflammatory cytokines, reactive oxygen species (ROS), and SOD activity levels was performed in the hippocampus. Data were evaluated by one-way ANOVA with Fisher's Protected Least Significant Difference (PLSD) test., Results: We showed that treatment with IFNβ1a was able to reverse memory impairment and to counteract microglia activation and upregulation of pro-inflammatory cytokines (IL-6, IL-1β) in the hippocampus of Aβ 1-42 -injected rats. The anti-inflammatory cytokine IL-10, significantly reduced in the Aβ 1-42 animals, recovered to control levels following IFNβ1a treatment. IFNβ1a also reduced ROS and lipids peroxidation and increased SOD1 protein levels in the hippocampus of Aβ 1-42 -injected rats., Conclusion: This study shows that IFNβ1a is able to reverse the inflammatory and cognitive effects of intra-hippocampal Aβ 1-42 in the rat. Given the role played by inflammation in AD pathogenesis and the established efficacy of IFNβ1a in the treatment of inflammatory diseases of the central nervous system such as multiple sclerosis, its use may be a viable strategy to inhibit the pro-inflammatory cytokine and oxidative stress cascade associated with Aβ deposition in the hippocampus of AD patients.

A growing body of evidence shows the protective role of insulin in Alzheimer's disease (AD). A nanogel system (NG) to deliver insulin to the brain, as a tool for the development of a new therapy for Alzheimer's Disease (AD), is designed and synthetized. A carboxyl-functionalized poly(N-vinyl pyrrolidone) nanogel system produced by ionizing radiation is chosen as substrate for the covalent attachment of insulin or fluorescent molecules relevant for its characterization. Biocompatibility and hemocompatibility of the naked carrier is demonstrated. The insulin conjugated to the NG (NG-In) is protected by protease degradation and able to bind to insulin receptor (IR), as demonstrated by immunofluorescence measurements showing colocalization of NG-In(FITC) with IR. Moreover, after binding to the receptor, NG-In is able to trigger insulin signaling via AKT activation. Neuroprotection of NG-In against dysfunction induced by amyloid β (Aβ), a peptide mainly involved in AD, is verified. Finally, the potential of NG-In to be efficiently transported across the Blood Brain Barrier (BBB) is demonstrated. All together these results indicate that the synthesized NG-In is a suitable vehicle system for insulin deliver in biomedicine and a very promising tool to develop new therapies for neurodegenerative diseases., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Natural killer (NK) cells provide a major defense against cytomegalovirus (CMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIRs), and human leukocyte antigens (HLA) class I molecules. This study assessed whether the KIR and HLA repertoire may influence the risk of developing symptomatic or asymptomatic disease after primary CMV infection in the immunocompetent host., Methods: Sixty immunocompetent patients with primary symptomatic CMV infection were genotyped for KIR and their HLA ligands, along with 60 subjects with a previous asymptomatic infection as controls., Results: The frequency of the homozygous A haplotype (only KIR2DS4 as activating KIR) was higher in symptomatic patients than controls (30% vs 12%, respectively; odds ratio [OR] = 3.24; P = .01). By logistic regression, the risk of developing symptomatic disease was associated with the homozygous A haplotype and the HLABw4(T) allele. Combining the 2 independent variables, we found that 37 out of 60 (62%) symptomatic patients but only 18 out of 60 (30%) of controls possessed the homozygous A haplotype or the HLABw4(T) allele with a highly significant OR (OR = 3.75, P < .0005)., Conclusions: Immunocompetent subjects carrying the homozygous A haplotype or the HLABw4(T) allele are at higher risk of developing symptomatic disease after primary CMV infection., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Ageing is a complex process that negatively impacts the development of the different systems and its ability to function. On the other hand, the rate of ageing in humans is not uniform, due to genetic heterogeneity and the influence of environmental factors. Thus, the ageing rate, measured as the decline of functional capacity and stress resistance, seems to be different in every individual. Therefore, attempts have been made to analyse this individual age, the so-called biological age, in comparison to chronological age. Age-related changes in body function or composition that could serve as a measure of biological age and predict the onset of age-related diseases and/or residual lifetime are termed biomarkers of ageing. Such biomarkers of ageing should help on the one hand to characterise this biological age and, as age is a major risk factor in many degenerative diseases, could be subsequently used on the other hand to identify individuals at high risk of developing age-associated diseases or disabilities. Unfortunately, most of the markers under discussion are related to age-related diseases rather than to age, so none of these markers discussed in literature is a true biomarker of ageing. Hence, we discuss some disease-related biomarkers useful for a better understanding of ageing and the development of new strategies to counteract it, essential for improving the quality of life of the elderly population. Biomarkers discussed are based on immunosenescence, inflammatory responses and oxidative stress, since the review is based on data from author laboratories rather than on an extensive review of the literature. However, this kind of knowledge is useful to anti-ageing strategies aimed to slow ageing and to postpone death by preventing infectious diseases and delaying the onset of age-related diseases.

Distribution of T29C TGFbeta1 gene polymorphism was analysed in 260 hypertensive and 134 normotensive subjects. Circulating TGFbeta1 and procollagen type III levels, microalbuminuria, left ventricular geometry and function were evaluated in all the hypertensives subgrouped according to T29C TGFbeta1 gene polymorphism. Circulating TGFbeta1 by ELISA technique, procollagen type III by a specific radioimmunoassay, microalbuminuria by radioimmunoassay, left ventricular geometry and function by echocardiography were determined. All groups were comparable for gender, age and sex. Regarding T29C TGFbeta1 gene polymorphism, prevalence of TC or CC genotypes was significantly (p<0.05) higher in hypertensives than normotensives. TC and CC hypertensives were characterized by a higher prevalence of subjects with microalbuminuria (p<0.001 TC vs TT; p<0.05 CC vs TT), left ventricular hypertrophy (p<0.01 TC and CC vs TT), and by increased levels of procollagen type III (p<0.05 TC and CC vs TT). TC hypertensives were also characterized by a significant increase (p<0.05) of LVM and LVM/h(2.7 )and of urinary albumin excretion (p<0.05) values than those detectable in TT hypertensives. Our data suggest that T29C TGFbeta1 gene polymorphism was associated to clinical characteristics suitable to recognize hypertensives with a higher severity of hypertension.

Centenarians are characterized by marked delay or escape from age-associated diseases that cause mortality at earlier ages. Jointly, atherosclerosis and its complications, such as myocardial infarction (AMI), significantly contribute to mortality in the elderly. Inflammation is a key component of atherosclerosis and inflammatory genes are good candidates for the risk of the development of atherosclerosis. Genetic traits contribute to the risk of AMI and allelic variations in inflammatory genes should boost the risk of disease. If proinflammatory genotypes significantly contribute to the risk of AMI, alleles associated with disease susceptibility should not be included in the genetic background favoring longevity. Hence, genotypes of natural immunity should play an opposite role in atherosclerosis and longevity. Metalloproteinase (MMPs) are involved in tissue remodeling and therefore play a remarkable role in inflammation-based disease. MMPs are a family of Zn(2+)-dependent enzymes with proteolytic activity against connective tissue proteins such as collagens, proteoglycans, and elastin, which appear to play important roles in the development and progression of the atherosclerotic lesion. There is evidence indicating a role played by the MMPs in the weakening of atherosclerotic plaque which predisposes to lesion disruption. In this study we performed a genetic study on -1562C/T MMP-9 single nucleotide polymorphism (SNP) in order to discern a possible role in AMI. We analyzed the distribution of this SNP in 115 AMI patients, 123 controls, and 34 centenarians from Sicily. We found no significant differences in the genetic distribution and allelic frequency of -1562C/T MMP-9 SNP between the studied groups. The present results are not in agreement with our previous findings, strengthening our hypothesis that genetic background protection against cardiovascular disease is a relevant component of the longevity trait, at least in the generation of Italian male centenarians under study. However, present results do not exclude that differential expression of MMP-9 playing an opposite role in AMI and longevity because other kinds of regulation might be more relevant than those linked to the SNP under study.

The role of inflammation in atherosclerosis is well recognized. We have evaluated the allele frequencies of the +869T/C and +915G/C polymorphisms (SNPs) at the TGF-beta1 gene and -1082G/A SNP at IL-10 promoter sequence, two well-known immunosuppressive and anti-inflammatory cytokines, in patients with carotid stenosis. Our data suggest a lack of association between these SNPs and the susceptibility to atherosclerosis although other reports have demonstrated this association. These results may be due to the pleiotropic effects of the cytokines and/or differences in haplotype combination that should be investigated to elucidate the role of TGF-beta1 and IL-10 polymorphisms in atherosclerosis.