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ABSTRACT Introduction Methods Results Discussion The recently published ACR/EULAR classification criteria score (3 points or more) both clinical and laboratory criteria to define the presence of antiphospholipid syndrome (APS). The clinical criteria have been better defined while laboratory criteria remain the same [lupus anticoagulant (LA), anticardiolipin (aCL) and anti ß2‐Glycoprotein I (aß2GPI) antibodies] but with different impact (points) on the classification of patients. APS is excluded if more than 3 years separate positive test for antiphospholipid antibodies (aPL) and clinical manifestation.The present study evaluates how many patients would be excluded by the new criteria among those enrolled as APS in the START 2 antiphospholipid registry. The analysis includes 380 patients (274 APS and 106 carriers).Of 274 patients classified as APS, 118 (43%) did not match the new ACR/EULAR criteria for various reasons. First, the determination of aCL and aß2GPI antibodies was performed by automated instrumentations not allowed in the new criteria. Second, laboratory test score was less than 3 and this was due to an isolated IgM aCL or IgM aß2GPI in most cases and to isolated LA unconfirmed after 12 weeks in few cases. Third, 2 patients had a positive laboratory tests more than 3 years after the clinical event.Of the 106 carriers, 62% had aCL and aß2GPI determined by ELISA thus meeting the ACL/EULAR laboratory criteria but were negative for clinical criteria.This study shows that many patients classified as APS in the START 2 registry do not match the classification using the new ACR/EULAR criteria. [ABSTRACT FROM AUTHOR]

The one- or two-electron reduction in quinone compounds gives rise to semiquinones and hydroquinones, respectively, which, in turn, can be oxidized back to quinones, generating a cyclic redox system with the production of reactive oxygen species (ROS). For these reasons, quinone derivatives participate in various biological processes in metabolic pathways, such as oxidative reactions and electron transport. In addition, natural quinone compounds as well as their semisynthetic and/or synthetically produced derivatives are of great pharmacological interest for the discovery and design of new drugs. As a result, their chemical reactivity as well as new methods for their synthesis are being investigated on an ongoing basis. Herein, a mild and efficient synthesis to obtain 2-(4-benzyl substituted)-1,4-dimethoxybenzene derivatives is reported. In addition, an evaluation of the effects on the quinone/diquinone ratio in the reaction product in relation to different ways of adding the oxidant CAN to the arene solution is discussed. [ABSTRACT FROM AUTHOR]

In this paper, we present demographic, clinical, anamnestic, cognitive, and functional data, as well as haematological, haematochemical, immunological, and genetic parameters of an exceptional individual: A.T., a semi-supercentenarian who held the title of the oldest living Italian male centenarian from 28 December 2020, to 23 September 2021. The purpose of this study is to provide fresh insights into extreme phenotypes, with a particular focus on immune-inflammatory parameters. To the best of our knowledge, this study represents the first phenotypic investigation of a semi-supercentenarian, illustrating both INFLA-score, a metric designed to assess the cumulative impact of inflammatory markers and indicators of age-related immune phenotype (ARIP), recognized as significant gauges of biological ageing. The aim of this study was, indeed, to advance our understanding of the role of immune-inflammatory responses in achieving extreme longevity. The results of laboratory tests, as well as clinical history and interview data, when compared to the results of our recent study on Sicilian centenarians, demonstrate an excellent state of health considering his age. Consistent with previous studies, we observed increased IL-6 inflammatory markers and INFLA score in A.T. More interestingly, the semi-supercentenarian showed values of ARIP indicators such as naïve CD4+ cells, CD4+/CD8+ ratio, and CD4+TN/TM ratio in the range of young adult individuals, suggesting that his immune system's biological age was younger than the chronological one. The results support the notion that the immune system can play a role in promoting extreme longevity. However, this does not rule out the involvement of other body systems or organs in achieving extreme longevity. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells play a role in defence against viral infections by killing infected cells or by producing cytokines and interacting with adaptive immune cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leucocyte antigens (HLA). Ninety-six Sicilian patients positive to Human Immunodeficiency Virus-1 (HIV) and ninety-two Sicilian patients positive to SARS-CoV-2 were genotyped for KIRs and their HLA ligands. We also included fifty-six Sicilian patients with chronic hepatitis B (CHB) already recruited in our previous study. The aim of this study was to compare the distribution of KIR–HLA genes/groups of these three different infected populations with healthy Sicilian donors from the literature. We showed that the inhibitory KIR3DL1 gene and the KIR3DL1/HLA-B Bw4 pairing were more prevalent in individual CHB. At the same time, the frequency of HLA-C2 was increased in CHB compared to other groups. In contrast, the HLA-C1 ligand seems to have no contribution to CHB progression whereas it was significantly higher in COVID-19 and HIV-positive than healthy controls. These results suggest that specific KIR–HLA combinations can predict the outcome/susceptibility of these viral infections and allows to plan successful customized therapeutic strategies. [ABSTRACT FROM AUTHOR]

Vaccination, being able to prevent millions of cases of infectious diseases around the world every year, is the most effective medical intervention ever introduced. However, immunosenescence makes vaccines less effective in providing protection to older people. Although most studies explain that this is mainly due to the immunosenescence of T and B cells, the immunosenescence of innate immunity can also be a significant contributing factor. Alterations in function, number, subset, and distribution of blood neutrophils, monocytes, and natural killer and dendritic cells are detected in aging, thus potentially reducing the efficacy of vaccines in older individuals. In this paper, we focus on the immunosenescence of the innate blood immune cells. We discuss possible strategies to counteract the immunosenescence of innate immunity in order to improve the response to vaccination. In particular, we focus on advances in understanding the role and the development of new adjuvants, such as TLR agonists, considered a promising strategy to increase vaccination efficiency in older individuals. [ABSTRACT FROM AUTHOR]

Polyunsaturated fatty acids (PUFA) are known to have a regulatory effect on oxidative and inflammatory processes. This study aimed to identify the relationship between blood PUFA status and circulatory markers of oxidative stress and inflammation in a cohort of 172 subjects. The population was divided by sex and into three age groups: adults (18–64 years old, n = 69), older adults (65–89 years old, n = 54), and long-lived individuals (LLIs, 90–111 years old, n = 49). Whole blood PUFA content was quantified using gas chromatography. Additionally, serum levels of C-reactive protein (CRP), paraoxonase (PON), Trolox equivalent antioxidant capacity (TEAC), and malondialdehyde (MDA) were measured. Our results showed that a higher omega-3 (n-3) index in adult females was a predictor of lower MDA concentrations (p = 0.038). Conversely, total n-3 PUFA and total n-6 PUFA were positively related to MDA values among older adult females and LLI men (p < 0.05), while total n-6 PUFA was inversely correlated with MDA levels in LLI females (p < 0.05). Interestingly, increased concentrations of total n-3 PUFA and n-3 index were positively correlated with higher TEAC values in LLI men (p = 0.007), while the arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio was inversely correlated with TEAC values among LLI females (p = 0.006). These findings suggest that cellular antioxidant capacity is inversely correlated with changes in the AA/EPA ratio in long-lived females, whereas n-3 PUFA may enhance blood antioxidant capacity in long-lived men. Overall, our study highlights the complex, sex-specific interactions between PUFA profiles and oxidative stress and inflammatory markers across different age groups. • Polyunsaturated fatty acids (PUFA) may influence oxidative stress and inflammation across the lifespan. • Higher omega-3 (n-3) PUFA levels are linked to better antioxidant capacity in long-lived men. • Arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio is inversely related to antioxidant capacity in long-lived females. • Adult females with higher n-3 index showed lower malondialdehyde (MDA). [ABSTRACT FROM AUTHOR]

People are living longer, but lifespan increase does not coincide with a boost in health-span. Thus, improving the quality of life of older people is a priority. Centenarians reach extreme longevity in a relatively good health status, escaping or delaying fatal or strongly invalidating diseases. Therefore, studying processes involved in longevity is important to explain the biological mechanisms of health and well-being, since knowledge born from this approach can provide valuable information on how to slow aging. We performed the present study in a well characterized very homogeneous sample of 173 people from Western Sicily, to update existing literature on some phenotypic aspects of aging and longevity and to propose a range of values for older people. We classified 5 age groups, from young adults to centenarians, to understand the age and gender-related variations of the different parameters under study. We collected anamnestic data and performed anthropometric, bioimpedance, molecular, haematological, oxidative, and hematochemical tests, adopting a multidimensional analysis approach. An important evidence of the present study is that there are differences related to both age and gender in several biomarkers. Indeed, gender differences seem to be still poorly considered and inadequately investigated in aging as well as in other medical studies. Moreover, we often observed comparable parameters between young and centenarians rather than non-agenarians and centenarians, hypothesizing a sort of slowdown, almost followed by a reversal trend, in the decay of systemic deterioration. The study of centenarians provides important indications on how to slow aging, with benefits for those who are more vulnerable to disease and disability. The identification of the factors that predispose to a long and healthy life is of enormous interest for translational medicine in an aging world. [ABSTRACT FROM AUTHOR]

Summary: Ageing dramatically affects number and function of both innate and adaptive arms of immune system, particularly T cell subsets, contributing to reduced vaccination efficacy, decreased resistance to infections and increased prevalence of cancer in older people. In the present paper, we analysed the age‐related changes in the absolute number of lymphocytes in 214 Sicilian subjects, and in the percentages of T and natural killer (NK) cells in a subcohort of donors. We compared these results with the immunophenotype of the oldest living Italian supercentenarian (aged 111 years). The results were also sorted by gender. The correlation between number/percentage of cells and age in all individuals. and separately in males and females, was examined using a simple linear regression analysis. We did not record the increase in the rate of inversion of the CD4/CD8 ratio, frequently reported as being associated with ageing in literature. Our observation was the direct consequence of a flat average trend of CD4+ and CD8+ T cell percentages in ageing donors, even when gender differences were included. Our results also suggest that CD4+ and CD8+ subsets are not affected equally by age comparing females with males, and we speculated that gender may affect the response to cytomegalovirus (CMV) infection. The supercentenarian showed a unique immunophenotypic signature regarding the relative percentages of her T cell subsets, with CD4+ and CD8+ T cell percentages and CD4+ naive T cell values in line with those recorded for the octogenarian subjects. This suggests that the supercentenarian has a naive 'younger' T cell profile comparable to that of a >80‐year‐old female. [ABSTRACT FROM AUTHOR]

This article shows demographic, clinical, anamnestic, cognitive, and functional data as well as biochemical, genetic, and epigenetic parameters of two exceptional siblings: Diega (supercentenarian) and Filippa (semisupercentenarian) Cammalleri. The purpose of this study is to provide new insights into the extreme phenotypes represented by semisupercentenarians and supercentenarians. Different studies have been published on supercentenarians, but to the best of our knowledge, this is the only concerning two sisters and the most detailed from a phenotypic point of view. Our findings agree with the suggestion that supercentenarians have an increasing relative resistance to age-related diseases, approximating the limits of the functional human reserve to address successfully the acute causes of death. More interestingly, our data agree with, and extend, the suggestion that inflammation and oxidative stress predict centenarian mortality. [ABSTRACT FROM AUTHOR]

Extracellular matrix metalloproteinases (MMPs) are a group of proteins that activate substrates by enzymatic cleavage and, on the basis of their activities, have been demonstrated to play a role in ageing. Thus, in order to gain insight into the pathophysiology of ageing and to identify new markers of longevity, we analysed the activity levels of MMP-2 and MMP-9 in association with some relevant haematochemical parameters in a Sicilian population, including long-living individuals (LLIs, ≥95 years old). A cohort of 154 healthy subjects (72 men and 82 women) of different ages (age range 20-112) was recruited. The cohort was divided into five subgroups: the first group with subjects less than 40 years old, the second group ranging from 40 to 64 years old, the third group ranging from 65 to 89 years old, the fourth group ranging from 90 to 94 years old, and the fifth group with subjects more than 95 years old. A relationship was observed between LLIs and MMP-2, but not between LLIs and MMP-9. However, in the LLI group, MMP-2 and MMP-9 values were significantly correlated. Furthermore, in LLIs, we found a positive correlation of MMP-2 with the antioxidant catabolite uric acid and a negative correlation with the inflammatory marker C-reactive protein. Finally, in LLIs MMP-9 values correlated directly both with cholesterol and with low-density lipoproteins. On the whole, our data suggest that the observed increase of MMP-2 in LLIs might play a positive role in the attainment of longevity. This is the first study that shows that serum activity of MMP-2 is increased in LLIs as compared to younger subjects. As far as we are concerned, it is difficult to make wide-ranging conclusions/assumptions based on these observations in view of the relatively small sample size of LLIs. However, this is an important starting point. Larger-scale future studies will be required to clarify these findings including the link with other systemic inflammatory and antioxidant markers. [ABSTRACT FROM AUTHOR]

Background: Although it is well known that the older people have been the most susceptible to COVID-19, there are conflicting data on the susceptibility of centenarians. Two epidemiological study have shown that older centenarians (> 101 years old at the time of the 2020 pandemic peak) are more resilient than the remaining centenarians, suggesting that this resilience might be linked to the 1918 Spanish Flu pandemic. To gain insight into this matter, specifically whether the resilience of older centenarians to SARS-CoV-2 infection is linked to the Spanish Flu they had been affected by, we conducted a retrospective serological study. This study examined serum samples from 33 centenarians, encompassing semi- (aged > 104 < 110 years, N = 7) and supercentenarians (aged > 109 years, N = 4), born between 1905 and 1922, against both SARS-CoV-2 and 1918 H1N1 pseudotype virus. Results: Anamnestic and laboratory data suggest that SARS-CoV-2 infection occurred in 8 centenarians. The infection appeared to have been asymptomatic or mild, and hospitalization was not required, despite 3 out of 8 being between 109 and 110 years old. The levels of anti-spike antibodies in centenarians infected and/or vaccinated were higher, although not significantly, than those produced by a random sample of seventy-year-old individuals used as controls. All centenarians had antibody levels against the 1918 H1N1 virus significantly higher (almost 50 times) than those observed in the quoted group of seventy-year-old subjects, confirming the key role in maintaining immunological memory from a priming that occurred over 100 years ago. Centenarians whose blood was collected prior to the pandemic outbreak demonstrated neutralising antibodies against the 1918 H1N1 virus, but all these subjects tested negative for SARS-CoV-2. Conclusion: This retrospective study shows that older centenarians are quite resilient to COVID-19, as they are capable of producing good levels of neutralising antibodies and experiencing mild or asymptomatic disease. This could be attributed to the 1918 Spanish flu pandemic through mechanisms other than the presence of cross-reactive antibodies between the 1918 H1N1 virus and SARS-CoV-2. Another possibility is that the association is purely temporal, solely correlated with the advanced age of resilient centenarians compared to those born after 1918, since older centenarians are known to have better control of immune-inflammatory responses. [ABSTRACT FROM AUTHOR]

This article, titled "The Role of Natural Products in Immunopharmacology," explores the use of natural products in treating various disorders, with a focus on their applications in pharmacology and nutraceuticals. The authors collected articles that describe natural products and their derivatives, rather than extracts, to better understand their biological effects. The article highlights specific natural products, such as oleuropein from olive leaves, Coriolus versicolor (CV) mushrooms, and polysaccharides from shiitake mushrooms, and discusses their potential therapeutic benefits. However, further research is needed to confirm their efficacy, safety, and potential interactions with other drugs. [Extracted from the article]

Interventions to extend life span represent the new perspective in aging investigation. Healthy dietary habits are important modifiable factors that can favor a healthy aging phenotype. Many studies have demonstrated benefits for metabolic syndrome and type 2 diabetes mellitus resulting from the traditional Mediterranean foods. Opuntia Ficus Indica (OFI), widespread in the Mediterranean basin, belongs to the Cactaceae family. It is known for its antioxidant and anti-inflammatory properties. Moreover, products containing extracts from OFI fruits or cladodes have been used to control obesity and other metabolic parameters, such as glycemia and lipid profile. The aim of this study was to analyze the antioxidant and anti-inflammatory effect of pasta with 3% of OFI cladode extracts added to show its beneficial effect in human health. We performed a single arm longitudinal intervention study in 42 healthy volunteers, administrating 500 g/week of this functional pasta for 30 days. Our pasta had antioxidant and anti-inflammatory properties with putative effect on the aging process and related metabolic diseases. We also demonstrated a hypoglycemic effect. The results are preliminary, but it is possible to speculate that our pasta could be considered an effective food for the prevention of age-related metabolic disorders. [ABSTRACT FROM AUTHOR]

The immune system of semi- (from ≥105 to <110 years old) and supercentenarians (≥110 years old), i.e. oldest centenarians, is thought to have characteristics that allow them to reach extreme longevity in relatively healthy status. Thus, we investigated variations of the two principal subsets of Tγδ, Vδ1, and Vδ2, and their functional subsets using the markers defining Tαβ cells, i.e. CD27, CD45RA, in a cohort of 28 women and 26 men (age range 19–110 years), including 11 long-living individuals (from >90 years old to<105 years old), and eight oldest centenarians (≥105 years old), all of them were previously analysed for Tαβ and NK cell immunophenotypes on the same blood sample collected on recruitment day. Naïve Vδ1 and Vδ2 cells showed an inverse relationship with age, particularly significant for Vδ1 cells. Terminally differentiated T subsets (TEMRA) were significantly increased in Vδ1 but not in Vδ2, with higher values observed in the oldest centenarians, although a great heterogeneity was observed. Both naïve and TEMRA Vδ1 and CD8+ Tαβ cell values from our previous study correlated highly significantly, which was not the case for CD4+ and Vδ2. Our findings on γδ TEMRA suggest that these changes are not unfavourable for centenarians, including the oldest ones, supporting the hypothesis that immune ageing should be considered as a differential adaptation rather than a general immune alteration. The increase in TEMRA Vδ1 and CD8+, as well as in NK, would represent immune mechanisms by which the oldest centenarians successfully adapt to a history of insults and achieve longevity. The aim of the present study was to investigate the impact of ageing on the blood levels of the two main Tγδ populations, including various subsets, in a cohort of 54 Sicilian individuals aged between 19 and 110 years (including eight semi- and supercentenarians). This cohort had previously been extensively studied for Tαβ and NK subsets. The results regarding Tγδ, when combined with the previous findings on Tαβ and NK, lend support to the idea that immune ageing should be regarded as a specific adaptation rather than a general immune alteration. In this context, the increase in TEMRA Vδ1 and CD8+ cells, along with NK CD3–CD56+CD16+, could represent immune mechanisms that enable the oldest centenarians to successfully adapt to a lifetime of antigenic challenges and achieve extreme longevity. Graphical Abstract [ABSTRACT FROM AUTHOR]

During the last two centuries the average lifespan has increased at a rate of approximately 3 months/year in both sexes, hence oldest old people are becoming the population with the fastest growth in Western World. Although the average life expectancy is increasing dramatically, the healthy lifespan is not going at the same pace. This underscores the importance of studies on the prevention of age-related diseases, in order to satisfactorily decrease the medical, economic and social problems associated to advancing age, related to an increased number of individuals not autonomous and affected by invalidating pathologies. In particular, data from experimental studies in model organisms have consistently shown that nutrient signalling pathways are involved in longevity, affecting the prevalence of age-related loss of function, including age-related diseases. Accordingly, nutrigerontology is defined as the scientific discipline that studies the impact of nutrients, foods, macronutrient ratios, and diets on lifespan, ageing process, and age-related diseases. To discuss the potential relevance of this new science in the attainment of successful ageing and longevity, three original studies performed in Sicily with local foods and two reviews have been assembled in this series. Data clearly demonstrate the positive effects of nutraceuticals, functional foods and Mediterranean Diet on several biological parameters. In fact, they could represent a prevention for many age-related diseases, and, although not a solution for this social plague, at least a remedy to alleviate it. Thus, the possibility to create a dietary pattern, based on the combined strategy of the use of both nutraceuticals and functional foods should permit to create a new therapeutic strategy, based not only on a specific bioactive molecule or on a specific food but on a integrated approach that, starting from the local dietary habits, can be led to a "nutrafunctional diet" applicable worldwide. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to analyse the nutraceutical properties of table green olives Nocellara del Belice, a traditional Mediterranean food. The Mediterranean Diet has as key elements olives and extra virgin olive oil, common to all Mediterranean countries. Olive oil is the main source of fat and can modulate oxidative stress and inflammation, whereas little is known about the role of olives. Moreover, emerging evidences underline the association between gut microbiota and food as the basis of many phenomena that affect health and delay or avoid the onset of some age-related chronic diseases. Methods: In order to show if table green olives have nutraceutical properties and/or probiotic effect, we performed a nutritional intervention, administering to 25 healthy subjects (mean age 38,3), 12 table green olives/day for 30 days. We carried out anthropometric, biochemical, oxidative stress and cytokines analyses at the beginning of the study and at the end. Moreover, we also collected fecal samples to investigate about the possible variation of concentration of Lactobacilli, after the olives consumption. Result: Our results showed a significant variation of one molecule related to oxidative stress, malondialdehyde, confirming that green olives could have an anti-oxidant effect. In addition, the level of interleukin-6 Nocellara del Belice decreased significantly, demonstrating how this food could be able to modulate the inflammatory response. Moreover, it is noteworthy the reduction of fat mass with an increase of muscle mass, suggesting a possible effect on long time assumption of table olives on body mass variation. No statistically significant differences were observed in the amount of, although a trend towards an increased concentration of them at the end of the intervention could be Lactobacilli related to the nutraceutical effects of olives. Conclusion: These preliminary results suggest a possible nutraceutical effect of daily consumption of green table olives Nocellara del Belice. To best of our knowledge, this is the first study performed to assess nutraceutical properties of this food. Of course, it is necessary to verify the data in a larger sample of individuals to confirm their role as nutraceuticals. [ABSTRACT FROM AUTHOR]

Cellular senescence is implicated in ageing and associated with a broad spectrum of age-related diseases. Importantly, a cell can initiate the senescence program irrespective of the organism's age. Various stress signals, including those defined as ageing hallmarks and alterations leading to cancer development, oncogene activation, or loss of cancer-suppressive functions, can trigger cellular senescence. The primary outcome of these alterations is the activation of nuclear factor (NF)-κB, thereby inducing the senescence-associated secretory phenotype (SASP). Proinflammatory cytokines and chemokines, components of this phenotype, contribute to chronic systemic sterile inflammation, commonly referred to as inflamm-ageing. This inflammation is linked to age-related diseases (ARDs), frailty, and increased mortality in older individuals. Additionally, senescent cells (SCs) accumulate in multiple tissues with age and are believed to underlie the organism functional decline, as demonstrated by models. An escalating effort has been dedicated to identify senotherapeutics that selectively target SCs by inducing apoptosis; these drugs are termed senolytics. Concurrently, small molecules that suppress senescent phenotypes without causing cell death are known as senomorphics. Both natural and synthetic senotherapeutics, along with immunotherapies employing immune cell-mediated clearance of SCs, currently represent the most promising strategies to combat ageing and ARDs. Indeed, it is fascinating to observe that information regarding the immune reaction to SCs indicates that regulation by specific lymphocyte subsets, elevated in the oldest centenarians, plays a role in attaining extreme longevity. Regardless, the application of methods already utilized in cancer treatment, such as CAR cells and monoclonal antibodies, broadens the spectrum of potential approaches to be utilized. [ABSTRACT FROM AUTHOR]

The immunophenotype of oldest centenarians, i.e. semi- and supercentenarians, could provide important information about their ability to adapt to factors associated with immune changes, including ageing per se and chronic Cytomegalovirus infection. We investigated, by flow cytometry, variations in percentages and absolute numbers of immune cell subsets, focusing on T cells, and pro-inflammatory parameters in a cohort of 28 women and 26 men (age range 19–110 years). We observed variability in hallmarks of immunosenescence related to age and Cytomegalovirus serological status. The eight oldest centenarians showed the lowest percentages of naïve T cells, due to their age, and the highest percentages of T-effector memory cells re-expressing CD45RA (TEMRA), according to their cytomegalovirus status, and high levels of serum pro-inflammatory parameters, although their means were lower than that of remaining 90+ donors. Some of them showed CD8 naïve and TEMRA percentages, and exhaustion/pro-inflammatory markers comparable to the younger ones. Our study supports the suggestion that immune ageing, especially of oldest centenarians, exhibits great variability that is not only attributable to a single contributor but should also be the full result of a combination of several factors. Everyone ages differently because he/she is unique in genetics and experience of life and this applies even more to the immune system; everybody has had a different immunological history. Furthermore, our findings on inflammatory markers, TEMRA and CMV seropositivity in centenarians, discussed in the light of the most recent literature, suggest that these changes might be not unfavourable for centenarians, and in particular for the oldest ones. Overall, our study supports the suggestion that immune ageing, especially of semi- and super-centenarians, exhibits great variability that is not attributable to a single contributor but should be the full result of a favourable combination of several factors. Furthermore, our findings on inflammatory markers, TEMRA and CMV seropositivity in centenarians discussed in the light of the most recent literature, suggest that these changes might be not unfavourable for centenarians, and, in particular, for the oldest ones. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is an ongoing, risky, and costly health problem that therefore always requires new treatment options. Moreover, although several drugs are available, only 36% of patients achieve glycaemic control, and patient adherence is a major obstacle. With monotherapy, T2DM and its comorbidities/complications often cannot be managed, and the concurrent administration of several hypoglycaemic drugs is required, which increases the risk of side effects. In fact, despite the efficacy of the drugs currently on the market, they generally come with serious side effects. Therefore, scientific research must always be active in the discovery of new therapeutic agents. Discussion: The present review highlights some of the recent discoveries regarding marine natural products that can modulate the various targets that have been identified as crucial in the establishment of T2DM disease and its complications, with a focus on the compounds isolated from marine invertebrates. The activities of these metabolites are illustrated and discussed. Objectives. The paper aims to capture the relevant evidence of the great chemical diversity of marine natural products as a key tool that can advance understanding in the T2DM research field, as well as in antidiabetic drug discovery. The variety of chemical scaffolds highlighted by the natural hits provides not only a source of chemical probes for the study of specific targets involved in the onset of T2DM, but is also a helpful tool for the development of drugs that are capable of acting via novel mechanisms. Thus, it lays the foundation for the design of multiple ligands that can overcome the drawbacks of polypharmacology. [ABSTRACT FROM AUTHOR]

The present review describes research on novel natural antitumor alkaloids isolated from marine invertebrates. The structure, origin, and confirmed cytotoxic activity of more than 130 novel alkaloids belonging to several structural families (indoles, pyrroles, pyrazines, quinolines, and pyridoacridines), together with some of their synthetic analogs, are illustrated. Recent discoveries concerning the current state of the potential and/or development of some of them as new drugs, as well as the current knowledge regarding their modes of action, are also summarized. A special emphasis is given to the role of marine invertebrate alkaloids as an important source of leads for anticancer drug discovery. [ABSTRACT FROM AUTHOR]

Chemical investigation of the Mediterranean ascidian A. conicum resulted in the isolation of two new meroterpenes, the conithiaquinones A ( 1) and B ( 2), in addition to two previously reported chromenols ( 3 and 4) and conicaquinones ( 5 and 6). The structures of conithiaquinones A and B were determined by interpretation of spectroscopic data, and regiochemical and stereochemical assignments were achieved with the aid of computational methods, including the recently developed DP4 NMR spectral prediction method. Both conithiaquinones A and B showed significant effects on the growth and viability of cells, with 1 showing interesting cytotoxicity against human breast cancer cells. [ABSTRACT FROM AUTHOR]

Chemical investigation of two species of marine ascidians, Aplidium elegans and Ciona edwardsii, collected in Mediterranean area, led to isolation of a series of alkyl sulfates (compounds 1-5) including three new molecules 1-3. Structures of the new metabolites have been elucidated by spectroscopic analysis. Based on previously reported cytotoxic activity of these type of molecules, compounds 1-3 have been tested for their effects on the growth of two cell lines, J774A.1 (BALB/c murine macrophages) and C6 (rat glioma) in vitro. Compounds 1 and 2 induced selective concentration-dependent mortality on J774A.1 cells. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of analogues of aplidinone A (7), a prenylated quinone isolated from the Mediterranean ascidian Aplidium conicum, has been performed. This work not only allowed confirming the structural assignment of aplidinone A, previously made with the support of GIAO shielding calculations, but, above all, made a series of structurally related quinone derivatives (compounds 8–13 and the natural metabolite) available for a screening in vitro for cytotoxic and pro-apoptotic activity and for SAR studies. The study evidenced one of the synthetic analogues (11) as a potent cytotoxic and pro-apoptotic agent against several tumor cell lines which also inhibits the TNFα-induced NF-κB activation in a human leukemia T cell line. This exemplifies the potential of a natural product to qualify as lead structure for medicinal chemistry campaigns, affording simplified analogues with better bioactivity and easier to synthesize. [Copyright &y& Elsevier]

Abstract: An exhaustive examination of the chemical constituents of the Mediterranean ascidian Clavelina phlegraea led to the isolation of clavaminols G–N (1–6), a new series of amino alcohols, which expand the family of modified marine sphingoids. Structures of the novel compounds 1–6 have been elucidated by spectroscopic analysis and chemical derivatization; bioactivities of compounds 1–6 have also been investigated and comparison of their pharmacological properties with those of previously isolated clavaminols A–F allowed us to perform an assessment of simple structure–activity relationships. [Copyright &y& Elsevier]

Abstract: Two new bromopyrrole alkaloids, damipipecolin (1) and damituricin (2), have been isolated from the Mediterranean sponge Axinella damicornis, and their structures established through spectroscopic methods. Compounds 1 and 2 extend the structural variety of the so far known pyrrole alkaloids; in these compounds, the 4-bromopyrrole 2-carboxylic acid is directly condensed with a non-protein cyclic α-amino acid, the (2R, 4R)-trans-4-hydroxypipecolic acid and (2R, 4R)-cis-N,N′-dimethyl-4-hydroxyproline (d-turicine) in 1 and 2, respectively. Compounds 1 and 2 were found to display a modulating effect of the serotonin receptor activity in vitro. [Copyright &y& Elsevier]

Abstract: The chemical investigation of the Mediterranean ascidian Clavelina phlegraea has led to the isolation of six new 2-amino-3-alkanol derivatives, clavaminols A–F (1–6). Their stereostructures were established by analysis of spectroscopic data and chemical conversion. Clavaminols A, B, C, and F were tested for their cytotoxic and pro-apoptotic properties and clavaminol A was shown to be the more potent cytotoxic compound of this series inducing cell death through activation of the apoptotic machinery. [Copyright &y& Elsevier]

Abstract: The Mediterranean sponge Axinella verrucosa has been investigated for its alkaloid composition and has been found to produce a complex mixture of bromopyrrole alkaloids. Along with the previously isolated compounds 5–18, four novel alkaloids of this class, compounds 1–4, have been isolated, and their structures established through spectroscopic methods. Compounds 1–4 were found to display neuroprotective activity against the agonists serotonin and glutamate in vitro. [Copyright &y& Elsevier]

Abstract: The isolation and characterization of the known pyrrole alkaloid agelongine ( 6 ) and of the new natural product daminin ( 7 ), the bromine-free analogue of 6 , from a specimen of the marine sponge Axinella damicornis is described. Compound 7 showed significant neuroprotective properties. Moreover, for the supply of sufficient material for future medicinal investigations, a short total synthesis of 7 was developed. [Copyright &y& Elsevier]

Two novel 9,11-secosterols, aplidiasterols A (3β,6β,11-trihydroxy-9,11-seco-5α-cholest-7-en-9-one, 1) and B (3β,5α,6β,11-tetrahydroxy-9,11-secocholest-7-en-9-one, 2), along with the known secosterols 3 and 4, were isolated from the Mediterranean ascidian Aplidium conicum and their structures were determined by spectroscopic data. Aplidiasterols A and B were found to be cytotoxic against rat glioma (C6) and murine monocyte/macrophage (J774) tumor cells in vitro. Compounds 1–4 represent the first example of secosterols isolated from tunicates. [Copyright &y& Elsevier]

Simple Summary: By analyzing inflammatory scores (INFLA-score, Systemic Inflammation Response Index—SIRI) and the Aging-Related Immune Phenotype (ARIP) in 249 participants aged 19–111 years, this study investigates the role of immune-inflammatory responses in semi- and supercentenarians who have survived significant challenges like pandemics. Statistical analyses indicated that the INFLA-score and SIRI increase with age, but no significant differences were observed between semi- and supercentenarians and other age groups. Moreover, ARIP values, specifically CD8 Naïve/Effector scores, calculated from a subcohort of 54 individuals, showed no notable differences across groups. These findings suggest that effective management of immune-inflammatory responses may play a role in achieving extreme longevity. Studying models of healthy aging and exceptional longevity is crucial to understanding a possible longevity signature, as most show resistance to age-related diseases. In particular, semi- and supercentenarians are a highly selected group, having survived significant adversities, including the Spanish flu and COVID-19 pandemics, indicating distinctive immune system characteristics. This paper analyzes the inflammatory scores (INFLA-score, Systemic Inflammation Response Index (SIRI)) and Aging-Related Immune Phenotype (ARIP) indicators calculated from the dataset of the DESIGN project, including 249 participants aged 19–111 years, aiming to understand the immune-inflammatory (IMFLAM) role in achieving longevity. Statistical analyses, including linear regression and one-way ANOVA, were performed to explore the correlations between these parameters and age. Both INFLA-score and SIRI showed a significant increase with age. However, no statistical differences were found when comparing the values of semi- and supercentenarians to other age groups, which are similar to adults and lower than younger centenarians. Regarding ARIP values, it is noteworthy that when comparing the CD8+ Naïve/Effector scores between groups, no significant differences were observed between the semi- and supercentenarian group and the other groups. These results support the idea that the control of IMFLAM response can promote extreme longevity. [ABSTRACT FROM AUTHOR]

In addition to the known 6-bromo-hypaphorine (2) and plakohypaphorine-A (3), the methanol extract of the Mediterranean tunicate Aplidium conicum was shown to contain conicamin, a novel indole alkaloid having histamine-antagonistic activity which structure was determined to be 1 on the basis of the spectral data. [Copyright &y& Elsevier]

The outcome of host-virus interactions is determined by a number of factors, some related to the virus, others to the host, such as environmental factors and genetic factors. Therefore, different individuals vary in their relative susceptibility to infections. Human cytomegalovirus (HCMV) is an important pathogen from a clinical point of view, as it causes significant morbidity and mortality in immunosuppressed or immunosenescent individuals, such as the transplanted patients and the elderly, respectively. It is, therefore, important to understand the mechanisms of virus infection control. In this review, we discuss recent advances in the immunobiology of HCMV-host interactions, with particular emphasis on the immunogenetic aspects (human leukocyte antigens, HLA; killer cell immunoglobulin-like receptors, KIRs; immunoglobulin genetic markers, GM allotypes) to elucidate the mechanisms underlying the complex host-virus interaction that determine various outcomes of HCMV infection. The results, which show the role of humoral and cellular immunity in the control of infection by HCMV, would be valuable in directing efforts to reduce HCMV spurred health complications in the transplanted patients and in the elderly, including immunosenescence. In addition, concerning GM allotypes, it is intriguing that, in a Southern Italian population, alleles associated with the risk of developing HCMV symptomatic infection are negatively associated with longevity. [ABSTRACT FROM AUTHOR]

4-Nitro and 7-nitro propranolol have been recently synthesized and characterized by us. (±)-4-NO2-propranolol has been shown to act as a selective antagonist of 6-nitrodopamine (6-ND) receptors in the right atrium of rats. As part of our follow-up to this study, herein, we describe the first synthesis of (±)-3-nitroatenolol as a probe to evaluate the potential nitration of atenolol by endothelium. Chiral chromatography was used to produce pure enantiomers. By using Riguera's method, which is based on the sign distribution of ΔδH, the absolute configuration of the secondary alcohol was determined. [ABSTRACT FROM AUTHOR]

Summary: Hepatitis B virus (HBV) infection causes a self‐limiting disease in most individuals. However, < 10% of infected subjects develop a chronic disease. Genetic host variability of polymorphic genes at the interface of innate and acquired immunity, such as killer immunoglobulin‐like receptors (KIR), their human leucocyte antigen (HLA) and IgG allotypes (GM), could explain this different clinical picture. We previously showed a protective role of the KIR2DL3 gene for the development of chronic hepatitis B (CHB), and a detrimental role of the KIR ligand groups, HLA‐A‐Bw4 and HLA‐C2. We have expanded the previous analysis genotyping patients for GM23 and GM3/17 allotypes. The comparison of the patients with CHB with those who resolved HBV infection showed that the presence of GM17 allele virtually eliminated the risk of developing CHB (OR, 0·03; 95% CI, 0·004–0·16; P < 0·0001). In addition, the combination of GM17, KIR2DL3, HLA‐A‐Bw4 and HLA‐C2 was highly sensitive to predict the outcome of HBV infection. [ABSTRACT FROM AUTHOR]

Summary: Natural killer (NK) cells provide a major defence against human cytomegalovirus (HCMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin‐like receptors (KIRs), and human leucocyte antigen (HLA) class I molecules. Also γ marker (GM) allotypes, able to influence the NK antibody‐dependent cell‐mediated cytotoxicity, appear to be involved in the immunological control of virus infections, including HCMV. In some cases, their contribution requires epistatic interaction with other genes of the immune system, such as HLA. In the present report, with the aim of gaining insight into the immune mechanisms controlling HCMV, we have studied the possible associations among humoral and NK responses, and HCMV infections. In a previous study we assessed whether the KIR and HLA repertoire might influence the risk of developing symptomatic (n = 60) or asymptomatic (n = 60) disease after primary HCMV infection in the immunocompetent host. In the present study, the immunocompetent patients with primary symptomatic HCMV infection were genotyped for GM3/17 and GM23 allotypes, along with the 60 participants with a previous asymptomatic infection as controls. Notwithstanding the presence of missing data record, advanced missing data recovery techniques were able to show that individuals carrying the GM23 allotypes, both homozygous and heterozygous, GM17/17, HLA‐C2 and Bw4T KIR‐ligand groups are associated with the risk of developing symptomatic infection. Our findings on the role of both cellular and humoral immunity in the control of HCMV infection should be of value in guiding efforts to reduce HCMV‐associated health complications in the elderly, including immunosenescence, and in transplantation. [ABSTRACT FROM AUTHOR]

Recently, the role of killer cell immunoglobulin-like receptor (KIR) in autoimmune diseases has received increasing attention. The present study was undertaken to determine the association of KIR genes and the human leukocytes antigen (HLA) ligands with Systemic Lupus Erythematosus (SLE) and accompanying oxidative stress. Presence or absence of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method by case-control study. A total of 45 SLE patients, and 60 healthy controls, all of Sicilian descent, were enrolled. Plasma values of the anti-oxidant molecule Taurine were determined in all subjects by capillary electrophoresis UV detection. The carrier frequency of the KIR2DS2 gene was significantly increased in SLE patients compared to healthy controls (73.3 versus 45.0%; OR = 3.36; 95% CI = 1.46–7.74; p = .005) suggesting a role of KIR2DS2 gene in the susceptibility to disease. We also observed a strong positive association between the presence of HLA-C1 ligands group and the disease (82.2% in SLE patients versus 41.7% in controls; OR = 6.47, 95% CI = 2.58–16.26; p < .0001). Stepwise logistic regression analysis supported the effect of the HLA-C1 ligands in SLE patients (OR = 7.06, 95% CI = 0.07–2.19; p = .002), while the KIR genes were no longer significant. Interestingly, we found that SLE patients HLA-C1 positive showed significantly decreased plasma levels of antioxidant activity marker Taurine (69.38 ± 28.49 μmol/L) compared to SLE patients HLA-C1 negative (108.37 ± 86.09 μmol/L) (p = .03). In conclusion, HLA-C1 ligands group was significantly associated with an increased risk of SLE as well as an increased oxidative stress status overall in SLE patients. [ABSTRACT FROM AUTHOR]

The interventions to slow aging, favoring active life expectancy, represent the new perspectives in ageing investigation. Some mechanisms that delay or prevent the onset of aging pathologies have been identified. Between them, a healthy lifestyle seems to reduce many risk factors. In particular, eating habits represent the most concrete, low-cost way to act on aging process. Mediterranean diet has received much attention since its antioxidant and anti-inflammatory effects have been consistently demonstrated. Unfortunately, many people follow a Western diet, poor in phytochemicals that represent the main source of beneficial effects of this dietary pattern. So, supplements administration should be considered, especially in subjects exposed to high level of oxidative stress and inflammation. So, we tested the properties of a commercial food supplement containing a series of plant polyphenols in combination with caffeine, bioperine (black pepper extract), and selenium in smoking healthy volunteers. Fifty participants have been recruited and hematochemical analyses and biochemistry tests have been performed, before and after 60 days of supplement intake. Thirteen subjects dropped out of the study. At the end of the intervention, the variation of inflammatory and oxidant markers has been evaluated, measuring urinary isoprostanes, serum advanced glycation end products, and oxidized low-density lipoproteins. The results showed that this supplement exhibits promising antioxidant and anti-inflammatory responses, especially in women, highlighting the role of supplementation in certain groups of subjects, for the control of oxidative stress as well as inflammatory status. So, its intake should be useful in delaying the onset of age-related diseases. [ABSTRACT FROM AUTHOR]

Immunosenescence and inflammaging facilitate the insurgence of chronic diseases. The Mediterranean diet is a non-invasive intervention to improve the chronic low-grade inflammatory status associated with aging. Olive oil oleuropein (OLE) and hydroxytyrosol (HT) demonstrated a controversial modulatory action on inflammation in vitro when tested at concentrations exceeding those detectable in human plasma. We studied the potential anti-inflammatory effects of OLE and HT at nutritionally relevant concentrations on peripheral blood mononuclear cells (PBMCs) as regards cell viability, frequency of leukocyte subsets, and cytokine release, performing an age-focused analysis on two groups of subjects: Adult (age 18–64 years) and Senior (age ≥ 65 years). OLE and HT were used alone or as a pre-treatment before challenging PBMCs with lipopolysaccharide (LPS). Both polyphenols had no effect on cell viability irrespective of LPS, but 5 µM HT had an LPS-like effect on monocytes, reducing the intermediate subset in Adult subjects. OLE and HT had no effect on LPS-triggered release of TNF-α, IL-6 and IL-8, but 5 µM HT reduced IL-10 secretion by PBMCs from Adult vs. Senior group. In summary, nutritionally relevant concentrations of OLE and HT elicit no anti-inflammatory effect and influence the frequency of immune cell subsets with age-related different outcomes. [ABSTRACT FROM AUTHOR]

Rhus coriaria Linn is a little plant growing in the Mediterranean basin, including Sicily, where it is known as Sicilian Sumac. Since antiquity, it has been used as a medicinal herb, considering its pharmacological properties and its recognized anti-inflammatory, antioxidant, and antimicrobial effects. Multiple studies have highlighted that the beneficial properties of Sumac extracts depend on the abundance of phytochemicals such as polyphenols, fatty acids, minerals, and fibers. Despite its wide use as a spice, the literature on Sumac effects on humans' health and aging is still scarce. Considering its great nutraceutical potential, Sumac could be used to treat age-related diseases such as those in which the inflammatory process plays a crucial role in manifestation and progression. Thus, Sumac could be an interesting new insight in the biomedical field, especially in aging biomedicine. [ABSTRACT FROM AUTHOR]

We recently identified 6-nitrodopamine and other nitro-catecholamines (6-nitrodopa, 6-nitroadrenaline), indicating that the endothelium has the ability to nitrate the classical catecholamines (dopamine, noradrenaline, and adrenaline). In order to investigate whether drugs could be subject to the same nitration process, we synthesized 4-nitro- and 7-nitropropranolol as probes to evaluate the possible nitration of the propranolol by the endothelium. The separation of the enantiomers in very high yields and excellent enantiopurity was achieved by chiral HPLC. Finally, we used Riguera's method to determine the absolute configuration of the enantiomers, through double derivatization with MPA and NMR studies. [ABSTRACT FROM AUTHOR]

The study of healthy human aging is important for shedding light on the molecular mechanisms behind aging to promote well‐being and to possibly predict and/or avoid the development of age‐related disorders such as atherosclerosis and diabetes. Herein, we have employed an untargeted mass spectrometry‐based approach to study age‐related protein changes in a healthy Sicilian plasma cohort including long‐lived individuals. This approach confirmed some of the previously known proteins correlated with age including fibulin‐1, dystroglycan, and gamma‐glutamyl hydrolase. Furthermore, our findings include novel proteins that correlate with age and/or with location and uric acid, which could represent a unique signature for healthy aging. [ABSTRACT FROM AUTHOR]

Differential genetically determined expression of transforming growth factor-β (TGF-β pathway and of vascular endothelial growth factor-A (VEGF-A) might modulate the molecular "milieu" involved in the etio-pathogenesis of non-melanoma skin cancer (NMSC). We have evaluated the frequency of some functionally relevant SNPs of TGF-β and VEGF-A genes in 70 NMSC patients and 161 healthy controls, typed for TGF-β1 rs1800471, TGF-β2 rs900, TGF-βR1 rs334348 and rs334349, TGF-βR2 rs4522809 and VEGF-A rs3025039 SNPs. TGF-βR2 rs1800629G allele and related genotypes were found to be associated with a possible protective role against NMSC, whereas VEGF-A rs3025039T was associated with an increased risk. To evaluate the effect of genotype combinations on NMSC susceptibility, we determined the frequencies of 31 pseudo-haplotypes due to non-random linkage among alleles of loci not lying on the same chromosome. Two pseudo-haplotypes that imply a minor allele of TGF-βR2 or minor allele of VEGF-A SNPs combined with major alleles of the other SNPs were, respectively, associated with a protective effect, and susceptibility to NMSC. In addition, a pseudo-haplotype involving minor alleles of TGF-β2 rs900, TGF-βR1 rs334348 and rs4522809 SNPs might be a susceptibility marker for NMSC. In conclusion, our data suggest that a complex interplay among the genetic polymorphisms of TGF-β, TGF-β receptors and VEGF-A genes might influence the net effect of genetic background of the patients on NMSC development. This might be relevant in the risk evaluation, diagnosis and treatment of NMSC. [ABSTRACT FROM AUTHOR]

Several studies on the genetics of longevity have been reviewed in this paper. The results show that, despite efforts and new technologies, only two genes, APOE and FOXO3A, involved in the protection of cardiovascular diseases, have been shown to be associated with longevity in nearly all studies. This happens because the genetic determinants of longevity are dynamic and depend on the environmental history of a given population. In fact, population-specific genes are thought to play a greater role in the attainment of longevity than those shared between different populations. Hence, it is not surprising that GWAS replicated associations of common variants with longevity have been few, if any, as these studies pool together different populations. An alternative way might be the study of long-life families. This type of approach is proving to be an ideal resource for uncovering protective alleles and associated biological signatures for healthy aging phenotypes and exceptional longevity. [ABSTRACT FROM AUTHOR]

Human ageing can be characterized by a profile of circulating microRNAs (miRNAs), which are potentially predictors of biological age. They can be used as a biomarker of risk for age-related inflammatory outcomes, and senescent endothelial cells (ECs) have emerged as a possible source of circulating miRNAs. In this paper, a panel of four circulating miRNAs including miR-146a-5p, miR-126-3p, miR-21-5p, and miR-181a-5p, involved in several pathways related to inflammation, and ECs senescence that seem to be characteristic of the healthy ageing phenotype. The circulating levels of these miRNAs were determined in 78 healthy subjects aged between 22 to 111 years. Contextually, extracellular miR-146a-5p, miR-126-3p, miR-21-5p, and miR-181a-5p levels were measured in human ECs in vitro model, undergoing senescence. We found that the levels of the four miRNAs, using ex vivo and in vitro models, progressively increase with age, apart from ultra-centenarians that showed levels comparable to those measured in young individuals. Our results contribute to the development of knowledge regarding the identification of miRNAs as biomarkers of successful and unsuccessful ageing. Indeed, they might have diagnostic/prognostic relevance for age-related diseases. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A small library of antiplasmodial methoxy-thiazinoquinones has been prepared. • Their structures were designed on the model of a previously identified hit, compound 1. • A new lead candidate with higher potency compared to the starting hit was identified. • The new lead had a good selectivity index and no toxicity against RBCs. • Computational studies shed light on its putative mechanism of action. Abstract A small library of antiplasmodial methoxy-thiazinoquinones, rationally designed on the model of the previously identified hit 1 , has been prepared by a simple and inexpensive procedure. The synthetic derivatives have been subjected to in vitro pharmacological screening, including antiplasmodial and toxicity assays. These studies afforded a new lead candidate, compound 9 , endowed with higher antiplasmodial potency compared to 1 , a good selectivity index when tested against a panel of mammalian cells, no toxicity against RBCs, a synergistic antiplasmodial action in combination with dihydroartemisinin, and a promising inhibitory activity on stage V gametocyte growth. Computational studies provided useful insights into the structural requirements needed for the antiplasmodial activity of thiazinoquinone compounds and on their putative mechanism of action. [ABSTRACT FROM AUTHOR]

Background: Innate immunity utilizes components of sensory signal transduction such as bitter and sweet taste receptors. In fact, empirical evidence has shown bitter and sweet taste receptors to be an integral component of antimicrobial immune response in upper respiratory tract infections. Since an efficient immune response plays a key role in the attainment of longevity, it is not surprising that the rs978739 polymorphism of the bitter taste receptor TAS2R16 gene has been shown to be associated with longevity in a population of 941 individuals ranging in age from 20 to 106 years from Calabria (Italy). There are many possible candidate genes for human longevity, however of the many genes tested, only APOE and FOXO3 survived to association in replication studies. So, it is necessary to validate in other studies genes proposed to be associated with longevity. Thus, we analysed the association of the quoted polymorphism in a population of long lived individuals (LLIs) and controls from another Italian population from Cilento. Methods: The analysis has been performed on data previously obtained with genome-wide association study on a population of LLIs (age range 90–109 years) and young controls (age range 18–45 years) from Cilento (Italy). Results: Statistical power calculations showed that the analysed cohort represented by 410 LLIs and 553 young controls was sufficiently powered to replicate the association between rs978739 and the longevity phenotype according to the effect size and frequencies described in the previous paper, under a dominant and additive genetic model. However, no evidence of association between rs978739 and the longevity phenotype was observed according to the additive or dominant model. Conclusion: There are several reasons for the failure of the confirmation of a previous study. However, the differences between the two studies in terms of environment of the population adopted and of the criteria of inclusion have made difficult the replication of the findings. [ABSTRACT FROM AUTHOR]