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Infertility represents a growing health problem in industrialized countries. Thus, a greater understanding of the molecular networks involved in this disease could be critical for the development of new therapies. A recent finding revealed that circadian rhythmicity disruption is one of the main causes of poor reproductive outcome. The circadian clock system beats circadian rhythms and modulates several physiological functions such as the sleep-wake cycle, body temperature, heart rate, and hormones secretion, all of which enable the body to function in response to a 24 h cycle. This intricated machinery is driven by specific genes, called “clock genes” that fine-tune body homeostasis. Stress of modern lifestyle can determine changes in hormone secretion, favoring the onset of infertility-related conditions that might reflect disfunctions within the hypothalamic–pituitary–gonadal axis. Consequently, the loss of rhythmicity in the suprachiasmatic nuclei might affect pulsatile sexual hormones release. Herein, we provide an overview of the recent findings, in both animal models and humans, about how fertility is influenced by circadian rhythm. In addition, we explore the complex interaction among hormones, fertility and the circadian clock. A deeper analysis of these interactions might lead to novel insights that could ameliorate the therapeutic management of infertility and related disorders.

Sex hormones are key determinants of gender-related differences and regulate growth and development during puberty. They also exert a broad range modulation of immune cell functions, and a dichotomy exists in the immune response between the sexes. Both clinical and animal models have demonstrated that androgens, estrogens, and progestogens mediate many of the gender-specific differences in immune responses, from the susceptibility to infectious diseases to the prevalence of autoimmune disorders. Androgens and progestogens mainly promote immunosuppressive or immunomodulatory effects, whereas estrogens enhance humoral immunity both in men and in women. This study summarizes the available evidence regarding the physiological effects of sex hormones on human immune cell function and the underlying biological mechanisms, focusing on gender differences triggered by different amounts of androgens between males and females.

Human blood has historically been considered a sterile environment. Recently, a thriving microbiome dominated by Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes phyla was detected in healthy blood. The localization of these microbes is restricted to some blood cell populations, particularly the peripheral blood mononuclear cells and erythrocytes. It was hypothesized that the blood microbiome originates from the skin–oral–gut axis. In addition, many studies have evaluated the potential of blood microbiome dysbiosis as a prognostic marker in cardiovascular diseases, cirrhosis, severe liver fibrosis, severe acute pancreatitis, type 2 diabetes, and chronic kidney diseases. The present review aims to summarize current findings and most recent evidence in the field.

Olive mill wastewater (OMWW), with its high level of phenolic compounds, simultaneously represents a serious environmental challenge and a great resource with potential nutraceutical activities. To increase the knowledge of OMWW’s biological effects, with an aim to developing a food supplement, we performed a chemical characterisation of the extract using the Liquid Chromatography–Quadrupole Time-of-flight spectrometry (LC–QTOF) and an in vitro genotoxicity/antigenotoxicity assessment on HepaRG ™ cells. Chemical analysis revealed that the most abundant phenolic compound was hydroxytyrosol. Biological tests showed that the extract was not cytotoxic at the lowest tested concentrations (from 0.25 to 2.5 mg/mL), unlike the highest concentrations (from 5 to 20 mg/mL). Regarding genotoxic activity, when tested at non-cytotoxic concentrations, the extract did not display any effect. Additionally, the lowest tested OMWW concentrations showed antigenotoxic activity (J-shaped dose–response effect) against a known mutagenic substance, reducing the extent of DNA damage in the co-exposure treatment. The antigenotoxic effect was also obtained in the post-exposure procedure, although only at the extract concentrations of 0.015625 and 0.03125 mg/mL. This behaviour was not confirmed in the pre-exposure protocol. In conclusion, the present study established a maximum non-toxic OMWW extract dose for the HepaRG cell model, smoothing the path for future research.

This review describes the complex interplay between inflammation, vasculopathy and fibrosis that involve the heart and peripheral small vessels, leading to endothelial stiffness, vascular damage, and early aging in patients with systemic lupus erythematosus and systemic sclerosis, which represents two different models of vascular dysfunction among systemic autoimmune diseases. In fact, despite the fact that diagnostic methods and therapies have been significantly improved in the last years, affected patients show an excess of cardiovascular mortality if compared with the general population. In addition, we provide a complete overview on the new techniques which are used for the evaluation of endothelial dysfunction in a preclinical phase, which could represent a new approach in the assessment of cardiovascular risk in these patients.

This study investigates the long-term trends (1992–2022) of nitrogen and phosphorus loadings exported by the River Po to the Adriatic Sea, to better analyse how changes in hydrology are affecting the timing and magnitude of river nutrient loads. We used 30 years of monitoring data in order to (a) identify the main temporal patterns and their interactions at a decadal, annual and seasonal scale, (b) estimate precipitation effects on load formation and evaluate whether and to which extent the hydrological regime affects nutrient export across the years and (c) analyse the nutrient export regime at a monthly scale and the main transport dynamic of N and P chemical species (hydrological vs. biogeochemical control). The long-term analysis shows a general decrease of both P and N loadings, but the trends are different between the elements and their chemical species, as well as undergoing different seasonal variations. We found a statistically significant relationships between precipitation and loads, which demonstrates that precipitation patterns drive the exported load at the intra- and interannual time scales considered in this study. Precipitation-induced load trends trigger seasonal changes in nutrient deliveries to the sea, peaking in spring and autumn. The nitrogen decrease is mainly concentrated in the summer dry period, while total phosphorus diminishes mainly in spring and autumn. This mismatch of N and P results in variable molar N:P ratios within the year. The effects of extreme drought and flood events, along with the progressive decrease in the snowmelt contribution to water fluxes, are expected to exacerbate the variability in the N and P loadings, which in turn is expected to perturbate the biodiversity, food webs and trophic state of the Northern Adriatic Sea.

VEXAS syndrome, a recently identified systemic autoinflammatory disorder, poses new diagnostic and management challenges. Based on experience with other autoinflammatory diseases, anti-interleukin (IL)-1, anti-IL-6, anti-tumor necrosis factor (TNF) biotechnological agents, and Janus kinase inhibitors (JAKis) have been widely employed in VEXAS patients. The aim of this study is to evaluate the global effectiveness and safety of biotechnological agents and JAKis using data from the real-world context. Clinical, laboratory, and therapeutic data from VEXAS patients were obtained from the international AIDA Network VEXAS registry. In total, 69 VEXAS patients were enrolled in the study. Among them, 12 patients (13 treatment courses) received IL-1 inhibitors, 12 patients (13 treatment courses) were administered anti-IL-6 agents, 8 patients (9 treatment courses) were treated with anti-TNF agents, and 16 patients (17 treatment courses) were treated with JAKis. A complete response was observed in 3 patients (23%) treated with anti-IL-1 agents, 2 patients (15%) receiving IL-6 inhibitors, 1 patient (11%) receiving TNF inhibitors, and 4 patients (23.5%) treated with JAKis. The mean prednisone (or equivalent) dosage significantly decreased during anti-IL-1 treatment (p = 0.01), while glucocorticoids changed during anti-IL-6, anti-TNF, and JAKi treatment in a non-significant fashion. A total of 21 patients experienced adverse events, 3 of which led to death (gut perforation, Legionnaires' disease, and infectious pneumonia) while on JAKis; treatment withdrawal was required for 8 out of 21 patients. IL-1 and IL-6 inhibitors, along with JAKis, represent promising therapeutic options for VEXAS patients, albeit careful monitoring is mandatory to control disease activity and ensure safety.

How systemic sclerosis starts impacts how the disease will behave Systemic sclerosis (SSc) is a rare autoimmune disease that affects the skin and internal organs. In most cases the disease starts with Raynaud’s phenomenon (RP), a discolouring of the fingers in reaction to cold temperatures; some other patients may experience different symptoms first, such as joint pain, skin changes or shortness of breath. Understanding which symptom appears first, and at what age, may help doctors identify patients who are more likely to develop severe disease. This study included 1,748 SSc patients enrolled in the Italian SPRING-SIR registry, divided patients into three groups: those who first developed RP (RP group), those who developed RP and other symptoms in the same year (Simultaneous), and those who developed non-RP symptoms first (NRP group). We found that patients in the RP group were younger at disease onset and often had milder disease. Patients in the Simultaneous group were more likely to develop diffuse skin disease, lung complications, and had a higher risk of death. Patients in the NRPgroup were rare but often had aggressive involvement of heart and lung. Overall, our results show that the timing of RP and non-RP symptoms can help predict disease course and survival in SSc. These findings may help doctors recognize higher-risk patients earlier and provide closer monitoring and tailored treatments.

Background: Hormonal changes in menopause might interact with the presentation of underlying autoimmune diseases, such as systemic sclerosis (SSc). Objectives: Our study aimed to evaluate the association of (1) current menopausal status, (2) early menopause, and (3) disease onset during fertile or post-menopausal age on SSc clinical phenotype in a large SSc cohort from the Italian Systemic sclerosis Progression INvestiGation (SPRING-SIR) registry. Design: Female SSc patients from the SPRING-SIR registry, fulfilling the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 classification criteria, with data on SSc disease onset, menopausal status, and menopausal age, were eligible. SSc onset was categorized as pre-menopausal if SSc onset happened >1 year before menopause or as post-menopausal onset if it occurred >1 year after menopause. An early menopause was defined by a menopausal age <45 years. Methods: Descriptive statistics and regression models were built to test the association between current menopausal status, pre-menopausal disease onset, and early menopause with SSc-related features. Results: At baseline, 1157/1538 (75%) patients were in menopause, 632 (50.4%) had a pre-menopausal SSc onset, and 130 (14.4%) reported an early menopause. Post-menopausal patients had more frequent limited cutaneous SSc, anti-centromere antibody positivity, interstitial lung disease, and gastrointestinal manifestations. Pre-menopausal onset cases showed more frequent diffuse cutaneous involvement and peripheral vasculopathy. Patients with early menopause had more frequent peripheral vasculopathy and interstitial lung disease, being early menopause an independent risk factor for digital ulcers and lower diffusing capacity of the lung for carbon monoxide. Conclusion: Current post-menopausal status and early menopause may impact SSc presentation, being associated with vascular and gastrointestinal manifestations. Menopausal status and age should therefore be thoroughly addressed, aiming at better disease management.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an adult-onset autoinflammatory condition resulting in severe, often treatment-refractory inflammation. Currently, there are no established treatment guidelines for VEXAS syndrome. To assess the efficacy and safety of conventional disease-modifying antirheumatic drugs (cDMARDs) in a cohort of VEXAS patients. Data from VEXAS patients were obtained from the International AIDA Network VEXAS registry. Data from 36 VEXAS patients were evaluated, with 28 (77.8%) treated with cDMARDs as monotherapy - and concomitant glucocorticoids (GC) - and 8 (22.2%) receiving a combination of different cDMARDs plus GC. Complete response (CR), partial response (PR), and failure to cDMARDs monotherapy were reported in 4/22 (18.2%), 11/22 (50%), and 7/22 (31.8%) courses, respectively. All patients were treated with GCs at the start of cDMARD monotherapy, and no GC discontinuation was observed later. No significant differences were observed in the GC dosage from the start of cDMARDs to the 3-month ( = 0.43), 6-month ( = 0.31), and 12-month ( = 0.21) visits. Conversely, the GC sparing resulted to be statistically significant when using methotrexate ( = 0.02). As for cDMARDs combinations, no cases achieved CR, while PR was observed in 5/9 (55.6%). Seventeen adverse events were reported, seven of which led to discontinuation. Many VEXAS patients report a partial benefit from cDMARDs, while a smaller yet not negligible number of patients exhibit a CR; cDMARDs remain a viable option for this disorder, especially when the initial GC dosage is low and the need for a steroid-sparing effect is not immediately urgent.