Exploring the Role of Lactoferrin in Managing Allergic Airway Diseases among Children: Unrevealing a Potential Breakthrough.

The prevalence of allergic diseases has dramatically increased among children in recent decades. These conditions significantly impact the quality of life of allergic children and their families. Lactoferrin, a multifunctional glycoprotein found in various biological fluids, is emerging as a promising immunomodulatory agent that can potentially alleviate allergic diseases in children. Lactoferrin's multifaceted properties make it a compelling candidate for managing these conditions. Firstly, lactoferrin exhibits potent anti-inflammatory and antioxidant activities, which can mitigate the chronic inflammation characteristic of allergic diseases. Secondly, its iron-binding capabilities may help regulate the iron balance in allergic children, potentially influencing the severity of their symptoms. Lactoferrin also demonstrates antimicrobial properties, making it beneficial in preventing secondary infections often associated with respiratory allergies. Furthermore, its ability to modulate the immune response and regulate inflammatory pathways suggests its potential as an immune-balancing agent. This review of the current literature emphasises the need for further research to elucidate the precise roles of lactoferrin in allergic diseases. Harnessing the immunomodulatory potential of lactoferrin could provide a novel add-on approach to managing allergic diseases in children, offering hope for improved outcomes and an enhanced quality of life for paediatric patients and their families. As lactoferrin continues to capture the attention of researchers, its properties and diverse applications make it an intriguing subject of study with a rich history and a promising future.

Efficacy and Tolerability of a Scutellaria lateriflora L. and Cistus × incanus L.-Based Chewing Gum on the Symptoms of Gingivitis: A Monocentric, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Preclinical studies have shown that the combination of Cistus × incanus L. and Scutellaria lateriflora L. extracts exerts beneficial effects on oral health against gingivitis. Thus, this study aimed to assess the tolerability of a chewing gum and its efficacy on gingivitis in a double-blind, placebo-controlled clinical trial. Enrolled subjects (n = 60, 18-70 years) were randomized to receive two chewing gums or a placebo daily for 3 months. At baseline (t0) and monthly (t1, t2, and t3) timepoints, the Quantitative Gingival Bleeding Index (QGBI), the Modified Gingival Index (MGI), and the Oral Health 15 items (OH-15)] were employed to assess potential improvements in gingivitis. Pain was self-quantified via the Visual Analogue Scale (VAS), and the Clinical Global Impression Scale for Severity of illness (CGI-S) helped in evaluating the oral general conditions. This study is listed on the ISRCTN registry. At t3, the QGBI, MGI, OH-15, VAS, and CGI-S values decreased in the treated but not in the placebo group (ß = 0.6 ± 0.1, t176 = 3.680, p < 0.001; ß = 0.87 ± 0.21, t115 = 4.263, p < 0.001; ß = 5.3 ± 2.5, t172 = 2.086, p = 0.038; ß = 3.16 ± 0.51, t88 = 6.253, p < 0.001; and ß = 1.09 ± 0.32, t83 = 3.419, p < 0.001, respectively). A significant improvement in gingival health occurred after a 3-month intervention with the chewing gums containing S. lateriflora and C. incanus extracts.

Exploring the Therapeutic Potential of Royal Jelly in Metabolic Disorders and Gastrointestinal Diseases.

Metabolic disorders, encompassing diabetes mellitus, cardiovascular diseases, gastrointestinal disorders, etc., pose a substantial global health threat, with rising morbidity and mortality rates. Addressing these disorders is crucial, as conventional drugs often come with high costs and adverse effects. This review explores the potential of royal jelly (RJ), a natural bee product rich in bioactive components, as an alternative strategy for managing metabolic diseases. RJ exhibits diverse therapeutic properties, including antimicrobial, estrogen-like, anti-inflammatory, hypotensive, anticancer, and antioxidant effects. This review's focus is on investigating how RJ and its components impact conditions like diabetes mellitus, cardiovascular disease, and gastrointestinal illnesses. Evidence suggests that RJ serves as a complementary treatment for various health issues, notably demonstrating cholesterol- and glucose-lowering effects in diabetic rats. Specific RJ-derived metabolites, such as 10-hydroxy-2-decenoic acid (10-HDA), also known as the "Queen bee acid," show promise in reducing insulin resistance and hyperglycemia. Recent research highlights RJ's role in modulating immune responses, enhancing anti-inflammatory cytokines, and suppressing key inflammatory mediators. Despite these promising findings, further research is needed to comprehensively understand the mechanisms underlying RJ's therapeutic effects.

In Vitro Assessment of Cortisol Release Inhibition, Bioaccessibility and Bioavailability of a Chemically Characterized Scutellaria lateriflora L. Hydroethanolic Extract.

Excess cortisol release is associated with numerous health concerns, including psychiatric issues (i.e., anxiety, insomnia, and depression) and nonpsychiatric issues (i.e., osteoporosis). The aim of this study was to assess the in vitro inhibition of cortisol release, bioaccessibility, and bioavailability exerted by a chemically characterized Scutellaria lateriflora L. extract (SLE). The treatment of H295R cells with SLE at increasing, noncytotoxic, concentrations (5-30 ng/mL) showed significant inhibition of cortisol release ranging from 58 to 91%. The in vitro simulated gastric, duodenal, and gastroduodenal digestions, induced statistically significant reductions (p < 0.0001) in the bioactive polyphenolic compounds that most represented SLE. Bioavailability studies on duodenal digested SLE, using Caco-2 cells grown on transwell inserts and a parallel artificial membrane permeability assay, indicated oroxylin A glucuronide and oroxylin A were the only bioactive compounds able to cross the Caco-2 cell membrane and the artificial lipid membrane, respectively. The results suggest possible applications of SLE as a food supplement ingredient against cortisol-mediated stress response and the use of gastroresistant oral dosage forms to partially prevent the degradation of SLE bioactive compounds. In vivo studies and clinical trials remain necessary to draw a conclusion on the efficacy and tolerability of this plant extract.

Efficacy of digestive enzyme supplementation in functional dyspepsia: A monocentric, randomized, double-blind, placebo-controlled, clinical trial.

Functional dyspepsia is a form of dyspepsia lacking in clear causes following clinical assessment. Dyspepsia is characterized by episodic or persistent abdominal pain or discomfort of the upper gastrointestinal (GI) tract. Its onset has been linked with a deficiency or dysfunction of digestive enzymes. Thus, consumption of digestive multi-enzymatic preparations may be effectively used for the reduction of symptoms. The aim of this study is to assess the effectiveness and tolerability of the supplementation of a normal diet with a multi-enzyme blend obtained from fungal fermentation, in a randomized, placebo-controlled, double-blind, clinical trial. Enrolled subjects (n = 120, male: 63, female: 57), aged 18-59 years, were randomized (allocation ratio 1:1) to receive either 2 capsules per day of the food supplement (containing 200 mg of the multi-enzyme blend/capsule) or placebo, for 2 months. The primary outcome of the study (i.e., improvements in quality of life) was evaluated by the Nepean Dyspepsia Index-SF (NDI-SF) questionnaire, while the secondary outcomes (i.e., severity of pain and the quality of sleep) were assessed through the Visual Analogue Scale (VAS) and Pittsburgh Sleep Quality Index (PSQI) questionnaire. The results showed an improvement in NDI-SF1, NDI-SF2-5, VAS, and PSQI scores in subjects treated with the multi-enzyme blend, indicating an improvement in quality of life and of sleep, and a decreased severity of pain, following the supplementation with digestive enzymes, without side effects. In conclusion, treatment with digestive enzymes was found to be effective in the reduction of functional dyspepsia symptoms and in the improvement of sleep quality, and is well-tolerated.

Anthocyanins as Immunomodulatory Dietary Supplements: A Nutraceutical Perspective and Micro-/Nano-Strategies for Enhanced Bioavailability.

Anthocyanins (ACNs) have attracted considerable attention for their potential to modulate the immune system. Research has revealed their antioxidant and anti-inflammatory properties, which play a crucial role in immune regulation by influencing key immune cells, such as lymphocytes, macrophages, and dendritic cells. Moreover, ACNs contribute towards maintaining a balance between proinflammatory and anti-inflammatory cytokines, thus promoting immune health. Beyond their direct effects on immune cells, ACNs significantly impact gut health and the microbiota, essential factors in immune regulation. Emerging evidence suggests that they positively influence the composition of the gut microbiome, enhancing their immunomodulatory effects. Furthermore, these compounds synergize with other bioactive substances, such as vitamins and minerals, further enhancing their potential as immune-supporting dietary supplements. However, detailed clinical studies must fully validate these findings and determine safe dosages across varied populations. Incorporating these natural compounds into functional foods or supplements could revolutionize the management of immune-related conditions. Personalized nutrition and healthcare strategies may be developed to enhance overall well-being and immune resilience by fully understanding the mechanisms underlying the actions of their components. Recent advancements in delivery methods have focused on improving the bioavailability and effectiveness of ACNs, providing promising avenues for future applications.

Arctium lappa (Burdock): Insights from ethnopharmacology potential, chemical constituents, clinical studies, pharmacological utility and nanomedicine.

Arctium lappa L. is a medicinal edible homologous plant, commonly known as burdock or bardana, which belongs to the Asteraceae family. It is widely distributed throughout Northern Asia, Europe, and North America and has been utilized for hundreds of years. The roots, fruits, seeds, and leaves of A. lappa have been extensively used in traditional Chinese Medicine (TCM). A. lappa has attracted a great deal of attention due to its possession of highly recognized bioactive metabolites with significant therapeutic potential. Numerous pharmacological effects have been demonstrated in vitro and in vivo by A. lappa and its bioactive metabolites, including antimicrobial, anti-obesity, antioxidant, anticancer, anti-inflammatory, anti-diabetic, anti-allergic, antiviral, gastroprotective, hepatoprotective, and neuroprotective activities. Additionally, A. lappa has demonstrated considerable clinical efficacies and valuable applications in nanomedicine. Collectively, this review covers the properties of A. lappa and its bioactive metabolites, ethnopharmacology aspects, pharmacological effects, clinical trials, and applications in the field of nanomedicine. Hence, a significant attention should be paid to clinical trials and industrial applications of this plant with particular emphasis, on drug discovery and nanotechnology.

Efficacy of a food supplement based on S-adenosyl methionine and probiotic strains in subjects with subthreshold depression and mild-to-moderate depression: A monocentric, randomized, cross-over, double-blind, placebo-controlled clinical trial.

Depression is one of the most serious chronic psychiatric disorders affecting people worldwide. Subthreshold depression (SD) is a form of subclinical depression with increased risk of major depressive disorder (MDD). Patients diagnosed with SD may not be eligible for antidepressant drugs and, particularly in the case of MDD, these antidepressants may have adverse effects which outweigh their therapeutic effects, leading to discontinuation of therapy. Food supplements could provide an alternative strategy. The aim of this study is to demonstrate the efficacy of a food supplement based on a combination of S-adenosyl methionine (SAMe, 200 mg/day) and probiotics (Lactobacillus helveticus Rosell®-52, Bifidobacterium longum Rosell®-175, 3 ×109 CFU/day) in reducing depression symptoms in a monocentric, randomised, double-blind, placebo-controlled, cross-over clinical trial. 80 Subjects were recruited and offered the food supplement or placebo daily for three months, according to a cross-over clinical trial design, followed by a six-week follow-up period. The efficacy of the food supplement was measured by means of the "Hamilton Depression Rating Scale" (HAM-D) and "Patient Health Questionnaire-9" (PHQ-9), using a mixed analysis of variance model, with random intercept, for statistical analysis. The food supplement showed a significant decrease of PHQ-9 and HAM-D scores resulting in reduced SD and MDD symptoms as compared to placebo. In conclusion, the daily intake of the food supplement based on SAMe and probiotic strains for a period of three months is effective in improving the quality of life of SD subjects who are not eligible for antidepressant therapies, and patients suffering from mild-to-moderate depression who are not sensitive or cannot tolerate conventional drugs.

Spice-Derived Bioactive Compounds Confer Colorectal Cancer Prevention via Modulation of Gut Microbiota.

Colorectal cancer (CRC) is the second most frequent cause of cancer-related mortality among all types of malignancies. Sedentary lifestyles, obesity, smoking, red and processed meat, low-fiber diets, inflammatory bowel disease, and gut dysbiosis are the most important risk factors associated with CRC pathogenesis. Alterations in gut microbiota are positively correlated with colorectal carcinogenesis, as these can dysregulate the immune response, alter the gut's metabolic profile, modify the molecular processes in colonocytes, and initiate mutagenesis. Changes in the daily diet, and the addition of plant-based nutraceuticals, have the ability to modulate the composition and functionality of the gut microbiota, maintaining gut homeostasis and regulating host immune and inflammatory responses. Spices are one of the fundamental components of the human diet that are used for their bioactive properties (i.e., antimicrobial, antioxidant, and anti-inflammatory effects) and these exert beneficial effects on health, improving digestion and showing anti-inflammatory, immunomodulatory, and glucose- and cholesterol-lowering activities, as well as possessing properties that affect cognition and mood. The anti-inflammatory and immunomodulatory properties of spices could be useful in the prevention of various types of cancers that affect the digestive system. This review is designed to summarize the reciprocal interactions between dietary spices and the gut microbiota, and highlight the impact of dietary spices and their bioactive compounds on colorectal carcinogenesis by targeting the gut microbiota.

8-Hydroxy-2-Deoxyguanosine and 8-Iso-Prostaglandin F2α: Putative Biomarkers to assess Oxidative Stress Damage Following Robot-Assisted Radical Prostatectomy (RARP).

Objective: Prostate cancer (PCa) is the most common type of cancer. Biomarkers help researchers to understand the mechanisms of disease and refine diagnostic panels. We measured urinary 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-iso-prostaglandin F2α (8-IsoF2α) to assess oxidative stress damage in PCa patients undergoing robot-assisted radical prostatectomy (RARP). Methods: Forty PCa patients were enrolled in the study. Urine was collected before (T0) and 3 months after the RARP procedure (T1). 8-OHdG and 8-IsoF2α were measured through liquid chromatography-tandem mass spectrometry. Sex- and age-matched healthy subjects served as controls (CTRL). Results: At T0, patients exhibited significantly higher levels of 8-OHdG than CTRL (p = 0.026). At T1, 23/40 patients who completed the 3-month follow-up showed levels of 8-OHdG that were significantly lower than at T0 (p = 0.042), and comparable to those of the CTRL subjects (p = 0.683). At T0, 8-Iso-PGF2α levels were significantly higher in PCa patients than in CTRL subjects (p = 0.0002). At T1, 8-Iso-PGF2α levels were significantly lower than at T0 (p < 0.001) and were comparable to those of CTRL patients (p = 0.087). Conclusions: A liquid chromatography-tandem mass spectrometry method reveals enhanced OHdG and 8-Iso-PGF2α in the urine of PCa patients. RARP normalizes such indices of oxidative stress. Large-sized sample studies and long-term follow-ups are now needed to validate these urinary biomarkers for use in the early prevention and successful treatment of PCa.

The Efficacy of S-Adenosyl Methionine and Probiotic Supplementation on Depression: A Synergistic Approach.

Depression is a common and serious health issue affecting around 280 million people around the world. Suicidal ideation more frequently occurs in people with moderate to severe depression. Psychotherapy and pharmacological drugs are the mainstay of available treatment options for depressive disorders. However, pharmacological options do not offer complete cure, especially in moderate to severe depression, and are often seen with a range of adverse events. S-adenosyl methionine (SAMe) supplementation has been widely studied, and an impressive collection of literature published over the last few decades suggests its antidepressant efficacy. Probiotics have gained significant attention due to their wide array of clinical uses, and multiple studies have explored the link between probiotic species and mood disorders. Gut dysbiosis is one of the risk factors in depression by inducing systemic inflammation accompanied by an imbalance in neurotransmitter production. Thus, concomitant administration of probiotics may be an effective treatment strategy in patients with depressed mood, particularly in resistant cases, as these can aid in dysbiosis, possibly resulting in the attenuation of systemic inflammatory processes and the improvement of the therapeutic efficacy of SAMe. The current review highlights the therapeutic roles of SAMe and probiotics in depression, their mechanistic targets, and their possible synergistic effects and may help in the development of food supplements consisting of a combination of SAMe and probiotics with new dosage forms that may improve their bioavailability.

Volanesorsen to treat severe hypertriglyceridaemia: A pooled analysis of randomized controlled trials.

BACKGROUND: Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat subjects with sHTG. The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat sHTG. We performed a systematic review and meta-analysis of RCTs on the efficacy and safety of volanesorsen as compared to placebo treatment in patients with severe HTG. METHODS: Studies were systematically searched in the PubMed, Web of Science and Scopus databases according to PRISMA guidelines. The last search was performed on 7 February 2022. RESULTS: Four studies showed significant reduction in TG after 3 months of treatment with volanesorsen as compared with placebo (MD: -73.9%; 95%CI: -93.5%, -54.2; p < .001 I2  = 89.05%; p < .001); VLDL-C level (MD: -71.0%; 95%CI: -76.6%, -65.4%; p < .001 I2  = 94.1%; p < .001); Apo-B48 level (MD: -69.03%; 95%CI: -98.59.4%, -39.47%; p < .001, I2  = 93.51%; p < .001) and Apo-CIII level (MD: -80.0%; 95%CI: -97.5%, -62.5; p < .001 I2  = 94.1%; p < .001) with an increase in HDL-C level (MD: +45.92%, 95%CI: +37.24%, +54.60%; p < .001 I2  = 94.34%; p < .001) and in LDL-C level (MD: +68.6%, 95%CI: +7.0%, +130.1%; p < .001 I2  = 96.18%; p < .001) without a significant elevation of Apo-B100 level (MD: +4.58%, 95%CI: -5.64%, +14.79%; p = .380 I2  = 95.09%; p < .001) in 139 volanesorsen patients as compared to 100 placebo-treated controls. Most of adverse events were mild and related to local injection site reactions. CONCLUSIONS: In patients with severe HTG, volanesorsen is associated with a significant reduction in TG, VLDL-C, Apo-B48 and non-HDL-C and increment of HDL-C as compared to placebo. Documented efficacy is accompanied by an acceptable safety profile.

Challenges in Metabolomics-Based Tests, Biomarkers Revealed by Metabolomic Analysis, and the Promise of the Application of Metabolomics in Precision Medicine.

Metabolomics helps identify metabolites to characterize/refine perturbations of biological pathways in living organisms. Pre-analytical, analytical, and post-analytical limitations that have hampered a wide implementation of metabolomics have been addressed. Several potential biomarkers originating from current targeted metabolomics-based approaches have been discovered. Precision medicine argues for algorithms to classify individuals based on susceptibility to disease, and/or by response to specific treatments. It also argues for a prevention-based health system. Because of its ability to explore gene-environment interactions, metabolomics is expected to be critical to personalize diagnosis and treatment. Stringent guidelines have been applied from the very beginning to design studies to acquire the information currently employed in precision medicine and precision prevention approaches. Large, prospective, expensive and time-consuming studies are now mandatory to validate old, and discover new, metabolomics-based biomarkers with high chances of translation into precision medicine. Metabolites from studies on saliva, sweat, breath, semen, feces, amniotic, cerebrospinal, and broncho-alveolar fluid are predicted to be needed to refine information from plasma and serum metabolome. In addition, a multi-omics data analysis system is predicted to be needed for omics-based precision medicine approaches. Omics-based approaches for the progress of precision medicine and prevention are expected to raise ethical issues.

Oxylipin profile in saliva from patients with cystic fibrosis reveals a balance between pro-resolving and pro-inflammatory molecules.

Oxylipins are signaling molecules originated by fatty acids that modulate vascular and bronchial tone, bronchial secretion, cytokine production and immune cell activity. The unbalanced production of pro-inflammatory and pro-resolving (i.e., anti-inflammatory) oxylipins has a relevant role in the pathogenesis of pulmonary inflammation like in cystic fibrosis (CF). We analyzed by LC-MRM/MS 65 oxylipins and 4 fatty acids in resting saliva from 69 patients with CF and 50 healthy subjects (controls). The salivary levels of 48/65 oxylipins were significantly different between CF patients and controls. Among these, EpETE, DHET, 6ketoPGE1 and HDHA were significantly higher in saliva from CF patients than in controls. All these molecules display anti-inflammatory effects, i.e., releasing of bronchial and vascular tone, modulation of cytokine release. While 20-hydroxyPGF2A, PGB2, EpDPE, 9 K-12-ELA, bicyclo-PGE2, oleic acid, LTC4, linoleic acid, 15oxoEDE, 20 hydroxyPGE2 and DHK-PGD2/PGE2 (mostly associated to pro-inflammatory effects) resulted significantly lower in CF patients than in controls. Our data suggest that the salivary oxylipins profile in CF patients is addressed toward a global anti-inflammatory effect. Although these findings need be confirmed on larger populations in prospective studies, they will contribute to better understand the pathogenesis of CF chronic inflammation and to drive targeted therapies based on the modulation of oxylipins synthesis and degradation.

Natural Polyphenols for the Preservation of Meat and Dairy Products.

Food spoilage makes foods undesirable and unacceptable for human use. The preservation of food is essential for human survival, and different techniques were initially used to limit the growth of spoiling microbes, e.g., drying, heating, salting, or fermentation. Water activity, temperature, redox potential, preservatives, and competitive microorganisms are the most important approaches used in the preservation of food products. Preservative agents are generally classified into antimicrobial, antioxidant, and anti-browning agents. On the other hand, artificial preservatives (sorbate, sulfite, or nitrite) may cause serious health hazards such as hypersensitivity, asthma, neurological damage, hyperactivity, and cancer. Thus, consumers prefer natural food preservatives to synthetic ones, as they are considered safer. Polyphenols have potential uses as biopreservatives in the food industry, because their antimicrobial and antioxidant activities can increase the storage life of food products. The antioxidant capacity of polyphenols is mainly due to the inhibition of free radical formation. Moreover, the antimicrobial activity of plants and herbs is mainly attributed to the presence of phenolic compounds. Thus, incorporation of botanical extracts rich in polyphenols in perishable foods can be considered since no pure polyphenolic compounds are authorized as food preservatives. However, individual polyphenols can be screened in this regard. In conclusion, this review highlights the use of phenolic compounds or botanical extracts rich in polyphenols as preservative agents with special reference to meat and dairy products.

Long-Aged Parmigiano Reggiano PDO: Trace Element Determination Targeted to Health.

The concentrations of four health-related trace elements were measured using Atomic Absorption Spectroscopy in long-ripened (24- and 40-months) Parmigiano Reggiano (PR) PDO cheese, obtained from both summer and winter milk. To date, there are limited data on PR trace element concentrations, and no data about long-ripened cheese, especially when ripened for 40 months. Thus, the aim of this investigation is to determine chromium, manganese, selenium, and zinc concentrations, improving the available data on these trace elements and increasing knowledge of the biological properties of PR linked to their content in this cheese. The results show that 40-month ripened PR is a source of selenium and chromium, according to definitions under the European Regulation 1924/2006, as a 30 g cheese portion contains 11 ± 2 µg (summer milk) and 10 ± 1 µg (winter milk) of selenium and 8 ± 1 µg (summer and winter milk) of chromium, providing in excess of 8.25 and 6 µg per portion, respectively. This represents 15% of nutrient reference intake values for adults. These findings allow for the claim to be made that PR possesses the health properties ascribed to food sources of selenium and chromium according to European Regulation 432/2012.

RASopathies and hemostatic abnormalities: key role of platelet dysfunction.

BACKGROUND: Bleeding anomalies have been reported in patients affected by Noonan syndrome. No study has been performed in patients with molecularly confirmed RASopathy. We aimed to characterize the frequency and types of bleeding disorders in patients with RASopathies and evaluate any significant association with laboratory findings. PATIENTS AND METHODS: Forty-nine individuals (PTPN11, n = 27; SOS1, n = 7; RIT1, n = 3; SPRED1, n = 1; LZTR1, N = 3; RAF1, n = 2; BRAF, n = 4; MEK1, n = 1; MEK2, n = 1), and 49 age- and sex-matched controls were enrolled. The "Paediatric Bleeding Questionnaire Scoring Key" was administered to patients and families. Laboratory screening tests including clotting factors dosing, platelet count, Prothrombin Time and Partial Thromboplastin Time, were employed both in patients and controls to characterize the bleeding diathesis. A subgroup of 29/49 patients and 29/49 controls was also tested for platelet function. RESULTS: Regardless of the gene involved, pathological paediatric bleeding scores were recorded in 14/49 (28.5%) patients. Indeed, 7 were mutated in PTPN11, 3 in SOS1, 2 in RIT1, 1 in BRAF, and 1 in MEK1. Compared to patients with normal bleeding scores, those with pathologic bleeding score showed higher prevalence of splenomegaly (p = 0.006), prolonged aPTT (p = 0.04), lower levels of coagulation factor V (FV, p = 0.001), FVII (p = 0.003), FX (p = 0.0008) and FXIII (p = 0.002), higher vWAg (p = 0.04), and lower platelet sensitivity to Ristocetin (p = 0.001), arachidonic acid (AA) (p = 0.009) and collagen (p = 0.01). The presence of hematomas inversely correlated with factor V (p = 0.002), factor VII (p = 0.003), factor X (p = 0.002) and factor XIII (p = 0.004) levels, and directly correlated with platelet response to collagen (p = 0.02) and AA (p = 0.01). The presence of splenomegaly directly correlated with the presence of hematoma (p = 0.006), platelet response to Ristocetin (p = 0.04) and AA (p = 0.04), and inversely correlated with factor V levels (p = 0.03). CONCLUSIONS: Patients with RASopathies and a bleeding tendency exhibit multiple laboratory abnormalities, including platelet-related disorders. Splenomegaly is frequently detected and might be a suggestive sign for qualitative platelet dysfunction. A comprehensive clinical assessment should be carried out at diagnosis, during the follow-up and before any surgical procedures. Since there is currently no consensus on management of bleeding complications, it is important that physicians closely monitor these patients.

An Untargeted Lipidomic Analysis Reveals Depletion of Several Phospholipid Classes in Patients with Familial Hypercholesterolemia on Treatment with Evolocumab.

RATIONALE: Familial hypercholesterolemia (FH) is caused by mutations in genes involved in low-density lipoprotein cholesterol (LDL-C) metabolism, including those for pro-protein convertase subtilisin/kexin type 9 (PCSK-9). The effect of PCSK-9 inhibition on the plasma lipidome has been poorly explored. OBJECTIVE: Using an ultra-high-performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry method, the plasma lipidome of FH subjects before and at different time intervals during treatment with the PCSK-9 inhibitor Evolocumab was explored. METHODS AND RESULTS: In 25 FH subjects, heterozygotes or compound heterozygotes for different LDL receptor mutations, untargeted lipidomic revealed significant reductions in 26 lipid classes belonging to phosphatidylcholine (PC), sphingomyelin (SM), ceramide (CER), cholesteryl ester (CE), triacylglycerol (TG) and phosphatidylinositol (PI). Lipid changes were graded between baseline and 4- and 12-week treatment. At 12-week treatment, five polyunsaturated diacyl PC, accounting for 38.6 to 49.2% of total PC at baseline; two ether/vinyl ether forms; seven SM; five CER and glucosyl/galactosyl-ceramide (HEX-CER) were reduced, as was the unsaturation index of HEX-CER and lactosyl-CER (LAC-CER). Although non quantitative modifications were observed in phosphatidylethanolamine (PE) during treatment with Evolocumab, shorter and more saturated fatty acyl chains were documented. CONCLUSIONS: Depletion of several phospholipid classes occurs in plasma of FH patients during treatment with the PCSK-9 inhibitor Evolocumab. The mechanism underlying these changes likely involves the de novo synthesis of SM and CER through the activation of the key enzyme sphingomyelin synthase by oxidized LDL and argues for a multifaceted system leading to vascular improvement in users of PCSK-9 inhibitors.

Safety and efficacy of alpha-lipoic acid oral supplementation in the reduction of pain with unknown etiology: A monocentric, randomized, double-blind, placebo-controlled clinical trial.

INTRODUCTION: Extensive evidence suggests that alpha-lipoic acid (ALA) is effective in diabetic neuropathy pain management. However, little is known on its safety and efficacy in reducing idiopathic pain in normoglycemic subjects. The aim of this study was to evaluate ALA food supplement safety and efficacy in the reduction of different forms of idiopathic pain. METHODS: Two-hundred and ten normoglycemic adults suffering from idiopathic pain (i.e. 57 subjects with primitive neuropathic pain, 141 subjects with arthralgia with unknown etiology, and 12 subjects with idiopathic myalgia) were randomized to receive placebo, 400 mg/day, or 800 mg/day of ALA. Participants underwent two visits (at baseline = t0, and after 2 months = t1) in which two validated questionaries for pain (numerical rating scale [NRS] and visual analogue scale [VAS]) were collected; fasting blood glucose assessment, adverse effects, and renal and hepatic toxicity were also monitored. RESULTS: At t1, none of subjects treated with ALA reported a decreased glycemia or adverse effects. The treated subjects showed a significant reduction in NRS (p < 0.001) while the placebo group did not show any NRS reduction (p = 0.86). Similar results were also obtained for VAS. Statistical analysis aimed at detecting possible differences in NRS and VAS scores among treatment groups based on the source of pain did not reveal any significant effect. CONCLUSIONS: Since the management of idiopathic pain is challenging for physicians, the use of ALA food supplements could be a feasible option, based on its safety and efficacy compared to commonly-used analgesic drugs.

The Serum Metabolome of Moderate and Severe COVID-19 Patients Reflects Possible Liver Alterations Involving Carbon and Nitrogen Metabolism.

COVID-19 is a global threat that has spread since the end of 2019, causing severe clinical sequelae and deaths, in the context of a world pandemic. The infection of the highly pathogenetic and infectious SARS-CoV-2 coronavirus has been proven to exert systemic effects impacting the metabolism. Yet, the metabolic pathways involved in the pathophysiology and progression of COVID-19 are still unclear. Here, we present the results of a mass spectrometry-based targeted metabolomic analysis on a cohort of 52 hospitalized COVID-19 patients, classified according to disease severity as mild, moderate, and severe. Our analysis defines a clear signature of COVID-19 that includes increased serum levels of lactic acid in all the forms of the disease. Pathway analysis revealed dysregulation of energy production and amino acid metabolism. Globally, the variations found in the serum metabolome of COVID-19 patients may reflect a more complex systemic perturbation induced by SARS-CoV-2, possibly affecting carbon and nitrogen liver metabolism.