Natural Sulfur-Containing Compounds: An Alternative Therapeutic Strategy against Liver Fibrosis

Liver fibrosis is a pathophysiologic process involving the accumulation of extracellular matrix proteins as collagen deposition. Advanced liver fibrosis can evolve in cirrhosis, portal hypertension and often requires liver transplantation. At the cellular level, hepatic fibrosis involves the activation of hepatic stellate cells and their transdifferentiation into myofibroblasts. Numerous pro-fibrogenic mediators including the transforming growth factor-β1, the platelet-derived growth factor, endothelin-1, toll-like receptor 4, and reactive oxygen species are key players in this process. Knowledge of the cellular and molecular mechanisms underlying hepatic fibrosis development need to be extended to find novel therapeutic strategies. Antifibrotic therapies aim to inhibit the accumulation of fibrogenic cells and/or prevent the deposition of extracellular matrix proteins. Natural products from terrestrial and marine sources, including sulfur-containing compounds, exhibit promising activities for the treatment of fibrotic pathology. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans are largely unknown. This review aims to provide a reference collection on experimentally tested natural anti-fibrotic compounds, with particular attention on sulfur-containing molecules. Their chemical structure, sources, mode of action, molecular targets, and pharmacological activity in the treatment of liver disease will be discussed

Antioxidant and immune response of the sea urchin Paracentrotus lividus to different re-suspension patterns of highly polluted marine sediments

Marine pollution due to disused industrial activities is a major threat to ecosystems and human health, for example through the effects of re-suspension of toxic substances that are present in contaminated sediments. Here, we examined the effects of different re-suspension patterns of polluted sediments from the site of national interest Bagnoli-Coroglio, on the immune system of the sea urchin Paracentrotus lividus. An indoor experiment was set up exposing sea urchins for 34 days to such sediments and evaluating the effects of two patterns of water turbulence, mimicking natural storms at sea. One group of animals experienced an “aggregated” pattern of turbulence, consisting in two events, each lasting 2 days, separated by only 3 calm days, while a second group experienced two events of turbulence separated by 17 calm days (spaced pattern). At different times from the beginning of the experiment, coelomic fluid was collected from the animals and immune cells were examined for cell count and morphology, oxidative stress variables, and expression of genes involved in metal detoxification, stress response and inflammation. Our results highlighted that the aggregated pattern of turbulence was more noxious for sea urchins. Indeed, their immune system was altered, over the exposure time, as indicated by the increase of red amoebocytes number. Moreover, despite of an increase of the antioxidant power, animals from this group displayed a very significant ROS over-production at the end of the experiment. Conversely, animals in the spaced condition activated a different immune response, mainly having phagocytes as actors, and were able to partially recover from the received stress at the end of the experiment. No changes in the expression of genes related to antioxidant and anti-inflammatory responses were observed in both groups. By contrast, a down-regulation of various metallothioneins (4, 6, 7 and 8) in the group subjected to aggregated pattern was observed, while metallothionein 8 was up-regulated in the animals from the group exposed to the spaced pattern of turbulence. This work provides the first evidence of how sea urchins can respond to different re-suspension patterns of polluted sediments by modulating their immune system functions. The present data are relevant in relation to the possible environmental restoration of the study site, whose priorities include the assessment of the effects of marine pollution on local organisms, among which P. lividus represents a key benthic species

A king and vassals' tale: Molecular signatures of clonal integration in Posidonia oceanica under chronic light shortage

Under unfavourable conditions, clonal plants benefit from physiological integration among ramets, sharing resources and information. Clonal integration can buffer against environmental changes and lets the plant clone work as a ‘macro’ organism. Molecular signals that regulate this phenomenon are completely unknown in marine plants. Here we present a first comprehensive study providing insights into the metabolic role of different types of ramets (i.e. apical vs. vertical) in the foundation species Posidonia oceanica. Plants were exposed to 80% diminishing irradiance level (LL) in a controlled mesocosm system. Subsequent multiscale variations in whole transcriptome expression, global DNA methylation level, photo-physiology, morphology and fitness-related traits, were explored at different exposure times. We tested the hypothesis that vertical shoots (the ‘vassals’) can provide vital resources to apical shoots (the ‘kings’) under energy shortage, thus safeguarding the whole clone survival. Whole transcriptome analysis of leaves and shoot-apical meristems (SAMs) emphasized signatures of molecular integration among ramets, which strongly correlated with higher organization-level responses. In both shoots types, the exposure to LL resulted in a growth slowdown throughout the experiment, which started from immediate signals in SAMs. In apical shoots, this was linked to an acclimative response, where they were suffering a mild stress condition, while in vertical ones it fell in a more severe stress response. Yet, they suffered from sugar starvation and showed a clear cellular stress response in terms of protein refolding and DNA repair mechanisms. Several epigenetic mechanisms modulated the observed gene-expression patterns and the cross-talk between DNA methylation and the cellular energetic status appeared to regulate shoot metabolism under LL. Synthesis. Our results demonstrate a high level of specialization of integrated ramets within seagrass clones and a ‘division of labour’ under adverse conditions. Vertical shoots appear to do ‘most of the job’ especially in terms of resource providing, whereas activated functions in apical shoots were restricted to few important processes, according to an ‘energy-saving’ strategy. The response of vertical shoots could be seen as a ‘sacrificing response’ allowing the survival of ‘the king’ that is key for ensuring propagation and population maintenance, and for the colonization of new environments

Ligation of the intersphincteric fistula tract (LIFT) to treat anal fistula: early results from a prospective observational study

Ligation of the intersphincteric tract (LIFT), a novel sphincter-saving technique, has been recently described with promising results. Literature data are still scant. In this prospective observational study, we present our experience with this technique

Ovothiol ensures the correct developmental programme of the sea urchin Paracentrotus lividus embryo

Ovothiols are π-methyl-5-thiohistidines produced in great amounts in sea urchin eggs, where they can act as protective agents against the oxidative burst at fertilization and environmental stressors during development. Here we examined the biological relevance of ovothiol during the embryogenesis of the sea urchin Paracentrotus lividus by assessing the localization of the key biosynthetic enzyme OvoA, both at transcript and protein level, and perturbing its protein translation by morpholino antisense oligonucleotide-mediated knockdown experiments. In addition, we explored the possible involvement of ovothiol in the inflammatory response by assessing ovoA gene expression and protein localization following exposure to bacterial lipopolysaccharide. The results of the present study suggest that ovothiol may be a key regulator of cell proliferation in early developing embryos. Moreover, the localization of OvoA in key larval cells and tissues, in control and inflammatory conditions, suggests that ovothiol may ensure larval skeleton formation and mediate inflammatory processes triggered by bacterial infection. This work significantly contributes to the understanding of the biological function of ovothiols in marine organisms, and may provide new inspiration for the identification of the biological activities of ovothiols in humans, considering the pharmacological potential of these molecules

Role of 0.4% glyceryl trinitrate ointment after haemorrhoidectomy: results of a prospective randomised study

INTRODUCTION: Conventional haemorrhoidectomy (CH) is well known to cause significant post-operative pain and delayed return to daily activities. Both surgical wounds and sphincterial apparatus spasms are likely responsible for the pain. In this study, we evaluated the role of glyceryl trinitrate ointment (GTN) in reducing post-operative pain, ameliorating wound healing and recovery after CH. PATIENTS AND METHODS: Between 01/08 and 12/11, 203 patients with symptomatic haemorrhoids were enrolled in the study and received (103 patients) or not (100 patients) 0.4 % GTN ointment for 6 weeks after surgery. Pain was assessed using a 10-cm linear visual analogue scale (VAS). Data on post-operative pain, wound secretion and bleeding, return to normal activities and complications were recorded. Data were analysed using Fisher's exact and Mann-Whitney tests. RESULTS: GTN-treated group experienced significantly less pain during the first week after surgery (p < 0.0001). This difference was more evident starting from post-operative day 4 (p < 0.0001). A significant higher percentage of untreated patients experienced severe pain (mean VAS score > 7) (10 % vs 31 %). There were significant differences in terms of secretion time (p = 0.0052) and bleeding time (p = 0.02) in favor of GTN. In addition, the duration of itching was less in the GTN group (p = 0.0145). Patients treated with GTN were able to an early return to daily activities compared to untreated (p < 0.0001). Fifteen GTN-treated patients (14.6 %) discontinued the application because of local discomfort and headache. CONCLUSIONS: GTN ointment enhances significantly post-operative recovery, reducing pain in terms of duration and intensity. This effect might be secondary to a faster wound healing expressed by reduced secretion, bleeding and itching time

Protocol for the unclassified primary antibody deficiency (unPAD) study:Characterization and classification of patients using the ESID online registry

BACKGROUND: Primary antibody deficiencies (PADs) without an identified monogenetic origin form the largest and most heterogeneous group of primary immunodeficiencies. These patients often remain undiagnosed for years and many present to medical attention in adulthood after several infections risking structural complications. Not much is known about their treatment, comorbidities, or prognosis, nor whether the various immunological forms (decreased total IgG, IgG subclass(es), IgM, IgA, specific antibody responses, alone or in combination(s)) should be considered as separate, clearly definable subgroups. The unclassified primary antibody deficiency (unPAD) study aims to describe in detail all PAD patients without an identified specific monogenetic defect regarding their demographical, clinical, and immunological characteristics at presentation and during follow-up. In constructing these patterns, the unPAD study aims to reduce the number of missed and unidentified PAD patients in the future. In addition, this study will focus on subclassifying unPAD to support the identification of patients at higher risk for infection or immune dysregulation related complications, enabling the development of personalized follow-up and treatment plans. METHODS AND ANALYSIS: We present a protocol for a multicenter observational cohort study using the ESID online Registry. Patients of all ages who have given informed consent for participation in the ESID online Registry and fulfill the ESID Clinical Working Definitions for ‘unclassified antibody deficiency’, ‘deficiency of specific IgG’, ‘IgA with IgG subclass deficiency’, ‘isolated IgG subclass deficiency’, ‘selective IgM deficiency’, ‘selective IgA deficiency’ or ‘common variable immunodeficiency’ will be included. For all patients, basic characteristics can be registered at first registration and yearly thereafter in level 1 forms. Detailed characteristics of the patients can be registered in level 2 forms. Consecutive follow-up forms can be added indefinitely. To ensure the quality of the collected data, all data will be fully monitored before they are exported from the ESID online Registry for analysis. Outcomes will be the clinical and immunological characteristics of unPAD at presentation and during follow-up. Subgroup analyses will be made based on demographical, clinical and immunological characteristics

Decline of gastric cancer mortality in common variable immunodeficiency in the years 2018-2022

Introduction: In patients with Common Variable Immunodeficiency, malignancy has been reported as the leading cause of death in adults, with a high risk of B-cell lymphomas and gastric cancer.Methods: We conducted a five-year prospective study aiming to update the incidence and mortality of gastric cancer and the incidence of gastric precancerous lesions in 512 CVID patients who underwent a total of 400 upper gastrointestinal endoscopies.Results: In the pre-pandemic period, 0.58 endoscopies were performed per patient/year and in the COVID-19 period, 0.39 endoscopies were performed per patient/year. Histology revealed areas with precancerous lesions in about a third of patients. Patients who had more than one gastroscopy during the study period were more likely to have precancerous lesions. Two patients received a diagnosis of gastric cancer in the absence of Helicobacter pylori infection. The overall prevalence of Helicobacter pylori infection in biopsy specimens was 19.8% and related only to active gastritis. Among patients who had repeated gastroscopies, about 20% progressed to precancerous lesions, mostly independent of Helicobacter pylori.Discussion: While gastric cancer accounted for one in five deaths from CVID in our previous survey, no gastric cancer deaths were recorded in the past five years, likely consistent with the decline in stomach cancer mortality observed in the general population. However, during the COVID-19 pandemic, cancer screening has been delayed. Whether such a delay or true decline could be the reason for the lack of gastric cancer detection seen in CVID may become clear in the coming years. Due to the high incidence of precancerous lesions, we cannot rely on observed and predicted trends in gastric cancer mortality and strongly recommend tailored surveillance programs

Struggling with COVID-19 in Adult Inborn Errors of Immunity Patients: A Case Series of Combination Therapy and Multiple Lines of Therapy for Selected Patients

Background: The SARS-CoV-2 infection is now a part of the everyday lives of immunocompromised patients, but the choice of treatment and the time of viral clearance can often be complex, exposing patients to possible complications. The role of the available antiviral and monoclonal therapies is a matter of debate, as are their effectiveness and potential related adverse effects. To date, in the literature, the amount of data on the use of combination therapies and on the multiple lines of anti-SARS-CoV-2 therapy available to the general population and especially to inborn error of immunity (IEI) patients is small. Methods: Here, we report a case series of five adult IEI patients managed as inpatients at three Italian IEI referral centers (Rome, Treviso, and Cagliari) treated with combination therapy or multiple therapeutic lines for SARS-CoV-2 infection, such as monoclonal antibodies (mAbs), antivirals, convalescent plasma (CP), mAbs plus antiviral, and CP combined with antiviral. Results: This study may support the use of combination therapy against SARS-CoV-2 in complicated IEI patients with predominant antibody deficiency and impaired vaccine response