Immunomodulatory effect of Tityus sp. in mononuclear cells extracted from the blood of rheumatoid arthritis patients

ABSTRACT Background: Pathophysiological mechanisms of rheumatoid arthritis arise because of a proinflammatory environment, generated by the interaction of autoreactive lymphocytes and proinflammatory mediators. Current strategies to mitigate the progression of the disease produce adverse effects, so there is a need for new therapeutic strategies and molecular targets to treat this disease. In this context, evidence suggests that scorpion venoms could modulate the immune response and some important cellular mechanisms of pharmacological interest. To evaluate the immunomodulatory effect of the venom of Tityus sp. (a possible new species close to Tityus metuendus) peripheral blood mononuclear cells of women diagnosed with RA were compared to cells of a control group. Methods: A case-control study was conducted with a sample of 10 women with a confirmed diagnosis of RA and controls matched by sex and age. The cytotoxicity of the venom was evaluated to find sublethal concentrations of the venom, and subsequently, their immunomodulatory capacity in terms of percentage of proliferation, cell activation, and cytokines production. Results: the venom of Tityus sp. produced a decrease in the percentage of proliferation in the CD3+, CD3+CD4+, and CD3+CD8+ cell subpopulations of RA patients and healthy controls, at concentrations of 252 and 126 µg/mL. However, the venom did not induce significant differences in the percentage of cell activation markers. The venom caused a decrease in IL-10 at a concentration of 252 µg/mL compared to untreated cells from patients and controls. The remaining cytokines did not show significant differences. Conclusion: the venom of Tityus sp. is a potential source of molecules with immunomodulatory ability in CD4 and CD8 T lymphocytes. This result directs venom characterization studies to identify pharmacological targets with immunomodulatory capacity in T lymphocytes to enhance research in the treatment of autoimmune disorders such as RA.

Larrea divaricata a native Argentine plant with potential activity against SARS-CoV-2? / ¿Larrea divaricata una planta nativa argentina con actividad potencial sobre SARS-CoV-2?

Larrea divaricata Cav. is an autochthonous South American plant popularly used in inflammatory and infectious diseases with reported anti - inflammatory, immunomodulatory, antimicrobial and antioxidant activities. Covid - 19 is an infection ca used by the severe acute respiratory syndrome coronavirus 2 (SARS - CoV - 2). This virus can cause pneumonia and even death in about 5% of the cases. The objective of the article was to demonstrate, through a literature review, that L. divaricata has sufficie nt attributes to be assayed against SARS - CoV - 2. For this, the chemical composition, reported activities and docking studies were taken into account. This review demonstrated that the plant extracts are capable of inhibiting the proliferation of fungi, bact eria and viruses and that they exert anti - inflammatory and immunomodulatory actions in different " in vitro " and " in vivo " models. These results suggest that the plant is a good candidate to be studied for the prevention and/or treatment of SARS - CoV - 2.

Larrea divaricata Cav. es una planta autóctona Sudamericana, utilizada popularmente en enfermedades inflamatorias e infecciosas, con activida d anti - inflamatoria, inmunomoduladora, antimicrobiana y antioxidante reportada. El Covid - 19 es una infección causada por una cepa de coronavirus, SARS - CoV - 2 (coronavirus tipo 2 causante del síndrome respiratorio agudo severo). Este virus puede originar neu monía e incluso la muerte en alrededor del 5% de los casos. Nuestro objetivo fue demostrar, a través de una revisión bibliográfica, que esta planta tiene atributos suficientes para ser ensayada en estudios contra SARS - CoV - 2. Se tuvo en cuenta la composici ón química, los antecedentes científicos y los estudios de acoplamiento molecular. Esta revisión permitió demostrar que extractos de la planta son capaces de inhibir la proliferación de hongos, bacterias y virus y que presentan acción anti - inflamatoria en diferentes modelos " in vitro " e " in vivo ", lo que los hace candidatos a ser estudiados en la prevención y/o tratamiento de la infección contra SARS - CoV - 2.

Origanum vulgare: peroxidase-, superoxide dismutase- and immunomodulatory activities on macrophages activated with Helicobacter pylori derivatives.

Helicobacter pylori, invades the gastric mucosa and is one of the causative agents of stomach cancer and peptic ulcers. Origanum vulgare, is a flavouring herb used worldwide. But little is known about the effects of extracts prepared by maceration in cold PBS. This study was aimed at determining the superoxide dismutase (SOD)- and peroxidase (Px)-like antioxidant activities as well as the immunomodulatory activity (anti-inflammatory/pro-inflammatory) of an aqueous extract of O. vulgare by evaluating the production of nitric oxide (NO) in macrophages stimulated with H. pylori derivatives. The cold extract presented SOD-like and Px-like activities with effective concentration 50 (EC50) values of Px = 489.7 ± 48 µg/ml and SOD= 384.7 ± 30 µg/ml. The extract was also capable of modulating the production of NO in macrophages stimulated by H. pylori derivatives by exerting a pro-inflammatory activity at high concentrations and an anti-inflammatory activity at low concentrations.

Antibacterial and immunological properties of piperine evidenced by preclinical studies: a systematic review.

Aim: To review in vitro, in vivo, and in silico studies examining the antibacterial and immunomodulatory properties of piperine (PPN). Methods: This systematic review followed PRISMA guidelines, and five databases were searched. Results: A total of 40 articles were included in this study. Six aspects of PPN activity were identified, including antibacterial spectrum, association with antibiotics, efflux pump inhibition, biofilm effects, protein target binding, and modulation of immune functions/virulence factors. Most studies focused on Mycobacterium spp. and Staphylococcus aureus. Cell lineages and in vivo models were employed to study PPN antibacterial effects. Conclusion: We highlight PPN as a potential adjuvant in the treatment of bacterial infections. PPN possesses several antibacterial properties that need further exploration to determine the mechanisms behind its pharmacological activity.

Immunomodulatory and Antioxidant Effects of Spray-Dried Encapsulated Kale Sprouts after In Vitro Gastrointestinal Digestion.

The health-related compounds present in kale are vulnerable to the digestive process or storage conditions. Encapsulation has become an alternative for their protection and takes advantage of their biological activity. In this study, 7-day-old Red Russian kale sprouts grown in the presence of selenium (Se) and sulfur (S) were spray-dried with maltodextrin to assess their capacity to protect kale sprout phytochemicals from degradation during the digestion process. Analyses were conducted on the encapsulation efficiency, particle morphology, and storage stability. Mouse macrophages (Raw 264.7) and human intestinal cells (Caco-2) were used to assess the effect of the intestinal-digested fraction of the encapsulated kale sprout extracts on the cellular antioxidant capacity, the production of nitric oxide (NOx), and the concentrations of different cytokines as indicators of the immunological response. The highest encapsulation efficiency was observed in capsules with a 50:50 proportion of the hydroalcoholic extract of kale and maltodextrin. Gastrointestinal digestion affected compounds' content in encapsulated and non-encapsulated kale sprouts. Spray-dried encapsulation reduced the phytochemicals' degradation during storage, and the kale sprouts germinated with S and Se showed less degradation of lutein (35.6%, 28.2%), glucosinolates (15.4%, 18.9%), and phenolic compounds (20.3%, 25.7%), compared to non-encapsulated ones, respectively. S-encapsulates exerted the highest cellular antioxidant activity (94.2%) and immunomodulatory activity by stimulating IL-10 production (88.9%) and COX-2 (84.1%) and NOx (92.2%) inhibition. Thus, encapsulation is an effective method to improve kale sprout phytochemicals' stability and bioactivity during storage and metabolism.

Immunomodulatory Activity of Probiotics in Models of Bacterial Infections.

As resistance to conventional antibiotics among bacteria continues to increase, researchers are increasingly focusing on alternative strategies for preventing and treating bacterial infections, one of which is microbiota modulation. The objective of this review is to analyze the scientific literature on the immunomodulatory effects of probiotics in bacterial infections. This is an integrative review of the literature based on systematic steps, with searches performed in the databases Medline, PubMed, Scopus, Embase, and ScienceDirect. The most prevalent bacterial genera used to evaluate infectious processes were Salmonella, Escherichia, Klebsiella, and Streptococcus. Lactobacillus was the most commonly used probiotic genus, with Lactobacillus delbrueckii subsp. bulgaricus is the most frequently used species. In most studies, prophylactic treatment with concentrations of probiotics equal to or greater than 8 log CFU/mL was chosen. However, there was considerable heterogeneity in terms of effective treatment duration, indicating that the results cannot be generalized across all studies. This review found that probiotics interact with the immune system through different mechanisms and have a positive effect on preventing different types of bacterial infections.

Extracellular Vesicles from Candida haemulonii var. vulnera Modulate Macrophage Oxidative Burst.

Members of the Candida haemulonii species complex are multidrug-resistant emergent yeast pathogens able to cause superficial and invasive infections in risk populations. Fungal extracellular vesicles (EVs) play a critical role in the pathogenicity and virulence of several species and may perform essential functions during infections, such as carrying virulence factors that behave in two-way communications with the host, affecting survival and fungal resistance. Our study aimed to describe EV production from Candida haemulonii var. vulnera and evaluate whether murine macrophage RAW 264.7 cells respond to their stimuli by generating an oxidative response after 24 h. For this purpose, reactive oxygen species detection assays demonstrated that high concentrations of yeast and EVs (1010 particles/mL) of Candida haemulonii did not change macrophage viability. However, the macrophages recognized these EVs and triggered an oxidative response through the classical NOX-2 pathway, increasing O2•- and H2O2 levels. However, this stress did not cause lipid peroxidation in the RAW 264.7 cells and neither lead to the activation of the COX-2-PGE2 pathway. Thus, our data suggest that low concentrations of C. haemulonii EVs are not recognized by the classical pathway of the oxidative burst generated by macrophages, which might be an advantage allowing the transport of virulence factors via EVs, not identified by the host immune system that could work as fine tube regulators during infections caused by C. haemulonii. In contrast, C. haemulonii var. vulnera and high EV concentrations activated microbicidal actions in macrophages. Therefore, we propose that EVs could participate in the virulence of the species and that these particles could be a source of antigens to be exploited as new therapeutic targets.

Medicinal Plants with Anti-dengue and Immunomodulatory Activity.

Dengue fever is a disease with a high mortality rate around the world, which is an important issue for the health authorities of many countries. As a result of this, the search for new drugs that are effective to combat this disease has become necessary. Medicinal plants have been used since ancient times to treat a wide list of diseases, including dengue fever. In this mini-review, 12 medicinal plants with known pharmacological properties are presented, which have been used in studies to evaluate their antiviral activity in vitro tests. Among the chemical agents involved in the antiviral response, found in the alcoholic extracts of these plants, are flavonoids, terpenes and alkaloids, which within the mechanism of action in blocking viral replication are considered entry inhibitors, fusion inhibitors, translation inhibitors and protease inhibitors. The present work shows whether these plants possess antiviral activity and the chemical compounds involved in this response.

Release of Bioactive Peptides from Erythrina edulis (Chachafruto) Proteins under Simulated Gastrointestinal Digestion.

The estimated and concerning rise in world population over the next few years and the consequent increase in food demand will lead to a deterioration in global food security. To avoid or reduce this world crisis, informed and empowered consumers are turning to sustainable and nutrient-rich foods that substitute animal products, also reducing their associated environmental impact. Moreover, due to the demonstrated influence of diet on the risk of high incidence and mortality of noncommunicable diseases, the current established food pattern is focused on the consumption of foods that have functionality for health. Among these new foods, traditional and underutilized plants are gaining interest as alternative protein sources providing nutritional and biological properties. In this work, the potential of Erythrina edulis (chachafruto) proteins as a source of multifunctional peptides after transit through the gastrointestinal tract has been demonstrated, with antioxidant and immunostimulating effects in both biochemical assays and cell culture. While low molecular weight peptides released during the digestive process were found to be responsible for protection against oxidative stress mediated by their radical scavenging activity, high molecular weight peptides exerted immunostimulating effects by upregulation of immunoresponse-associated biomarkers. The findings of this study support the promising role of chachafruto proteins as a new antioxidant and immunostimulatory ingredient for functional foods and nutraceuticals.

Agaricus bisporus ß-(1 → 6)-d-glucan induces M1 phenotype on macrophages and increases sensitivity to doxorubicin of triple negative breast cancer cells.

Mushroom ß-d-glucans have demonstrated immunomodulatory activity, which is initiated by their recognition by specific receptors on immune system cells surfaces. Studies indicated that ß-d-glucans may present a synergistic effect with chemotherapy drugs. In this study, a linear ß-(1 â†’ 6)-d-glucan (B16), isolated from A. bisporus and previously characterized (Mw: 8.26 × 104 g/mol), was evaluated about its capacity to modulate THP-1 macrophages towards an M1 phenotype and induce an antitumoral activity. This was evidenced by the production of pro-inflammatory markers upon B16 treatment (30; 100 µg/mL). The breast tumor cells (MDA-MB-231) viability was not affected by treatment with B16, however, their viability markedly decreased upon treatment with the drug doxorubicin. The results showed a synergic effect of B16 and doxorubicin, which reduced the viability of MDA-MB-231 cells by 31%. Furthermore, B16 treatment provided a sustainable M1 state environment and contributed to increase the sensitivity of breast cancer cells to the doxorubicin treatment.

Antimicrobial and Immunomodulatory Activities of Dried Extracts of Echinacea Purpurea

Abstract The use of Echinacea purpurea (EP), a plant native from North America, is widely diffused throughout the world, presenting many pharmacological applications, mainly for the treatment of infections of respiratory and urinary tracts. Due to the widespread commercialization of EP-based products, an effective evaluation of their pharmacological properties is essential to assure efficacy during clinical use. In this study, in vitro tests were performed to evaluate the antimicrobial activity of dried extracts of EP by the microdilution method. In addition, a phagocytosis model was employed to assess the immunomodulatory potential of the extracts. The increase in reactive oxygen species production, as well as the intracellular proliferation rate of Cryptococcus gatti after phagocytosis by macrophages in the presence of EP dried extracts were also evaluated. The analyzed samples showed no significant antibacterial activity; however, a slight antifungal activity was verified. Positive effects of EP extracts on the modulation of cellular immune response were observed in different experiments, indicating that this mechanism may contribute to the control and treatment of infections.

Polysaccharides and extracts from Agaricus brasiliensis Murill - A comprehensive review.

Edible mushrooms have been increasingly introduced into the human diet, which has driven research into their functional properties. Thus, Agaricus brasiliensis Murill or Agaricus blazei Murill (ABM) is a species native to the Brazilian biome, whose fruiting body has been used not only for dietary purposes, but also in the development of functional foods or as source of molecules of pharmacological interest. The bioactivity of ABM has been related to the presence of polysaccharides, although the contribution of other metabolites cannot be discharged. This work describes the polysaccharides isolation methodology and preparation of the extracts of ABM and their biological activities. Furthermore, it presents a general outline of its characterizations regarding composition, chemical structure and properties in solution. The ABM and its chemical constituents exhibit several biological activities that support their potential use for prevention or treatment of diseases with inflammatory background, such as cancer, diabetes and atherosclerosis. The mechanism of action of the extracts and polysaccharides from ABM is mainly related to a modulation of immune system response or reduction of inflammatory response. This review shows that the ABM has great potential in the pharmaceutical, biotechnological and food sectors that deserves additional research using standardized products.

Hematobin is a novel immunomodulatory protein from the saliva of the horn fly Haematobia irritans that inhibits the inflammatory response in murine macrophages.

BACKGROUND: The horn fly Haematobia irritans is a blood-sucking ectoparasite responsible for substantial economic loss of livestock. Like other hematophagous arthropods species, the successful blood-feeding of H. irritans is highly dependent on the modulation of the host's hemostasis and immune system. Here, we evaluated the biological activity of hematobin (HTB), a protein recently identified in the H. irritans saliva, on macrophage biology. The goal was to understand the putative interactions between the components of H. irritans saliva and the early host immune responses. RESULTS: Thioglycolate-elicited peritoneal macrophages from BALB/c mice were stimulated by lipopolysaccharide (LPS) plus interferon-γ (IFN-γ) in the presence or absence of recombinant HTB. The presence of the salivary protein in the cultures inhibited nitric oxide production and decreased the inducible nitric oxide synthase (iNOS) expression induced by LPS plus IFN-γ. The tumor necrosis factor-α (TNF-α) and interleukin-12p40 (IL-12p40) levels were also reduced in the macrophages pre-incubated with HTB; these findings correlated to the decreased NF-κB expression. The biological activities described here were not associated with changes in annexin V binding to macrophages suggesting that HTB does not induce cell death. In addition, the activity of HTB seems to be specific to macrophages because no changes were observed in lymphocyte proliferation or cytokine production. CONCLUSIONS: We describe here the first bioactive salivary protein of H. irritans. We characterized its ability to modulate macrophage inflammatory response, and the results can help explain how horn flies modulate the host immune system to feed on blood.

Antioxidant and immunomodulatory activities of Oviductus ranae in mice

Oviductus ranae (OR) is a traditional Chinese medicine, which was first recorded in the Compendium of Materia Medica in the Ming Dynasty. OR contains high amounts of proteins and elicits therapeutic effects on neurasthenia, insomnia, and respiratory symptoms, which are related to oxidative stress and immunodeficiency. This study aimed to obtain the potential of OR for the development of functional food possessing antioxidant and immune-enhancement functions in the same dose. In antioxidant evaluation, OR can significantly decrease malondialdehyde and protein carbonyls (P < 0.05, P < 0.01) and significantly increase total superoxide dismutase and glutathione in a dose-dependent manner (P< 0.05, P < 0.01) against ethanol-induced oxidative stress in mice at 0.1, 1.0, and 3.0 g/kg BW. In immunomodulatory evaluation, OR could significantly enhance the phagocytosis of liver macrophages (P < 0.05, P < 0.01), delayed-type hypersensitivity response (P < 0.05, P < 0.01), hemolytic activity (P < 0.05), antibody-producing cells (P < 0.05), and natural killer cell activity (P < 0.05) in the same dose range described in antioxidant evaluation compared with those in the normal control. OR slightly influenced lymphocyte proliferation, peritoneal macrophage phagocytosis, and immune organ indices in mice. Thus, 3.0 g/kg BW OR showed potential for the development of functional food with antioxidant and immune-enhancement activities

The influence of sweet pepper pectin structural characteristics on cytokine secretion by THP-1 macrophages.

Pectins can modulate the biological responses interacting directly with immune cells. The observed responses can strongly be affected by polysaccharide structural features. We analyzed the intrinsic activation capacity of native and modified sweet pepper pectin on cytokine secretion by THP-1 macrophages as well as compare their effects in the presence of lipopolysaccharide. Modified pectin was obtained by partial acid hydrolysis which promoted the removal of side chains as well as the reduction of molecular weight and the degree of methyl esterification of native pectin. The results showed that both fractions had no effect on THP-1 viability. Native pectin at 300µg/mL increased TNF-α, IL-1ß and IL-10 cytokine secretion by THP-1 macrophages. However, in the presence of lipopolysaccharide, it can attenuate the inflammatory response by reducing the production of the pro-inflammatory cytokines TNF-α and IL-1ß and increasing the anti-inflammatory cytokine IL-10, as well as decreasing the TNF-α/IL-10 and IL-1ß/IL-10 ratios. The structural modifications caused by acid hydrolysis affected the intrinsic activation capacity of native pectin to modulate the cytokines secretion. These results indicate that degree of methyl esterification, molecular weight and presence of side chains are important structural features of pectins involved in the modulation of cytokine secretion by THP-1 macrophages.

Immunomodulatory and therapeutic potential of a mucin-specific mycelial lectin from Aspergillus panamensis.

The present study reports the evaluation of immunomodulatory and therapeutic potential of a purified Aspergillus panamensis lectin. The immunomodulatory potential of the purified lectin was determined in swiss albino mice by studying its effect on anaphylaxis reaction, arthus reaction, respiratory burst activity, nitric oxide production and quantification of cytokine levels. The therapeutic potential of the lectin was evaluated in male wistar rat models by studying its curative effect on ulcerative colitis. The purified lectin inhibited systemic anaphylaxis and arthus reaction. It enhanced the functional ability of macrophages which was evident from increase in reduction of nitroblue tetrazolium dye and nitric oxide production. It also stimulated the production of Th-1 cytokine IFN-γ and Th-2 cytokine IL-6. Maximum immunomodulatory effect was seen at lectin concentration of 1.5mg/kg body weight. The lectin also showed curative effect against trinitrobenzene sulphonic acid induced ulcerative colitis. The results of this study adequately reflect the role of purified A. panamensis lectin in improving the immune status of mice models. They also show the effect of lectin in reducing the severity of incidence and decrease in clinical symptoms of ulcerative colitis.

Gomesin acts in the immune system and promotes myeloid differentiation and monocyte/macrophage activation in mouse.

Due to the cytotoxic effect of antimicrobial peptides (AMP) against several microorganism and tumor cells has been proposed their association with the immune system. However, just a few reports have shown this relationship. In this study, mice were treated with gomesin, a ß-hairpin AMP that exhibit high cytotoxicity against bacterial and tumor cells. Different effects in the immune system were observed, such as, decrease of CD3+ in T lymphocytes (Control: 17.7±1.4%; Gomesin: 7.67±1.2%) and in hematopoietic progenitors and increase of hematopoietic stem cell (Control: 0.046±0.004%; Gomesin: 0.067±0.003%), B220+ B lymphocytes (Control: 38.63±1.5%; Gomesin: 47.83±0.48%), and Mac-1+F4/80+ macrophages (Control: 11.76±3.4%; Gomesin: 27.13±4.0%). Additionally, macrophage increase was accompanied by an increase of macrophage phagocytosis (Control 20.85±1.53; Gomesin 31.32±1 Geometric mean), interleukin 6 (Control: 47.24±1.9ng/mL; Gomesin: 138.68±33.68ng/mL) and monocyte chemoattractant protein-1 (Control: 0.872±0.093ng/mL; Gomesin: 1.83±0.067ng/mL). Thus, this report showed immunomodulatory activity of gomesin in the immune system of mice.

Dextran: Influence of Molecular Weight in Antioxidant Properties and Immunomodulatory Potential.

Dextrans (α-d-glucans) extracted from Leuconostoc mesenteroides, with molecular weights (MW) of 10 (D10), 40 (D40) and 147 (D147) kDa, were evaluated as antioxidant, anticoagulant and immunomodulatory drugs for the first time. None presented anticoagulant activity. As for the antioxidant and immunomodulatory tests, a specific test showed an increase in the dextran activity that was proportional to the increase in molecular weight. In a different assay, however, activity decreased or showed no correlation to the MW. As an example, the reducing power assay showed that D147 was twice as potent as other dextrans. On the other hand, all three samples showed similar activity (50%) when it came to scavenging the OH radical, whereas only the D10 sample showed sharp activity (50%) when it came to scavenging the superoxide ion. D40 was the single dextran that presented with immunomodulatory features since it stimulated the proliferation (~50%) of murine macrophages (RAW 264.7) and decreased the release of nitric oxide (~40%) by the cells, both in the absence and presence of lipopolysaccharides (LPS). In addition, D40 showed a greater scavenging activity (50%) for the hydrogen peroxide, which caused it to also be the more potent dextran when it came to inhibiting lipid peroxidation (70%). These points toward dextrans with a 40 kDa weight as being ideal for antioxidant and immunomodulatory use. However, future studies with the D40 and other similarly 40 kDa dextrans are underway to confirm this hypothesis.