Mushroom polyphenols as immune system balancers: What's the mechanism behind it and possible interactions with dietary fibers?

Mushroom polyphenols have been proposed as a new therapy that can improve the immune system. Different immune cells express multiple types of polyphenol receptors that recognize and allow cellular uptake of polyphenols, which subsequently activate signaling pathways to initiate immune responses. Polyphenols can be useful for immunocompromised patients with malignancies, viral or bacterial infections and chronic disorders of organ systems, as well as for those whose immunity is naturally weakened. Cosmetic formulations rich in mushroom polyphenols have the potential to regulate inflammatory skin disorders, as well as eczema or atopic dermatitis and photocarcinogenesis. As primary antioxidants, polyphenols have an important role in preserving immune cells in a reduced environment and in protecting them against oxidative damages and immunosuppression as well as maintaining their suitable function. As signaling pathway modulators, mushroom polyphenols can affect immune cell regulation, cytokine synthesis, and gene expression, in both innate and adaptive immune responses. There are different pathways in the integrated immunomodulatory polyphenol response, such as: 1) the nuclear NF-κB signaling pathway leading to suppression of various inflammatory cytokines expression, and enzymes such as COX-2; 2) MAPK signaling pathways that play a key role in many fundamental cellular processes such as cell growth, proliferation, death and differentiation, and also regulate gene transcription and the activity of transcription factors involved in inflammation; 3) arachidonic acid signaling pathway leading to a decrease in the release of inflammatory mediators; and 4) the Nrf2 / ARE signaling pathway involved in the activation of genes encoding cytoprotective and antioxidant enzymes. Given that polyphenols represent great potential in the design of immune-boosting formulations in line with their widespread structural diversity, it should be noted that some functionality issues require further clarification. For instance different observations and conclusions were reported by the scientists in absence of enzymes involved in their biosynthesis steps. Concerning the dietary application of mushroom polyphenols, it is necessary to mention that after oral consumption they are recognized by the human body as xenobiotics and often a small amount is absorbed in the intestine. Likewise, there are significant differences between the activities of the metabolic form of phenols and their form in the mushroom nutraceutical matrix. For an example, dihydoferulic acid, a metabolite of the ferulic acid, expresses anti-inflammatory activity, opposite to metabolites derived after sulfation and glucuronidation. The scientific focus is on improving and increasing polyphenols bioavailability by designing colloidal systems and using nanosystems. Moreover many studies have found that polyphenols can interact with macromolecules like dietary fibers, i.e. chitin and β-glucans. It has been shown that these interactions can affect the bioaccessibility of polyphenols in a food matrix as well as in nutraceutical formulations. Therefore, chitin and β-glucans have an impact on polyphenols’ immunomodulating activities if they were applied together in commercial formulations. Another disadvantage in the commercialization of polyphenol-based formulations is quantitative and qualitative variations in their content among different mushroom species. As secondary metabolites with a protective role e.g. phenols, their content in mushrooms depends on the locality and environmental conditions of growth. Using extracts or preparations that are based on mycelia grown under controlled conditions may be the solution for the reduction of the natural variability in polyphenol composition. Integrated information on all aspects of functionality will confirm the use of polyphenol-rich mushroom formulations as effective enhancers of immunity

MOLNUPIRAVIR COMPARED TO NIRMATRELVIR/RITONAVIR FOR COVID-19 IN HIGH-RISK PATIENTS WITH HAEMATOLOGICAL MALIGNANCY IN EUROPE. A MATCHED-PAIRED ANALYSIS FROM THE EPICOVIDEHA REGISTRY

Introduction: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections, which reduce both hospitalization and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, while molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir, because it displays less frequent drug-drug interactions and contraindications. A caveat connected to molnupiravir derives from the mode of action inducing viral mutations. In clinical trials on patients without haematological malignancy, mortality rate reduction of molnupiravir appeared less pronounced than that of nirmatrelvir/ritonavir. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, we here assess the effectiveness of molnupiravir compared to nirmatrelvir/ritonavir in our cohort of patients with haematological malignancies. Methods: Clinical data of patients treated either with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and baseline haematological malignancy severity to controls treated with nirmatrelvir/ritonavir. Results: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (IQR 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 57% (n=66) of the patients had controlled baseline haematological malignancy, 13% (n=15) stable, and 30% (n=35) had active disease at COVID-19 onset in each of the groups. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of vaccinated patients was observed in both groups (molnupiravir n=77, 66% vs nirmatrelvir/ritonavir n=87, 75%), those treated with nirmatrelvir/ritonavir had more often received four doses (n=27, 23%) as compared to patients treated with molnupiravir (n=5, 4%, p<0.001). No differences were detected in COVID-19 severity (p=0.39) or hospitalization (p=1.0). No statistically significant differences were identified in overall mortality rate (p=0.78) or in survival probability (d30 p=0.19, d60 p=0.67, d90 p=0.68, last day of follow up p=0.68). In all patients, deaths were either attributed to COVID-19 or the infection contributed to death as per treating physician's judgement. Conclusions: In high-risk patients with haematological malignancies and COVID-19, molnupiravir showed rates of hospitalization and mortality comparable to those of nirmatrelvir/ritonavir in this matched-pair analysis. Molnupiravir appears to be a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy

Autonomous B-cell receptor signaling and genetic aberrations in chronic lymphocytic leukemia-phenotype monoclonal B lymphocytosis in siblings of patients with chronic lymphocytic leukemia

Clonal expansion of CD5-expressing B cells, commonly designated as monoclonal B lymphocytosis (MBL), is a precursor condition for chronic lymphocytic leukemia (CLL). The mechanisms driving subclinical MBL B-cell expansion and progression to CLL, occurring in approximately 1% of affected individuals, are unknown. An autonomously signaling B-cell receptor (BCR) is essential for the pathogenesis of CLL. The objectives of this study were functional characterization of the BCR of MBL in siblings of CLL patients and a comparison of genetic variants in MBL-CLL sibling pairs. Screening of peripheral blood by flow cytometry detected 0.2-480 clonal CLL-phenotype cells per microliter (median: 37/μL) in 34 of 191 (17.8%) siblings of CLL patients. Clonal BCR isolated from highly purified CLL-phenotype cells induced robust calcium mobilization in BCR-deficient murine pre-B cells in the absence of external antigen and without experimental crosslinking. This autonomous BCR signal was less intense than the signal originating from the CLL BCR of their CLL siblings. According to genotyping by single nucleotide polymorphism array, whole exome, and targeted panel sequencing, CLL risk alleles were found with high and similar prevalence in CLL patients and MBL siblings, respectively. Likewise, the prevalence of recurrent CLL-associated genetic variants was similar between CLL and matched MBL samples. However, copy number variations and small variants were frequently subclonal in MBL cells, suggesting their acquisition during subclinical clonal expansion. These findings support a stepwise model of CLL pathogenesis, in which autonomous BCR signaling leads to a non-malignant (oligo)clonal expansion of CD5+ B cells, followed by malignant progression to CLL after acquisition of pathogenic genetic variants

Selenium enriched mushrooms as food additives and dietary supplements

Edible and medicinal mushrooms have been used worldwide due to their nutritional value and known pharmaceutical properties, which are related to the physiologically beneficial substances in the form of primary and secondary metabolites. Their chemical composition and biological activity depend on the medium on which they grow and applied supplementation. Numerous studies have shown that mushrooms can absorb selenium (Se) during growth on the fortified solid substrate or liquid medium, in a concentration that can meet the daily needs of humans. The capacity of some mushroom to absorb Se depends on multiple factors, including mushroom strain, composition of the medium, ecological pa rameters as well as on the form and concentration in which this mineral is added to the me dium. It was previously reported that strains Pleurotus sp, Agaricus bisporus, Ganoderma lu cidum, and Cordyceps militaris absorbed high concentrations of Se when sodium selenite or selenate were applied. However, higher toxicity of inorganic salts that suppressed mycelium growth of Hericium erinaceum, Lentinus edodes, Coriolus versicolor, and Pleurotus spp. com paring to modified zeolites with Se and organic selenitetriglycerides from Selol, Se-yeast, and selenourea was proven. Chemical characterization of polysaccharide and methanol ex tracts isolated from fruiting bodies or mycelia culture showed that most of the Se-enriched mushrooms had a higher content of total carbohydrates (especially β-glucans), proteins, fla vonoids, and phenols comparing to the non-enriched samples. As a consequence, selenized mushrooms showed improved antioxidant and antimicrobial properties. A significant per centage of Se was incorporated not only in the form of L-selenomethionine, but also other organic compounds, such as biologically active polysaccharides. It is believed that the syn ergism of Se and bioactive polysaccharides present in fungi could enhance their antitumor and immunostimulating functions, which lead to numerous health benefits. Obtained re sults classify Se-polysaccharides as promising dietary supplements and Se-enriched mush rooms as delicious functional food or food additives, due to the slow release of selenium and lower toxicity compared to the inorganic compounds. Selenium fortified mushrooms and their extracts used as food additives are expected to prolong the shelf life of the food products since some of them are proved to exhibit higher superoxide dismutase and catalase activity retaining their quality, aroma, and color for a long time of storage

Immunomodulatory, insulinotropic, and cytotoxic activities of phylloseptins and plasticin-TR from the Trinidanian leaf frog Phyllomedusa trinitatis.

International audienceThe aim of the study was to determine the in vitro immunomodulatory, cytotoxic, and insulin‐releasing activities of seven phylloseptin‐TR peptides and plasticin‐TR, first isolated from the frog Phyllomedusa trinitatis. The most cationic peptides, phylloseptin‐1.1TR and phylloseptin‐3.1TR, showed greatest cytotoxic potency against A549, MDA‐MB231, and HT‐29 human tumor‐derived cells and against mouse erythrocytes. Phylloseptin‐4TR was the most hydrophobic and the most effective peptide at inhibiting production of the proinflammatory cytokines TNF‐α and IL‐1β by mouse peritoneal cells but was without effect on production of the antiinflammatory cytokine IL‐10. Phylloseptin‐2.1TR and phylloseptin‐3.3TR were the most effective at stimulating the production of IL‐10. The noncytotoxic peptide, plasticin‐TR, inhibited production of TNF‐α and IL‐1β but was without effect on IL‐10 production. The results of CD spectroscopy suggest that the different properties of plasticin‐TR compared with the immunostimulatory activities of the previously characterized plasticin‐L1 from Leptodactylus laticeps may arise from greater ability of plasticin‐TR to oligomerize and adopt a stable helical conformation in a membrane‐mimetic environment. All peptides stimulated release of insulin from BRIN‐BD11 rat clonal β cells with phylloseptin‐3.2TR being the most potent and effective and phylloseptin‐2.1TR the least effective suggesting that insulinotropic potency correlates inversely with helicity. The study has provided insight into structure‐activity relationships among the phylloseptins. The combination of immunomodulatory and insulinotropic activities together with low cytotoxicity suggests that phylloseptin‐3.3TR and plasticin‐TR may represent templates for the development of agents for use in antiinflammatory and type 2 diabetes therapies

Diverse Expression of IL-32 in Diffuse and Intestinal Types of Gastric Cancer

Introduction. Gastric cancer (GC) represents one of the most common cancers worldwide, frequently diagnosed at advanced stages with poor prognosis, indicating on need for new diagnostic and prognostic markers. The aim of the study was to determine the expression of IL-32, proinflammatory and angiogenic mediators, in patients with diffuse and intestinal gastric cancer and the relationship with clinicopathological aspects. Material and Methods. The tissue samples of diffuse and intestinal types of tumor of 70 patients with gastric cancer were analyzed. Expression of IL-32, VEGF, IL-17, and CD31 was measured by immunohistochemistry. Results. IL-32 expression was significantly lower in tissue samples from patients with diffuse type of gastric cancer that is also a severe and more progressive form (TNM stages III and IV, poor histological differentiation, and higher nuclear grade III). Expression of IL-17 was also decreased in patients with diffuse type of gastric cancer. Microvascular density was diminished in diffuse type of gastric cancer. Conclusions. Downregulated expression of IL-32 in tumor tissue of patients with diffuse type of gastric cancer may implicate on its role in limiting ongoing proinflammatory and proangiogenic processes. This emphasizes on unrecognized role of IL-32 in biology of diffuse type of gastric cancer