Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?

MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.

L-arginine mitigates bleomycin-induced pulmonary fibrosis in rats through regulation of HO-1/PPAR-γ/ß-catenin axis.

Pulmonary fibrosis is a chronic and progressively deteriorating lung condition that can be replicated in laboratory animals by administering bleomycin, a chemotherapeutic antibiotic known for its lung fibrosis-inducing side effects. L-arginine, a semi-essential amino acid, is recognized for its diverse biological functions, including its potential to counteract fibrosis. This study aimed to evaluate the antifibrotic properties of L-arginine on bleomycin-induced pulmonary fibrosis in rats. The administration of a single intratracheal dose of bleomycin resulted in visible and microscopic damage to lung tissues, an uptick in oxidative stress markers, and an elevation in inflammatory, apoptotic, and fibrotic indicators. A seven-day treatment with L-arginine post-bleomycin exposure markedly improved the gross and histological architecture of the lungs, prevented the rise of malondialdehyde and carbonyl content, and enhanced total antioxidant capacity alongside the activities of antioxidant enzymes. Also, L-arginine attenuated the expression of the pro-fibrotic factors, transforming growth factor-ß and lactate dehydrogenase in bronchoalveolar lavage fluid. In the lung tissue, L-arginine reduced collagen deposition, hydroxyproline concentration, and mucus production, along with decreasing expression of α-smooth muscle actin, tumor necrosis factor-α, caspase-3, matrix metalloproteinase-9, and ß-catenin. Moreover, it boosted levels of nitric oxide and upregulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), heme oxygenase-1 (HO-1), and E-cadherin and downregulating the expression of ß-catenin. These findings suggest that L-arginine has preventive activities against bleomycin-induced pulmonary fibrosis. This effect can be attributed to the increased production of nitric oxide, which modulates the HO-1/PPAR-γ/ß-catenin axis.

Assessment of the treatment effectiveness of men with mild and medium degree of erectile dysfunction.

OBJECTIVE: . Aim: To assess the effectiveness of monotherapy and complex treatment of patients with erectile dysfunction depending on its severity. PATIENTS AND METHODS: Materials and Methods: Men with moderate and mild erectile dysfunction took part in the study, who, in turn, were divided into groups, depending on the treatment, with the evaluation of the results of the International Index of Erectile Function (MIEF-15), the state of cavernous hemodynamics and the function of the vascular endothelium before and after treatment. RESULTS: Results: In patients with an average degree of severity, who received complex treatment including a course of low-energy shock wave therapy, against the background of taking sildenafil and L-arginine, the best results were obtained in the quality of erection and increased cavernous blood flow, which positively affected satisfaction with sexual intercourse and overall satisfaction. It has also been proven that the function of the endothelium was improved in patients receiving L-arginine, due to which there was a probable decrease in endothelin-1. A probable improvement of erectile function was obtained in the group of patients with a mild degree who received L-arginine, and there was no statistical difference from the indicators in the group who received sildenafil, which was confirmed by the data of dopplerography. CONCLUSION: Conclusions: Patients with an average degree of erectile dysfunction require comprehensive treatment. The use of L-arginine can be an alternative to phosphodiesterase type 5 inhibitors in the treatment of mild erectile dysfunction.

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial.

Importance: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. Objective: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. Design, Setting, and Participants: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. Intervention: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. Main Outcomes and Measures: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. Results: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo). Conclusions and Relevance: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. Trial Registration: ClinicalTrials.gov Identifier: NCT02709512.

Impact of citrulline substitution on clinical outcome after liver transplantation in carbamoyl phosphate synthetase 1 and ornithine transcarbamylase deficiency.

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.

Arginine-Nanoenzyme with Timely Angiogenesis for Promoting Diabetic Wound Healing.

The successful treatment of diabetic wounds requires strategies that promote anti-inflammation, angiogenesis, and re-epithelialization of the wound. Excessive oxidative stress in diabetic ulcers (DUs) inhibits cell proliferation and hinders timely vascular formation and macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2, resulting in a persistent inflammatory environment and a nonhealing wound. We designed arginine-nanoenzyme (FTA) with mimic-catalase and arginine-loading. 2,3,4-trihydroxy benzaldehyde and arginine (Arg) were connected by a Schiff base bond, and the nanoassembly of Arg to FTA was driven by the coordination force between a ferric ion and polyphenol and noncovalent bond force such as a hydrogen bond. FTA could remove excess reactive oxygen species at the wound site in situ and convert it to oxygen to improve hypoxia. Meanwhile, Arg was released and catalytically metabolized by NO synthase in M1 to promote vascular repair in the early phase. In the late phase, the metabolite of Arg catalyzed by arginase in M2 was mainly ornithine, which played a vital role in promoting tissue repair, which implemented angiogenesis timely and prevented hypertrophic scars. Mechanistically, FTA activated the cAMP signaling pathway combined with reducing inflammation and ameliorating angiogenesis, which resulted in excellent therapeutic effects on a DU mice model.

Effect of topical application of ibuprofen/arginine on the in-office bleaching-induced tooth sensitivity: A randomized, triple-blind controlled trial.

OBJECTIVE: The application of anti-inflammatories as topical desensitizers before dental bleaching is an approach to reduce bleaching-induced tooth sensitivity (TS). This randomized controlled trial compared the risk and intensity of TS and the color change resulting from in-office dental bleaching after using an experimental desensitizing gel containing ibuprofen and arginine. METHODS: Sixty-two participants with upper canine shades A2 or darker were randomly assigned to either the ibuprofen-arginine desensitizing group or the placebo group. The desensitizing gel was applied for 15 min before in-office bleaching with 35 % hydrogen peroxide gel for 50 min (2 sessions). To assess the absolute risk and intensity of TS, visual (0-10) and numeric rating (0-5) scales were used, and group comparisons were made using the McNemar test, Wilcoxon test, and paired Student t-test (α = 0.05). Color change was evaluated using Vita Classical, Vita Bleachedguide (ΔSGU), and Vita EasyShade (ΔEab, ΔE00, and ΔWID) before and one month after the bleaching procedure. Group comparisons for color change were done using a paired t-test (α = 0.05). RESULTS: The odds ratio for TS was 0.14 [95 % CI 0.02 to 0.6], meaning lower odds of TS for the desensitizing gel. A lower intensity of TS was also observed for the experimental group (p < 0.005) up to 48 h after bleaching. All color evaluation tools demonstrated effective and similar whitening for both groups (p > 0.05). CONCLUSIONS: Using the experimental desensitizing gel containing ibuprofen and arginine effectively reduced the risk and intensity of TS without compromising the bleaching efficacy. CLINICAL RELEVANCE: The topical application of ibuprofen/arginine on the in-office bleaching reduced risk and intensity of bleaching-induced tooth sensitivity.

Dual-Fuel Propelled Nanomotors with Two-Stage Permeation for Deep Bacterial Infection in the Treatment of Pulpitis.

Bacterial infection-induced inflammatory response could cause irreversible death of pulp tissue in the absence of timely and effective therapy. Given that, the narrow structure of root canal limits the therapeutic effects of passive diffusion-drugs, considerable attention has been drawn to the development of nanomotors, which have high tissue penetration abilities but generally face the problem of insufficient fuel concentration. To address this drawback, dual-fuel propelled nanomotors (DPNMs) by encapsulating L-arginine (L-Arg), calcium peroxide (CaO2 ) in metal-organic framework is developed. Under pathological environment, L-Arg could release nitric oxide (NO) by reacting with reactive oxygen species (ROS) to provide the driving force for movement. Remarkably, the depleted ROS could be supplemented through the reaction between CaO2 with acids abundant in the inflammatory microenvironment. Owing to high diffusivity, NO achieves further tissue penetration based on the first-stage propulsion of nanomotors, thereby removing deep-seated bacterial infection. Results indicate that the nanomotors effectively eliminate bacterial infection based on antibacterial activity of NO, thereby blocking inflammatory response and oxidative damage, forming reparative dentine layer to avoid further exposure and infection. Thus, this work provides a propagable strategy to overcome fuel shortage and facilitates the therapy of deep lesions.

Modulatory effects of supplementation of Lentinula edodes mycelia extract and l-arginine on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice.

Some chemotherapeutic drugs can induce cancer cell death and enhance antitumor T-cell immunity in cancer-bearing hosts. Immunomodulatory reagents could augment such chemotherapy-induced effects. We previously reported that oral digestion of Lentinula edodes mycelia (L.E.M.) extract or  l-arginine supplementation can augment antitumor T-cell responses in cancer-bearing mice. In this study, the effects of L.E.M. extract with or without  l-arginine on the therapeutic efficacy of immunogenic chemotherapy by 5-fluorouracil (5-FU)/oxaliplatin (L-OHP) and/or cyclophosphamide (CP) are examined using two mouse colon cancer models. In MC38 and CT26 cancer models, therapy with 5-FU/L-OHP/CP significantly suppressed tumor growth, and supplementation with L.E.M. extract halved the tumor volumes. However, the modulatory effect of L.E.M. extract was not significant. In the CT26 cancer model, supplementation with L.E.M. extract and  l-arginine had no clear effect on tumor growth. In contrast, their addition to chemotherapy halved the tumor volumes, although the effect was not significant. There was no difference in the cytotoxicity of tumor-specific cytotoxic T cells generated from CT26-cured mice treated by chemotherapy alone versus chemotherapy combined with L.E.M. extract/ l-arginine. These results indicate that the antitumor effects of immunogenic chemotherapy were too strong to ascertain the effects of supplementation of L.E.M. extract and  l-arginine, but these reagents nonetheless have immunomodulatory effects on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice.

Promising role of protein arginine methyltransferases in overcoming anti-cancer drug resistance.

Drug resistance remains a major challenge in cancer treatment, necessitating the development of novel strategies to overcome it. Protein arginine methyltransferases (PRMTs) are enzymes responsible for epigenetic arginine methylation, which regulates various biological and pathological processes, as a result, they are attractive therapeutic targets for overcoming anti-cancer drug resistance. The ongoing development of small molecules targeting PRMTs has resulted in the generation of chemical probes for modulating most PRMTs and facilitated clinical treatment for the most advanced oncology targets, including PRMT1 and PRMT5. In this review, we summarize various mechanisms underlying protein arginine methylation and the roles of specific PRMTs in driving cancer drug resistance. Furthermore, we highlight the potential clinical implications of PRMT inhibitors in decreasing cancer drug resistance. PRMTs promote the formation and maintenance of drug-tolerant cells via several mechanisms, including altered drug efflux transporters, autophagy, DNA damage repair, cancer stem cell-related function, epithelial-mesenchymal transition, and disordered tumor microenvironment. Multiple preclinical and ongoing clinical trials have demonstrated that PRMT inhibitors, particularly PRMT5 inhibitors, can sensitize cancer cells to various anti-cancer drugs, including chemotherapeutic, targeted therapeutic, and immunotherapeutic agents. Combining PRMT inhibitors with existing anti-cancer strategies will be a promising approach for overcoming anti-cancer drug resistance. Furthermore, enhanced knowledge of the complex functions of arginine methylation and PRMTs in drug resistance will guide the future development of PRMT inhibitors and may help identify new clinical indications.

Bioactive glass and arginine dentifrices reduce root sensitivity during daily activities following non-surgical periodontal therapy: A randomized controlled trial.

BACKGROUND: Evidence on the efficacy of calcium sodium phosphosilicate (CSPS) and arginine dentifrices on reducing root sensitivity (RS) following non-surgical periodontal therapy (NSPT) is limited. The aim of this study was to compare the efficacy of these dentifrices in reducing RS during daily activities in patients undergoing NSPT. METHODS: Using a double-blind randomized controlled trial, CSPS, arginine, or control dentifrices were randomly assigned to 45 RS individuals following NSPT. The participants used the dentifrices 2×/day for 8 weeks. A self-reported visual analog scale (VAS) was assessed during daily activities. RESULTS: Self-reported VAS scores were similar among the three groups at each time point. The with-in group analysis revealed that the arginine dentifrice reduced RS from Week 1-8 compared with baseline in response to cold. Similarly, the CSPS dentifrice reduced RS at Week 4 and 8. The CSPS and arginine dentifrices exhibited RS relief resulting from toothbrushing starting at Week 4 and 2, respectively. In response to air, RS relief was observed from Week 4 in the arginine group. The number of patients with VAS > 2 in response to cold declined at Week 2 and 4 in the CSPS and arginine groups, respectively. In response to toothbrushing, only 10% in the test groups still had RS at Week 8. In response to air, the number of RS patients only in the arginine group decreased at Week 4. CONCLUSION: The CSPS and arginine dentifrices provided comparable RS relief during daily activities within 2-4 weeks and remained effective up to 8 weeks.

The Emerging Role of Prediabetes and Its Management: Focus on L-Arginine and a Survey in Clinical Practice.

The worldwide impressive growth of metabolic disorders observed in the last decades, especially type 2 diabetes mellitus and obesity, has generated great interest in the potential benefits of early identification and management of patients at risk. In this view, prediabetes represents a high-risk condition for the development of type 2 diabetes mellitus and cardiovascular diseases, and an ideal target to intercept patients before they develop type 2 diabetes gaining a prominent role even in international guidelines. For prediabetic individuals, lifestyle modification is the cornerstone of diabetes prevention, with evidence of about 50% relative risk reduction. Accumulating data also show potential benefits from pharmacotherapy. In this context, the only available data pertain to metformin as a pharmaceutical drug and vitamin D and L-arginine as nutraceuticals. L-arginine appears to be a very interesting tool in the clinical management of patients with pre-diabetes. In this review we summarize the current knowledge on the role of L-arginine in prediabetes as a potentially useful preventive strategy against the progression to type 2 diabetes, with a particular focus on the underlying molecular mechanisms and the past and ongoing trials. In this article we also report the interesting data about the perception of the prediabetic condition and its therapeutic management in the clinical practice in Italy. An early identification and a prompt management of people with prediabetes appears to be of paramount importance to prevent the progression to diabetes and avoid its cardiovascular consequences.

Efficacy of L-arginine and Pycnogenol ® in the treatment of male erectile dysfunction: a systematic review and meta-analysis.

Background: The objective of this meta-analysis was to review clinical trials of the combination of Pycnogenol ® and L-arginine (PAL) in the treatment of erectile dysfunction in men and to observe the effect of PAL combined therapy on sexual function in patients with erectile dysfunction (ED), and we hope to provide more choices of drugs for treating patients with ED. Methods and analysis: The study was constructed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We searched seven databases from inception to 15 February 2023, for a comprehensive search of clinical trials using relevant keywords. Continuous variables in this meta-analysis were calculated using the mean difference and 95% confidence interval. All relevant statistical analyses were performed using RevMan v. 5.4 software. Results: Three studies with 184 patients were included in the present meta-analysis. There were no significant differences in the basic characteristics of the included studies. The results of the current meta-analysis showed that there were significant differences in the international index of erectile function scores (erectile domain), intercourse satisfaction scores, orgasmic function scores, overall satisfaction scores, and sexual desire scores between the combination treatment group and the control group. There was no significant difference in improving the testosterone levels between the two groups. Conclusion: These results indicate that the combination of PAL may have a significant effect on improving sexual function in patients with mild to moderate ED. This study will provide clinicians with more options for treating patients with ED. More randomized controlled trials are needed in the future to further demonstrate the effect of combination therapy on sexual function in patients with ED. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#myprosperoUnique, Identifier: CRD42023411781.

Enteral citrulline supplementation versus placebo on SOFA score on day 7 in mechanically ventilated critically ill patients: the IMMUNOCITRE randomized clinical trial.

BACKGROUND: Restoring plasma arginine levels through enteral administration of L-citrulline in critically ill patients may improve outcomes. We aimed to evaluate whether enteral L-citrulline administration reduced organ dysfunction based on the Sequential Organ Failure Assessment (SOFA) score and affected selected immune parameters in mechanically ventilated medical intensive care unit (ICU) patients. METHODS: A randomized, double-blind, multicenter clinical trial of enteral administration of L-citrulline versus placebo for critically ill adult patients under invasive mechanical ventilation without sepsis or septic shock was conducted in four ICUs in France between September 2016 and February 2019. Patients were randomly assigned to receive enteral L-citrulline (5 g) every 12 h for 5 days or isonitrogenous, isocaloric placebo. The primary outcome was the SOFA score on day 7. Secondary outcomes included SOFA score improvement (defined as a decrease in total SOFA score by 2 points or more between day 1 and day 7), secondary infection acquisition, ICU length of stay, plasma amino acid levels, and immune biomarkers on day 3 and day 7 (HLA-DR expression on monocytes and interleukin-6). RESULTS: Of 120 randomized patients (mean age, 60 ± 17 years; 44 [36.7%] women; ICU stay 10 days [IQR, 7-16]; incidence of secondary infections 25 patients (20.8%)), 60 were allocated to L-citrulline and 60 were allocated to placebo. Overall, there was no significant difference in organ dysfunction as assessed by the SOFA score on day 7 after enrollment (4 [IQR, 2-6] in the L-citrulline group vs. 4 [IQR, 2-7] in the placebo group; Mann‒Whitney U test, p = 0.9). Plasma arginine was significantly increased on day 3 in the treatment group, while immune parameters remained unaffected. CONCLUSION: Among mechanically ventilated ICU patients without sepsis or septic shock, enteral L-citrulline administration did not result in a significant difference in SOFA score on day 7 compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02864017 (date of registration: 11 August 2016).

Untargeted and Targeted Metabolomics Reveal the Active Peptide of Eupolyphaga sinensis Walker against Hyperlipidemia by Modulating Imbalance in Amino Acid Metabolism.

The active peptide (APE) of Eupolyphaga sinensis Walker, which is prepared by bioenzymatic digestion, has significant antihyperlipidemic effects in vivo, but its mechanism of action on hyperlipidemia is not clear. Recent studies on amino acid metabolism suggested a possible link between it and hyperlipidemia. In this study, we first characterized the composition of APE using various methods. Then, the therapeutic effects of APE on hyperlipidemic rats were evaluated, including lipid levels, the inflammatory response, and oxidative stress. Finally, the metabolism-regulating mechanisms of APE on hyperlipidemic rats were analyzed using untargeted and targeted metabolomic approaches. The results showed that APE significantly reduced the accumulation of fat, oxidative stress levels, and serum pro-inflammatory cytokine levels. Untargeted metabolomic analysis showed that the mechanism of the hypolipidemic effect of APE was mainly related to tryptophan metabolism, phenylalanine metabolism, arginine biosynthesis, and purine metabolism. Amino-acid-targeted metabolomic analysis showed that significant differences in the levels of eight amino acids occurred after APE treatment. Among them, the expression of tryptophan, alanine, glutamate, threonine, valine, and phenylalanine was upregulated, and that of arginine and proline was downregulated in APE-treated rats. In addition, APE significantly downregulated the mRNA expression of SREBP-1, SREBP-2, and HMGCR. Taking these points together, we hypothesize that APE ameliorates hyperlipidemia by modulating amino acid metabolism in the metabolome of the serum and feces, mediating the SREBP/HMGCR signaling pathway, and reducing oxidative stress and inflammation levels.

Joint analysis of the metabolomics and transcriptomics uncovers the dysregulated network and develops the diagnostic model of high-risk neuroblastoma.

High-risk neuroblastoma (HR-NB) has a significantly lower survival rate compared to low- and intermediate-risk NB (LIR-NB) due to the lack of risk classification diagnostic models and effective therapeutic targets. The present study aims to characterize the differences between neuroblastomas with different risks through transcriptomic and metabolomic, and establish an early diagnostic model for risk classification of neuroblastoma.Plasma samples from 58 HR-NB and 38 LIR-NB patients were used for metabolomics analysis. Meanwhile, NB tissue samples from 32 HR-NB and 23 LIR-NB patients were used for transcriptomics analysis. In particular, integrative metabolomics and transcriptomic analysis was performed between HR-NB and LIR-NB. A total of 44 metabolites (P < 0.05 and fold change > 1.5) were altered, including 12 that increased and 32 that decreased in HR-NB. A total of 1,408 mRNAs (P < 0.05 and |log2(fold change)|> 1) showed significantly altered in HR-NB, of which 1,116 were upregulated and 292 were downregulated. Joint analysis of both omic data identified 4 aberrant pathways (P < 0.05 and impact ≥ 0.5) consisting of glycerolipid metabolism, retinol metabolism, arginine biosynthesis and linoleic acid metabolism. Importantly, a HR-NB risk classification diagnostic model was developed using plasma circulating-free S100A9, CDK2, and UNC5D, with an area under receiver operating characteristic curve of 0.837 where the sensitivity and specificity in the validation set were both 80.0%. This study presents a novel pioneering study demonstrating the metabolomics and transcriptomics profiles of HR-NB. The glycerolipid metabolism, retinol metabolism, arginine biosynthesis and linoleic acid metabolism were altered in HR-NB. The risk classification diagnostic model based on S100A9, CDK2, and UNC5D can be clinically used for HR-NB risk classification.

Dietary Supplements for Erectile Dysfunction: Analysis of Marketed Products, Systematic Review, Meta-Analysis and Rational Use.

The use of nutraceutical products to enhance male sexual performance has a long history, especially with regard to the treatment of erectile dysfunction (ED). Alternative treatments for ED are becoming increasingly popular, with growing interest from consumers, as well as increased revenue for manufacturers. Dietary supplements (DSs), which are a mixture of active ingredients, are mainly sold online. In randomized controlled trials, the molecules contained in DSs have demonstrated varying degrees of effectiveness, or even have no evidence to support their use. However, none of the studies carried out provided sufficient evidence to consider these products a first-line therapy. Therefore, the combination of the various active ingredients, especially in relation to the daily dose, leaves doubts about the real effectiveness. In order to evaluate the potential efficacy of DS formulations, we analyzed the products marketed in Italy using a scoring approach. A systematic review of the literature was performed to evaluate the effect of DS and to detect the active ingredients able to improve erectile function-called effective ingredients (EIs)-and their minimal effective daily dose (mED). A metanalysis identified some nutraceuticals, such as Panax ginseng, Tribulus terrestris and L-arginine, that are able to improve male sexual function. Based on the scoring system, 2 (8%) supplements matched with the cluster of higher expected efficacy, 3 (12%) with the lower efficacy cluster and 20 (80%) matched with the criterion of no expected efficacy. DSs marketed in Italy are usually blends of many substances that are frequently employed at a negligible dose or without any evidence.

TREATMENT OPTIMIZATION IN MANAGEMENT OF COMBINED PATHOLOGY - ARTERIAL HYPERTENSION AND POST-COVID SYNDROME IN ELDERLY PATIENTS.

OBJECTIVE: The aim: Purpose of the study. Our research is aimed at the increase in the treatment effectiveness for combined pathology, namely, arterial hypertension (AH) and post-COVID syndrome in elderly patients at the stage of providing medical care by family medicine general practitioners with the use of statins, anti¬platelet agents, as well as endothelial-protective drug - L-arginine and anxiolytic effect - mebicar against the background of basic antihypertensive therapy. PATIENTS AND METHODS: Materials and methods: The study included treatment and observation of 50 elderly patients with hypertension and post-COVID syndrome. The average age was 68.7«1.89 years. RESULTS: Results: The use of mebicar with moderate tranquilizing (anxiolytic) effect and endothelium-protector - L-arginine in the comprehensive treatment of elderly patients with combined pathology - AH and post-COVID syndrome contributed to the elimination of the main clinical symptoms (headache, poor sleep) in a shorter time; provided significant decrease in the level of systolic blood pressure, reactive anxiety, the decrease in total blood cholesterol, and improvement in blood rheology. CONCLUSION: Conclusions: Treatment optimization for combined pathology - arterial hypertension and post-COVID syndrome in elderly patients with the use of L-arginine and mebicar in comprehensive treatment, improves the quality of patients' life, reduces the treatment duration.