Digging into the intrinsic capacity concept: Can it be applied to Alzheimer's disease?

Historically, aging research has largely centered on disease pathology rather than promoting healthy aging. The World Health Organization's (WHO) policy framework (2015-2030) underscores the significance of fostering the contributions of older individuals to their families, communities, and economies. The WHO has introduced the concept of intrinsic capacity (IC) as a key metric for healthy aging, encompassing five primary domains: locomotion, vitality, sensory, cognitive, and psychological. Past AD research, constrained by methodological limitations, has focused on single outcome measures, sidelining the complexity of the disease. Our current scientific milieu, however, is primed to adopt the IC concept. This is due to three critical considerations: (I) the decline in IC is linked to neurocognitive disorders, including AD, (II) cognition, a key component of IC, is deeply affected in AD, and (III) the cognitive decline associated with AD involves multiple factors and pathophysiological pathways. Our study explores the application of the IC concept to AD patients, offering a comprehensive model that could revolutionize the disease's diagnosis and prognosis. There is a dearth of information on the biological characteristics of IC, which are a result of complex interactions within biological systems. Employing a systems biology approach, integrating omics technologies, could aid in unraveling these interactions and understanding IC from a holistic viewpoint. This comprehensive analysis of IC could be leveraged in clinical settings, equipping healthcare providers to assess AD patients' health status more effectively and devise personalized therapeutic interventions in accordance with the precision medicine paradigm. We aimed to determine whether the IC concept could be extended from older individuals to patients with AD, thereby presenting a model that could significantly enhance the diagnosis and prognosis of this disease.

Systematic vitamin D supplementation is associated with improved outcomes and reduced thyroid adverse events in patients with cancer treated with immune checkpoint inhibitors: results from the prospective PROVIDENCE study.

BACKGROUND: Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs). METHODS: We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion. RESULTS: Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34-0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40-0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03-0.85). CONCLUSION: The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs.

Dietary Phytoestrogen Intake and Cognitive Status in Southern Italian Older Adults.

BACKGROUND: Aging society faces significant health challenges, among which cognitive-related disorders are emerging. Diet quality has been recognized among the major contributors to the rising prevalence of cognitive disorders, with increasing evidence of the putative role of plant-based foods and their bioactive components, including polyphenols. Dietary polyphenols, including phytoestrogens, have been hypothesized to exert beneficial effects toward brain health through various molecular mechanisms. However, the evidence on the association between dietary phytoestrogen intake and cognitive function is limited. The aim of this study was to investigate the association between phytoestrogen intake and cognitive status in a cohort of older adults living in Sicily, Southern Italy. METHODS: Dietary information from 883 individuals aged 50 years or older was collected through a validated food frequency questionnaire. Cognitive status was assessed through the Short Portable Mental Status Questionnaire. RESULTS: The highest total isoflavone (including daidzein and genistein) intake was inversely associated with cognitive impairment compared to the lowest (odds ratio (OR) = 0.43, 95% confidence interval (CI): 0.20-0.92). Higher intake of total lignans and, consistently, all individual compounds (with the exception of secoisolariciresinol) were inversely associated with cognitive impairment only in the unadjusted model. CONCLUSIONS: A higher intake of phytoestrogens, especially isoflavones, was associated with a better cognitive status in a cohort of older Italian individuals living in Sicily. Taking into account the very low intake of isoflavones in Italian diets, it is noteworthy to further investigate selected populations with habitual consumption of such compounds to test whether these results may be generalized to the Italian population.

Unveiling the Hidden Therapeutic Potential of Carnosine, a Molecule with a Multimodal Mechanism of Action: A Position Paper.

Carnosine (ß-alanyl-L-histidine) is a naturally occurring endogenous dipeptide and an over-the-counter food supplement with a well-demonstrated multimodal mechanism of action that includes the detoxification of reactive oxygen and nitrogen species, the down-regulation of the production of pro-inflammatory mediators, the inhibition of aberrant protein formation, and the modulation of cells in the peripheral (macrophages) and brain (microglia) immune systems. Since its discovery more than 100 years ago, a plethora of in vivo preclinical studies have been carried out; however, there is still substantial heterogeneity regarding the route of administration, the dosage, the duration of the treatment, and the animal model selected, underlining the urgent need for "coordinated/aligned" preclinical studies laying the foundations for well-defined future clinical trials. The main aim of the present position paper is to critically and concisely consider these key points and open a discussion on the possible "alignment" for future studies, with the goal of validating the full therapeutic potential of this intriguing molecule.

How Does Contraceptive Use Affect Women's Sexuality? A Novel Look at Sexual Acceptability.

Among the components of a healthy life, sexuality is essential, contributing to both the psychophysical and social well-being of women and, consequently, to their quality of life. A poorly investigated standpoint is the acceptability of contraceptive methods, both in terms of their tolerability and metabolic neutrality and in terms of their impact on sexual life. In this context, we will provide an overview of the different methods of contraception and their effects on female sexuality, from biological changes to organic, social, and psychological factors, which can all shape sexuality. A MEDLINE/PubMed review of the literature between 2010 and 2021 was conducted using the following key words and phrases: hormonal contraception, contraceptives, female sexual function, libido, sexual arousal and desire, and sexual pain. Recent studies have supported the effects of contraceptives on women's sexuality, describing a variety of positive and negative events in several domains of sexual function (desire, arousal, orgasm, pain, enjoyment). However, satisfaction with sexual activity depends on factors that extend beyond sexual functioning alone. A more holistic approach is needed to better understand the multitude of factors linked to women's sexuality and contraception. Contraceptive counseling must consider these important elements since they are closely related to good compliance and maximize non-contraceptive health benefits.

Polyphenols and neuroprotection: Therapeutic implications for cognitive decline.

Dietary polyphenols have been the focus of major interest for their potential benefits on human health. Several preclinical studies have been conducted to provide a rationale for their potential use as therapeutic agents in preventing or ameliorating cognitive decline. However, results from human studies are scarce and poorly documented. The aim of this review was to discuss the potential mechanisms involved in age-related cognitive decline or early stage cognitive impairment and current evidence from clinical human studies conducted on polyphenols and the aforementioned outcomes. The evidence published so far is encouraging but contrasting findings are to be taken into account. Most studies on anthocyanins showed a consistent positive effect on various cognitive aspects related to aging or early stages of cognitive impairment. Studies on cocoa flavanols, resveratrol, and isoflavones provided substantial contrasting results and further research is needed to clarify the therapeutic potential of these compounds. Results from other studies on quercetin, green tea flavanols, hydroxycinnamic acids (such as chlorogenic acid), curcumin, and olive oil tyrosol and derivatives are rather promising but still too few to provide any real conclusions. Future translational studies are needed to address issues related to dosage, optimal formulations to improve bioavailability, as well as better control for the overall diet, and correct target population.

Effects of hormone therapy containing 2 mg drospirenone and 1 mg 17ß-estradiol on postmenopausal exacerbation of Meniere's disease: Preliminary study.

The present study aimed to evaluate the effects of 2 mg drospirenone (DRSP) and 1 mg 17ß-estradiol (E2) hormone therapy (HT) in combination with rehabilitation therapy for postmenopausal women with Meniere's disease (MD). The combined drug hormone treatment was denoted as DRSP/E2. A total of 65 postmenopausal female patients with MD and severe distress were enrolled in the present prospective study. A total of 31 women comprised the study group (group A), undergoing HT and rehabilitation therapy, whereas 34 women who opted for rehabilitation therapy alone comprised the control group (group B). Vestibular function and distress associated with MD were assessed by stabilometry and the Dizziness Handicap Inventory (DHI) questionnaire, respectively. The data were collected at baseline and during the 3- and 6-month follow-up visits. The areas of the stabilometric ellipses exhibited a higher reduction in group A compared with group B with regard to the baseline values at both follow-up assessments (P<0.001). At baseline, both groups exhibited severe self-perceived discomfort, with similar DHI scores of 72.3±3.7 (group A) and 70.6±3.9 (group B; P=0.07). At the 3-month follow-up, both groups underwent a gradual improvement, which was significantly higher in group A (47.5±3.7) compared with in group B (64.2±3.3; P<0.001). At the 6-month follow-up, the DHI scores were improved in group A (43.4±3.4) compared with in group B (58.5±3.1; P<0.001). Therefore, DRSP/E2 HT was effective in reducing the fluid overload, which is characteristic of MD. The findings of the present study demonstrated that integrated therapy based on the administration of DRSP/E2 HT and rehabilitation may be more effective compared with rehabilitation alone for the management of postmenopausal exacerbation of MD.

Improving Cognition with Nutraceuticals Targeting TGF-ß1 Signaling.

Rescue of cognitive function represents an unmet need in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). Nutraceuticals deliver a concentrated form of a presumed bioactive(s) agent(s) that can improve cognitive function alone or in combination with current approved drugs for the treatment of cognitive disorders. Nutraceuticals include different natural compounds such as flavonoids and their subclasses (flavan-3-ols, catechins, anthocyanins, and flavonols), omega-3, and carnosine that can improve synaptic plasticity and rescue cognitive deficits through multiple molecular mechanisms. A deficit of transforming growth factor-ß1 (TGF-ß1) pathway is an early event in the pathophysiology of cognitive impairment in different neuropsychiatric disorders, from depression to AD. In the present review, we provide evidence that different nutraceuticals, such as Hypericum perforatum (hypericin and hyperforin), flavonoids such as hesperidin, omega-3, and carnosine, can target TGF-ß1 signaling and increase TGF-ß1 production in the central nervous system as well as cognitive function. The bioavailability of these nutraceuticals, in particular carnosine, can be significantly improved with novel formulations (nanoparticulate systems, nanoliposomes) that increase the efficacy and stability of this peptide. Overall, these studies suggest that the synergism between nutraceuticals targeting the TGF-ß1 pathway and current approved drugs might represent a novel pharmacological approach for reverting cognitive deficits in AD patients.

Epilobium angustifolium L. extract with high content in oenothein B on benign prostatic hyperplasia: A monocentric, randomized, double-blind, placebo-controlled clinical trial.

Benign prostatic hyperplasia (BPH) is a common condition in adult men. Especially in Europe, increasing attention has been focused on E. angustifolium extracts (EAEs), which are widely used for their positive effects on the symptoms of BPH, although human clinical trials are limited. The aim of this monocentric, randomized, double-blind, placebo-controlled clinical trial is to evaluate if a daily intake of hard, gastric-resistant capsules containing a chemically characterized EAE (500 mg) for 6 months may allow a significant improvement in symptoms in subjects with BPH. This study was conducted in 128 adult men, randomly assigned to receive either EAE food supplement (N = 70) or placebo (N = 58), who underwent four visits (baseline = t0, after 15 days = t1, after 2 months = t2 and after 6 months = t3) in an outpatient setting to evaluate post-void residual (PVR) and prostate volume (PV) by means of prostate ultrasound, prostate-specific antigen (PSA) and neutrofile/lymphocyte ratio (N/L), nocturia before the clinical visits and International Prostate Specific Score (IPSS) registered by the physicians. EAE food supplement induced a significant decrease in the PVR and consequently nocturia improving the quality of life as suggested by the decrease of IPSS. No subjects reported adverse effects related to oral intake of EAE food supplement. Moreover, EAE food supplement did not show hepatic or renal toxicity. In conclusion, EAE food supplements can be used in subjects with BPH, to improve their quality of life and general renal function.

A standardized polyphenol mixture extracted from poplar-type propolis for remission of symptoms of uncomplicated upper respiratory tract infection (URTI): A monocentric, randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: The most common symptoms of mild upper respiratory tract infections (URTIs) are sore throat, muffled dysphonia, and swelling and redness of the throat, which result from the inflammation process following acute bacterial or viral infection. HYPOTHESIS/PURPOSE: As propolis is a natural resinous substance traditionally used to maintain oral cavity and upper respiratory tract health due to its antimicrobial and anti-inflammatory properties, the aim of this study is to evaluate the efficacy of an oral spray based on poplar-type propolis extract with a known and standardized polyphenol content, on the remission of the symptoms associated with mild uncomplicated URTIs. STUDY DESIGN: A monocentric, randomized, double-blind, placebo-controlled clinical trial was performed. METHODS: This study was conducted in 122 healthy adults who had perceived mild upper respiratory tract infections. Participants, randomly assigned to receive either propolis oral spray (N = 58) or placebo (N = 64), underwent four visits (baseline = t0, after 3 days = t1 and after 5 days = t2 and after a follow-up of 15 days = t3) in an outpatient setting. Propolis oral spray total polyphenol content was 15 mg/ml. The dosage was 2-4 sprays three times/day (corresponding to 12-24 mg of polyphenols/day), for five days. The duration of the study was 8 weeks. RESULTS: After 3 days of treatment, 83% of subjects treated with propolis oral spray had remission of symptoms, while 72% of subjects in the placebo group had at least one remaining symptom. After five days, all subjects had recovered from all symptoms. This means that resolution from mild uncomplicated URTIs took place two days earlier, instead of taking place in five days as recorded in the control group. There was no relationship between the ingestion of propolis oral spray or placebo and adverse reactions. CONCLUSION: Propolis oral spray can be used to improve both bacterial and viral uncomplicated URTI symptoms in a smaller number of days without the use of pharmacological treatment, leading to a prompt symptom resolution.

A Pilot Screening of Agro-Food Waste Products as Sources of Nutraceutical Formulations to Improve Simulated Postprandial Glycaemia and Insulinaemia in Healthy Subjects.

The control of glucose homeostasis is the main goal for both the prevention and management of diabetes and pre-diabetes. Numerous drugs are available, despite their side effects. This is constantly leading people to be inclined to natural alternative treatments. Evidence indicates antioxidant-based nutraceuticals as an optimal tool for the glycaemic control. Currently, a great interest has been focused on the valorisation of agro-food by-products as sources of bioactive compounds including polyphenols. In this sense, we tested the efficacy of novel nutraceutical products based on polyphenolic extract from nectarines (NecP), tomato peels (TP), and olive leaves (EOL) on glycaemic and insulinemic responses. The three formulations contained, respectively, 0.007 mg abscisic acid (ABA)/g, 0.5 mg carotenoids/g, and 150 mg oleuropein/g. Twenty healthy subjects consumed a regular glucose solution (RG) or a treatment beverage (TB) obtained by mixing RG with the individual formulations (TB NecP, TB EOL, and TB TP), separately, and on different days. All three formulations significantly lowered the 30 min glucose plasma peak (p < 0.05 for all); similarly, NecP and TP also significantly lowered the 30 min insulin plasma peak (p < 0.05 for all). These results may lead to the hypothesis of a formulation of a multi-component nutraceutical with a synergistic efficacy for the glycaemic control.

Effect of Annurca Apple Polyphenols on Intermittent Claudication in Patients With Peripheral Artery Disease.

Peripheral arterial disease (PAD) is an atherosclerotic process involving both modifiable and nonmodifiable risk factors. Prospective cohort studies show that patients with PAD have a 6-fold greater risk of death from cardiovascular disease than those without PAD. Currently, there is no effective treatment for PAD. The study was a randomized, placebo-controlled trial, involving 180 patients, aged 35 to 75. The subjects were divided into 2 groups. One group underwent 24 weeks of nutraceutical treatment consisting in the administration of 4 capsules of Annurca apple polyphenolic extract (AMS)/day. The placebo group was administered with identically appearing capsules containing only maltodextrin. Primary outcome measures were: walking autonomy, ankle-brachial index, acceleration time. In the AMS group, at the end of the treatment period, walking autonomy was increased on average by 69% (p <0.05), while slighter effects were registered as regards ankle-brachial index (+25%; p <0.05) and acceleration time (-3.6%; p <0.05), when compared with baseline. Placebo group revealed no significant differences as regards variations of all outcomes measures (p >0.05). Our preliminary results may indicate AMS product as a promising natural and safe tool for treatment of symptoms related to PAD.

Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity.

Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by "designing in" functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was ∼ 20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization.

Promotion of behavioural change in people with hypertension: an intervention study.

OBJECTIVE: To assess the efficacy of a comprehensive motivational approach in reducing blood pressure in Italian patients with hypertension. METHOD: Two hundred and ninety-two first visit patients with hypertension without diabetes and dyslipidemia and with BMI < 28 were enrolled. One hundred and forty-two were randomly assigned to a Control group (C) and 150 to an Intervention group (I). A ten-multiple-choice questionnaire was developed to evaluate the effect of the intervention on lifestyle modification. Patients were given the questionnaire, had their BP measured and drug therapy registered before educational intervention and 12 months later. Group I patients participated in the focus group and in the role play 2 and 4 months, respectively, after recruitment. Group C patients received the oral information. MAIN OUTCOME MEASURE: Blood pressure values and lifestyle modification. An intention to treat analysis was undertaken. Analysis was performed using SPSS version 15.0. RESULTS: Of the 150 group I patients, 58 participated in both focus group and role play, 30 participated only in focus group and the remaining 62 never participated. After 12 months, there was a significant reduction of BP for group I (P < 0.001) and a significant reduction only for systolic BP in group C (P = 0.01). Diastolic BP and systolic BP decreased more markedly in group I than in group C, with P < 0.001 for both. We found a significant improvement of lifestyle modification after 12 months of follow-up concerning some aspects in both groups. CONCLUSION: Our findings show that a motivational approach is a powerful tool for achieving better blood pressure control and is an essential skill for all healthcare professionals.