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Abstract: The in vitro effects of four heat-inactivated bacterial species on the cellular innate immune responses of the gilthead seabream (Sparus aurata L.) were investigated. Head–kidney leucocytes were isolated and incubated for 30min with two bacteria isolated from seabream skin (Pdp11 and 51M6; members of the Vibrionaceae and in the genus Shewanella) and two bacteria used as probiotics in humans and cattle (Lactobacillus delbrüeckii subsp. lactis and Bacillus subtilis) at 5×105, 5×106 or 5×107 CFU/ml. After incubation, different cellular innate immune parameters (leucocyte peroxidase content, phagocytosis, respiratory burst activity and cytotoxicity) were evaluated. The leucocyte peroxidase content was significantly higher after incubation with 51M6 at 5×107 CFU/ml. Head–kidney phagocytes were able to engulf the four bacterial species in all four cases, L. delbrüeckii subsp. lactis and B. subtilis being the most actively phagocytized. The incubation of seabream leucocytes with 51M6, L. delbrüeckii subsp. lactis and B. subtilis resulted in a great increase in respiratory burst activity. Cytotoxic activity was generally stimulated in a dose-dependent manner, the enhancement obtained with 5×107 CFU/ml being statistically significant. The usefulness of in vitro assays for screening and selecting candidate probiotic bacteria, as well as for optimising their effective dose, is discussed in relation with their immune-modulatory properties. [Copyright &y& Elsevier]

The article talks about the protection of intraperitoneal administration of β-1,3/1,6-glucan to rainbow trout, Oncorhynchus mykiss (Walbaum), against Loma salmonae. The clinical signs of the infection of the microsporidial gil disease include respiratory distress and high-mortality rates. More information is given in the article.

Abstract: To determine the effect of chitin, chitosan and levamisole on the immune response and growth of common carp (Cyprinus carpio) under field conditions, fish were fed with these compounds for a period of 90 days and then challenged with Aeromonas hydrophila. Dietary supplementation of chitosan, levamisole and chitin enhanced the growth of all treated fish significantly (P <0.05) compared to fish fed with non-supplemented diet. The highest growth was recorded in the chitosan fed fish (94.92±9.36 g) followed by levamisole (93.25±8.4 g) and chitin (63.54±4.7 g). Lysozyme, white blood cell count (WBC) and NBT assay were studied to assess the immune response of carps. Dietary supplementation of chitin, chitosan and levamisole significantly stimulated the lysozyme activity (P <0.001), and NBT reduction (P <0.001). When the treated fish were challenged with A. hydrophila on the 45th day, the relative percentage survival (RPS) was significantly higher in chitosan fed fishes (80%) followed by levamisole (66.7%), and chitin (40%). However, the RPS decreased to 68.9%, 57.8% and 37.5% on the 90th day after the challenge with A. hydrophila. The results indicate that dietary intake of chitosan enhances the innate immune system and survivability of common carp (C. carpio) in ponds. The role of chitosan, chitin and levamisole as immunostimulants with regard to protection against A. hydrophila infection is discussed. [Copyright &y& Elsevier]

Abstract: The present study was performed to determine the efficacy and immunoreversal effects of four well-known dietary immunomodulators viz., lactoferrin, β-1,3 glucan, levamisole and vitamin C on the innate immune response of healthy and cyclophosphamide (CYP) induced immunocompromised Asian catfish, Clarias batrachus. Fish specimens were divided into 5 groups and each group was fed with diets supplemented with or without an appropriate dose of immunostimulant. Cyclophosphamide at a rate of 200 mg/kg body weight was injected intraperitoneally for 3 consecutive days to induce an immunocompromised state in control fish. After 72 h post injection, fish of all the groups were bled and innate immune parameters, both humoral (haemagglutination titre and total serum myeloperoxidase content) and cellular (respiratory burst and phagocytic activities), were determined. The results showed that all the substances delivered as feed supplements significantly (P <0.05) enhanced most of the non-specific immune parameters in both healthy and immunosuppressed subgroups compared to their respective controls. Levamisole induced significantly increase in blood phagocytic activities in both healthy and immunocompromised fish as observed from raised respiratory burst and myeloperoxidase activity as compared to control. Feeding of vitamin C significantly enhanced phagocytic activity and myeloperoxidase content. On the other hand, all parameters were positively influenced by lactoferrin and glucan feeding in both groups compared to their respective controls. [Copyright &y& Elsevier]

Abstract: We previously reported that Ulva rigida polysaccharides enhance the respiratory burst activity of turbot kidney leucocytes. In the present study, water-soluble polysaccharides were separated into several components to determine the relationship between their structure and their effects on cell activity. U. rigida polysaccharides were found to be composed mainly of uronic acids, rhamnose and xylose with smaller amounts of other sugars. Anion exchange chromatography was used to separate the polysaccharides into acid (94%) and neutral sugars (6%). U. rigida polysaccharides induced respiratory burst activity of turbot kidney leucocytes and the effect was found to be related to the acid fraction. The acid fraction was separated into four fractions, according to the molecular size, and all had stimulatory capacity. Acid sugars contained mainly large homogeneous sulphated polysaccharides. The capacity to induce the respiratory burst was lost after desulphation of the polysaccharides, but was recovered again after non-specific resulphation. The acid polysaccharides induced also IL-1β expression in turbot peritoneal leucocytes. As above, this effect was lost after desulphation of the polysaccharides. The present results indicate that the sulphate groups are required for induction of turbot innate immune responses by U. rigida polysaccharides. [Copyright &y& Elsevier]

Abstract: An efficient and scalable synthesis of the potent vaccine adjuvant RC-529 ( 3 ) and TLR4 agonist CRX-524 ( 4 ) is described in eight steps from 1,3,4,6-tetra-O-acetyl-2-amino-2-benzyloxycarbonyl-2-deoxy-β-d-glucopyranose ( 10c ) in ca. 25% overall yield. The synthesis features the strategic use of the N-Cbz group for β-glycosylation and the selective N,N,O-triacylation of common advanced intermediate 15 with (R)-3-tetradecanoyloxy or decanoyloxytetradecanoic acid ( 8 , 9 ) late in the synthesis. A new method for preparing and enhancing the enantiopurity of (R)-3-hydroxytetradecanoic acid ( 6 ), a key component of 3 and 4 as well as bacterial lipid A, is also described. [Copyright &y& Elsevier]

Abstract: The production of fish larvae is often hampered by high mortality rates, and it is believed that most of this economic loss due to infectious diseases is ca. 10% in Western European aquaculture sector. The development of strategies to control the pathogen load and immuno-prophylactic measures must be addressed further to realise the economic “potential” production of marine fish larvae and thus improve the overall production of adult fish. The innate defence includes both humoral and cellular defence mechanisms such as the complement system and the processes played by granulocytes and macrophages. A set of different substances such as β-glucans, bacterial products, and plant constituents may directly initiate activation of the innate defence mechanisms acting on receptors and triggering intracellular gene activation that may result in production of anti-microbial molecules. These immunostimulants are often obtained from bacterial sources, brown or red algae and terrestrial fungi are also exploited as source of novel potentiating substances. The use of immunostimulants, as dietary supplements, can improve the innate defence of animals providing resistance to pathogens during periods of high stress, such as grading, reproduction, sea transfer and vaccination. The immunomodulation of larval fish has been proposed as a potential method for improving larval survival by increasing the innate responses of the developing animals until its adaptive immune response is sufficiently developed to mount an effective response to the pathogen. To this end it has been proposed that the delivery of immunostimulants as a dietary supplement to larval fish could be of considerable benefit in boosting the animals innate defences with little detriment to the developing animal. Conversely, there is a school of thought that raises the concern of immunomodulating a neotanous animal before its immune system is fully formed as this may adversely affect the development of a normal immune response. [Copyright &y& Elsevier]

The potential effect of the intraperitoneal or dietary administration of propolis, a honeybee product, on gilthead seabream (Sparus aurata L.) innate immune responses was evaluated. Fish were intraperitoneally injected with 5mg of water (WEP), ethanol (EEP) or both (WEP+EEP) extracts of propolis and sampled after 1, 3, 5 and 10 days. When administered in the diet, propolis was dissolved in ethanol and added to a pellet diet at a concentration of 0, 0.1 or 10gkg-1 diet, the fish being sampled after 1, 2, 4 and 6 weeks of feeding. Humoral (alternative complement activity and peroxidase content) and cellular (leucocyte peroxidase, phagocytosis, cytotoxicity and respiratory burst activity) immune responses were evaluated in both cases. The results suggest that propolis has limited immunostimulatory effects although intraperitoneal administration was more effective than dietary intake. The effects that were noted were at cellular level, namely, phagocytosis and cytotoxicity. [Copyright &y& Elsevier]

This paper presents data from an investigation of the mode of action of five different crustacean immunostimulants presented to European lobster (Homarus gammarus) granulocytes cultured in vitro. The experiments were designed to test whether or not the immunostimulants could cause the short-term up-regulation of genes coding for immune proteins without causing the cells to degranulate. Quantitative measurements of mRNA transcript abundance were made using real-time PCR and it was first necessary to isolate the complete gene sequences coding for the proteins prophenoloxidase (proPO), β-1,3-glucan binding protein (βGBP) and β-actin (β-act) in the lobster. These sequences were used to design TaqMan™ primer and fluorescent probe sets. The presented data indicated that the majority of the tested immunostimulants did not induce the up-regulation of immune-related gene expression in the granulocytes in isolation. Alternative modes of action, including the in vivo up-regulation of gene expression in haemopoetic tissues, are discussed. [Copyright &y& Elsevier]

Immunoglobulin M (IgM) is a major component of the teleost humoral immune system. Despite the significance of IgM levels as an immune parameter, there are relatively few studies on changes induced in its total levels in serum. This study examines the effects of several immunomodulators (vitamin A, chitin, yeast cells or levamisole, which act as immunostimulants, and crowding, hypoxia or anaesthetics, which act as stressors) upon the total serum IgM levels of non-immunized gilthead seabream (Sparus aurata L.). Total serum IgM levels of fish fed with the assayed immunostimulant-supplemented diets were statistically higher than those in fish fed a non-supplemented diet, especially in the case of levamisole. On the other hand, serum IgM levels of fish subjected to different stressors were not affected by crowding, hypoxia or certain anaesthetics. However, benzocaine and a narcotic dose of 2-phenoxyethanol provoked a great reduction, while quinaldine sulphate increased IgM levels to a significant degree. These results show how the seric IgM levels can be differently affected by some immunomodulators and the important role they may play in the regulation of total circulating IgM levels in seabream. The possibility of using total serum IgM for assessing immunostimulation, disease diagnosis and stress symptoms during fish farming is discussed. [Copyright &y& Elsevier]

The aims of this study were (i) to identify alternative Mx stimulatory compounds in Atlantic salmon (Salmo salar L.) and to characterise the kinetics and intensity of the stimulated responses and (ii) to investigate the effect of temperature on such responses by semi-quantitative RT-PCR. Mx transcripts were measured in Atlantic salmon parr kept at 14 °C and injected with either LPS, the synthetic double-stranded polyribonucleotide poly I:C, Vibrio anguillarum serotypes I and II-ordalii bacterin, β-glucan, whole yeast cells or yeast RNA. Sampling periods lasted until transcripts were undetectable or up to three weeks after immunisation. The effect of temperature on poly I:C-induced Mx response was studied by injecting parr kept at 6 °C. Newly hatched salmon fry were immersed once, twice or three times in the Vibrio bacterin diluted five or 10 times and sampled for three weeks.None of the yeast compounds induced Mx expression in Atlantic salmon parr. LPS induced a very low Mx response 2 and 3 days after injection. The Vibrio bacterin administered by injection in parr (but not by immersion in fry) resulted in strong Mx induction on days 2 and 3, disappearing by day 6. Poly I: C-induced Mx responses that were more intense and longer lasting than those induced by the bacterin, peaking on day 3 and lasting over 6 days, disappearing by day 9 at 14 °C. Lower temperature caused a longer lasting Mx response to poly I:C (at least 21 days), which peaked on days 7–14, with a similar intensity and no delayed onset as compared with the response at 14 °C. However, some toxicity of the poly I:C was indicated in treatments at 6 °C. [Copyright &y& Elsevier]

Background Evidence for the scientific basis of purported therapeutic effects and adverse effects of herbal supplements continues to grow. Many herbal supplements are touted for their immunostimulatory properties, and both in vitro and in vivo experiments have supported this claim. Although this explains their beneficial effects in preventing or curtailing disease, to our knowledge, no immunostimulatory herbal supplements have been reported to exacerbate disorders of immune system overactivity. Observations We describe 3 patients whose autoimmune disease onset and/or flares correlated with ingestion of herbal supplements with proven immunostimulatory effects. Echinacea and the alga Spirulina platensis are implicated in 2 patients' flares of pemphigus vulgaris, and a supplement containing the algae Spirulina platensis and Aphanizomenon flos-aquae was ingested by a third patient days before both onset and a severe flare of dermatomyositis. The third patient showed heterozygosity for a tumor necrosis factor α (TNF-α) promoter polymorphism (–308A), leading to increased production of TNF-α, which may have predisposed her to developing dermatomyositis. Conclusions Immunostimulatory herbal supplements may exacerbate preexisting autoimmune disease or precipitate autoimmune disease in persons genetically predisposed to such disorders. Increased production of TNF-α may play a role, although more research is needed to clarify the mechanisms of such phenomena. [ABSTRACT FROM AUTHOR]

In this study, we investigated the effects of water-soluble extracts (WSE) from seaweed species Ulva rigida C. Agardh, Enteromorpha sp., Codium tomentosum (Huds) Stackh., Fucus vesiculosus L., Pelvetia canaliculata (L.) Decne et Thur, Dictyota dichotoma (Huds) Lamour, Chondrus crispus Stackh and Porphyra umbilicalis (L.) J. Agardh, on the respiratory burst of turbot phagocytes, in search of biologically active substances with immunostimulating capacities. The stimulatory capacities of the extracts varied greatly, depending on their origin, the concentrations used and the time of incubation. The best responses were induced by the extracts obtained from U. rigida, Enteromorpha sp. and C. crispus. Pre-incubation of the phagocyte cells with U. rigida and C. crispus extracts and subsequent incubation with phorbol myristate acetate (PMA) showed that these cells responded to further stimulation by this substance and, at some concentrations, they showed higher respiratory burst activity than control cells stimulated by PMA alone, suggesting that the extracts had a priming effect. We also tested the effects of protein-free water-soluble extracts (PF-WSE) and of the polysaccharide fractions (PSF) obtained from the PF-WSE of U. rigida and C. crispus. These extracts induced an increase in the respiratory burst activity of turbot phagocytes, suggesting that most of the stimulatory capacity of the water-soluble extracts was associated with polysaccharides. [Copyright &y& Elsevier]

The aim of this study was to determine the effect on non-specific defence mechanisms in rainbow trout (Oncorhynchus mykiss) fed diets containing different doses of β-glucan (MacroGard), Schizosaccharomyces pombe and S. pombe P450. Over a period of 3 weeks, fish were given 0.1% and 1% MacroGard, 0.1% and 1% S. pombe, 0.1% and 1% S. pombe P450 in their food. Then phagocytosis, intracellular and extracellular respiratory burst activity, total protein, and specific growth ratio and condition factor values were determined. After feeding for 3 weeks with three different immunostimulants, extracellular and intracellular respiratory burst and phagocytic activity were significantly increased in the groups fed 1% MacroGard and 0.1% S. pombe P450 compared with the control group and the other experimental groups (P < 0.05). Respiratory burst activity was higher in all the experimental groups than in the control group. Phagocytic activity was elevated in all the experimental groups except that fed 0.1% MacroGard (P < 0.05). Total protein levels were higher in all the experimental groups than in the control group, but the difference was not significant (P < 0.05). The results indicate that rainbow trout fed different doses of MacroGard, S. pombe and S. pombe P450 all showed increased intracellular and extracellular respiratory burst activity, and phagocytic activity. However, there was no effect on total protein. In conclusion, S. pombe P450 could confer the same non- specific immunity as MacroGard. [ABSTRACT FROM AUTHOR]

Curculigo orchioides Gaerten belongs to the family Amaryllidaceae. The rhizomes of the plants are used for the treatment of decline in strength, jaundice and asthma. Its methanolic extract has been shown to enhance phagocytic activity of macrophages.Present studies have led to the isolation of two phenolic glycosides and a purified glycoside fraction. These were studied for their effect on macrophage migration index (MMI), haemagglutination (HA) titre, plaque forming cell (PFC), PHA-induced blast transformation of lymphocytes (BTL) and delayed type hypersensitivity (DTH). Significant immunostimulant activity was found in purified glycoside-rich fraction isolated from the ethyl acetate extract. The exact structure of the active glycoside is yet to be determined.The enhancement of HA titre and PFC count on one hand and that of DTH response on the other indicates that glycoside fraction stimulates both humoral and Cell-mediated immune responses. Glycoside fraction stimulates immune response by acting both on macrophages and the lymphocytes. [Copyright &y& Elsevier]

The present study evaluated the effect of oral administration of three types of glucan on the resistance of gilthead seabream to Photobacterium damselae subsp. piscicida and on the activity of its phagocytes. Groups of fish were fed with a basal diet (controls) or with the basal diet supplemented with glucan for two different periods of time before being bath challenged with the bacterium. Groups of fish fed with 1 and 10 g kg−1 of glucan for a short period (2 weeks with glucan and 1 week with the basal diet) showed a higher degree of protection against pasteurellosis than the control group. This was especially pronounced in groups of fish fed with the higher concentrations of glucan. The respiratory burst and phagocytic activity of spleen phagocytes varied with time but no significant differences were found between groups in the third week when the challenge was carried out. The group of fish fed with 1 g kg−1 of glucan for longer periods of time (2 weeks with glucan, 1 week with the basal diet, 2 weeks with glucan, and 1 week with the basal diet) also showed enhanced protection against P. damselae. However, the group fed with 5 g kg−1 had mortality rates comparable to the control group, and protection in the group fed with 10 g kg−1 of glucan was significantly lower than in the control group. These results suggest that glucans can be used in the diet to prevent or reduce mortalities in gilthead seabream due to pasteurellosis, and they show the importance of the concentration and the period of administration of glucan to obtain optimal protection against this disease. [Copyright &y& Elsevier]

The immunomodulatory action of superoxide dismutase (SOD) and its possible use as an indicator of immune responses in American white shrimp (Litopenaeus vannamei) were studied. Juvenile shrimp were immersed in aerated β-glucan and sulfated polysaccharide solutions for 6 h. SOD activity in haemocytes and muscle was quantified to evaluate whether β-glucan and sulfated polysaccharide induce immunostimulatory activity. Haemocytes and muscle showed similar increased levels of SOD activity (1.5- and 1.4-fold that of control, respectively). Total haemocyte count decreased within the first 24 h after challenge with immunostimulants, but total haemocyte count and total soluble haemocyte protein increased over normal values after 48–120 h. Single immunostimulation with β-glucan and sulfated polysaccharide is sufficient to generate an increase in the antioxidant activity of L. vannamei SOD. [Copyright &y& Elsevier]

Within aquaculture, prebiotics are composed of complex carbohydrate molecules that cannot be digested by the fish directly but are metabolised by the microbial communities within the host gut, with the desire that "healthy" bacterial species are promoted with subsequently improved performance of the fish, there are likely some direct responses of intestinal cells to these dietary components. The sources and processing of prebiotics, which fall under the overarching theme of "functional feeds" are highly varied between species and types of prebiotics administered. How these feeds exert their effect, and the host responses are hard to determine, but new technologies and the development of high-throughput technologies (omics) are enabling the mechanisms and methods of action to be further understood. The recent advances in the availability of 'omics' technologies with the transition from single gene assays to microarray and RNA-seq in fish health have enabled novel functional ingredients to be analysed. This review will focus on recent studies on targeted gene expression and 'omics' technologies to characterize immune responses. Comparisons between the immunomodulatory effect of different prebiotics have been made and specific examples of how transcriptomics techniques have been used to identify immune responses to prebiotics are given., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The concept of immunomodulation was proposed by Edward Jenner, while working on polio vaccine in 1796. Many of the autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, psoriatic arthritis and system lupus erythematosus, viral diseases and, some cancers are characterized with elevated levels of "immunocytokine" gene expression, including, tumor necrosis factor-α, various interleukins, cytotoxic T-cell antigen-4, B-cell activating factor. For the treatment of these diseases, the immunologically-based therapies play the major role. In these lines, the usage of phytomedicines as immunostimulants/ immunosuppressants have been enhanced considerably in last few decades and also used as a prophylactic treatment for various ailments. Phytochemicals such as flavonoids, terpenoids, polysaccharides, lactones, alkaloids, glycosides and saponins present in several plants, have been confirmed to exhibit immunomodulating properties. This review focuses on the traditional plants and their constituents which have been extensively used as immunomodulators. We have also highlighted the mechanism of action of these plant constituents related to autophagy and adjuvanticity of drugs., Competing Interests: The authors report no conflict of interest., (©2022 The Authors.)

The aim of this study was to analyze whether, and to what extent, long–term exposure to cadmium, administered in sublethal concentrations by the oral route, caused changes in the immune potential of hemocytes in adult female Steatoda grossa spiders. We used artificial and natural immunostimulants, namely phorbol 12–myristate 13–acetate (PMA) and bacterial cell suspension based on Gram–positive (G+, Staphylococcus aureus) and Gram–negative (G−, Pseudomonas fluorescens) bacteria, to compare the status of hemocytes in nonstimulated individuals and those subjected to immunostimulation. After cadmium exposure, the percentage of small nongranular hemocytes in response to G+ cell suspension and PMA mitogen was decreased. Furthermore, in the cadmium–intoxicated spiders the percentage of plasmatocytes after immunostimulation remained lower compared to the complementary control group. Exposure to cadmium also induced several degenerative changes, including typical apoptotic and necrotic changes, in the analyzed types of cells. Immunostimulation by PMA mitogen and G+ bacterial suspension resulted in an increase in the number of cisterns in the rough endoplasmic reticulum of granulocytes, in both the control group and cadmium–treated individuals. These changes were accompanied with a low level of metallothioneins in hemolymph. Chronic cadmium exposure may significantly weaken the immune defense system of spiders during infections. [Display omitted] • Sublethal concentrations of cadmium change the proportion of different types of hemocytes in spider hemolymph. • Long-term exposure to cadmium administered through the digestive tract enhances degenerative changes in spider hemocytes. • Chronic cadmium exposure may weaken the immune defense system of spiders during infections. • Synthesis of metallothionein's in the midgut glands of spiders plays a protective role for the exposure of hemocytes to excess metal concentrations [ABSTRACT FROM AUTHOR]

The sea cucumber Apostichopus japonicus (Selenka, 1867) is a commercially important cultured animal; however, due to the weakened immunity of A. japonicus or the prevalence of pathogenic bacteria, various diseases are emerging during aquaculture of this species. Antibiotics are effective agents to control bacterial infection to a certain degree, but they have the drawbacks of generating antibiotic resistant bacteria, destructing microbial ecosystems, and finally deteriorating the environment and the host. Thus, the exploration of effective and ecofriendly alternatives to prevent bacterial infection has increasingly attracted much attention. In this review, the ecofriendly agents including immunostimulants to enhance the immune responses of A. japonicus and the antagonists to inhibit the bacterial pathogens are summarized and evaluated to better the knowledge and the practice in the conquering various bacterial diseases in aquaculture of A. japonicus. • The main diseases occur in culture of A. japonicus are described. • The main ecological strategies practiced in A. japonicus are summarized. • The challenges in the development of ecological strategies are proposed. [ABSTRACT FROM AUTHOR]

Immunostimulants, as feed additives, play an important role in maintaining fish health and enhancing their overall growth by providing resistance against diseases in cultured fish. At the initial stages of life of fish, innate immunity is the essential mechanism in their survival. Later, innate immunity has an instructive role in adapting acquired immune response and homeostasis through different receptor proteins. Several studies have been conducted to analyze the effect of dietary immunostimulants like algae, plant extracts, vitamins, herbs, probiotics, and prebiotics-containing diets in Indian major carps. Many bacterial, fungal and viral pathogens are responsible for high death rates in both wild and cultured fish. It's a major limiting factor for world aquaculture industries. Recognition of invading pathogens by different pathogen recognition receptor plays an important role for the activation of different pathways to initiate protective immune responses. Hence, there is a growing need to control the devastating effects of diseases without recourse to toxic chemicals or antibiotics. Keeping with alternative approaches without using toxic chemicals to control fish diseases in mind, many immunostimulants are used, which enhance immune responses along with their gene expression level through different signaling pathway. The objective of this review is to summarize and evaluate the current knowledge of various immunostimulants and their immune responses in three Indian major carps namely Catla catla, Labeo rohita and Cirrhinus mrigala, which are preferred by the people., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Simple Summary: Activation of immune cells is bioenergetically expensive, requiring precise control of cellular metabolism. This applies also to innate immune cells. The current study shows that the immunostimulants, Astragalus, Hyaluronic acid, Imiquimod, and Poly I:C can modulate the expression of genes involved in the innate antiviral immune, as well as genes associated with metabolism, in the early life stages of Atlantic salmon. Disease resistance of fish larvae may be improved by bath treatment in water containing immunostimulants. Pattern recognition receptors, such as TLR3, TLR7, and MDA5, work as an "early warning" to induce intracellular signaling and facilitate an antiviral response. A single bath of newly hatched larvae, with Astragalus, upregulated the expression of IFNα, IFNc, ISG15, MDA5, PKR, STAT1, TLR3, and TLR7 immune genes, on day 4 post treatment. Similar patterns were observed for Hyaluronic acid and Poly I:C. Increased expression was observed for ISG15, MDA5, MX, STAT1, TLR3, TLR7, and RSAD2, on day 9 for Imiquimod. Metabolic gene expression was stimulated on day 1 after immunostimulant bath in ULK1, MYC, SLC2A1, HIF1A, MTOR, and SIX1, in Astragalus, Hyaluronic acid, and Imiquimod. Expression of NOS2 in Poly I:C was an average fourfold above that of control at the same timepoint. Throughout the remaining sampling days (2, 4, 9, 16, 32, and 45 days post immunostimulant bath), NOS2 and IL1B were consistently overexpressed. In conclusion, the immunostimulants induced antiviral gene responses, indicating that a single bath at an early life stage could enable a more robust antiviral defense in fish. Additionally, it was demonstrated, based on gene expression data, that cell metabolism was perturbed, where several metabolic genes were co-regulated with innate antiviral genes. [ABSTRACT FROM AUTHOR]

Comparative studies on the immunostimulating (paramunizing) effectiveness of BCG, levamisole, Corynebacterium parvum and preparations of pock viruses in various in vitro and in vivo tests There are 3 classical immunostimulants: BCG, levamisole and C. parvum. For some years in veterinary medicine two immunostimulants from pock or parapock viruses have been employed as paramunity inducers with success (PIND-AVI, PIND-ORF). In order to explore in detail the functional bases of the above preparations, they were compared by the following tests: 1. In 2 infection models (vesicular stomatitis and Aujesky virus; 2. In a tumour model (radiation induced osteosarcoma in the mouse); 3. The chromium 51 test to demonstrate spontaneous (natural) cytotoxicity; 4. An indirect plaque reduction test to detect stimulation from interferon; and 5. The lymphocyte transformation test. The results showed that the effect of the individual immunostimulants can vary very widely. Both paramunity inducers were effective in all the 5 tests and were harmless. PIND-AVI, however, activated above all the lymphocyte, whereas PIND-ORF had NK (natural mouse spleen killer cells) activity and was the only one of the 5 immunostimulants which also stimulated interferon production. C. parvum, BCG and levamisole were significantly less effective and they were also pyrogenic and in some cases also toxic. The main point arising from the study is that when using immunostimulants it is essential to know precisely how they act and also the damaging effects of the individual agents if the desired effects are to be achieved without harm to the patients. The 5 test systems which we used seem to be the ones of choice for the purpose. Special attention is directed to preparations of pock viruses which act as harmless but effective immunostimulants. Zusammenfassung Es gibt drei klassische Immunstimulantien: BCG, Levamisol und C. parvum. In der Tiermedizin werden seit Jahren 2 Immunstimulantien, die aus Pocken- bzw. Parapockenviren hergestellt werden, als sog. Paramunitätsinducer mit Erfolg verwendet (PIND-AVI, PIND-ORF). Um die funktionellen Grundlagen obiger Präparate detailliert erfassen zu können, sind sie in folgenden Testen vergleichend untersucht worden: 1. in 2 Infektionsmodellen ( Stomatitis vesicularis-, Aujeszky-Virus), 2. in einem Tumormodell (strahleninduziertes Osteosarkom der Maus), 3. im Chromium 51-Test zum Nachweis der spontanen, natürlichen Zytotoxizität, 4. im indirekten Plaque-Reduktions-Test zum Nachweis der Stimulierung von Interferon und 5. im Lymphozyten-Transformationstest. Die Untersuchungsergebnisse weisen darauf hin, daß die Wirkung der einzelnen Immunstimulantien sehr unterschiedlich sein kann. Die beiden Paramunitätsinducer waren in allen Testen wirksam und unschädlich. Trotzdem unterschieden sie sich. PIND-AVI aktivierte vor allem die Lymphozyten, während PIND-ORF besonders die NK-Aktivität und, als einziges der 5 Präparate, auch die Interferonbildung stimulierte. C. parvum, BCG und Levamisol schnitten wesentlich schlechter ab, waren zudem pyrogen und in bestimmten Konzentrationen auch toxisch. Als Fazit der Arbeit ergibt sich, daß beim Einsatz von Immunstimulantien genaue Kenntnisse über die Wirkungsmechanismen und die Unschädlichkeit der einzelnen Präparate notwendig sind, um sie wirksam und gezielt anwenden zu können. Die von uns benutzten 5 Testsysteme scheinen sich hierfür gut zu eignen. Auf die Herstellung von unschädlichen Immunstimulantien aus Pockenviren mit einer breiten Wirksamkeit wird aufmerksam gemacht. [ABSTRACT FROM AUTHOR]

The microbial immunostimulant OK-432 has been studied intensively in preclinical systems and has shown promise as an anticancer agent in trials that have been conducted over the past 20 years in Japan. To date, no systematic dose response evaluation of this agent has defined its dose-limiting toxicity or immunobiological activity. A phase IA study has been conducted in 25 patients with metastatic cancer at the University of Pittsburgh Cancer Institute Melanoma Center, establishing 30 KE as the maximal tolerable dosage, on the basis of cutaneous reactions. Subsequently, 48 patients with resected high-risk melanoma participated in a phase IB study of OK-432. This study has evaluated the immunomodulatory activity of OK-432 at five dosages ranging from 1 KE to 20 KE, administered ID twice weekly for 3 months. A formal analysis of the treated population in comparison to the randomized control group has been conducted, and profound immunological effects have been defined in the group of patients treated with OK-432. Patients who participated in this trial had a significant depression of OK-432- inducible cytokine production (interleukin-1β, interferon γ, and tumor necrosis factor α) at baseline. Treatment with OK-432 reversed this deficit for interferon γ (IFNγ) production in a dose-dependent manner, and mitigated the inhibition for interleukin-1 (IL-1) across all dosage groups. The impact of OK-432 upon other immunological functions of the treated cohorts is more variable, with durable suppression of mononuclear cell superoxide production, and in vitro cytotoxicity to tumor. Immunological characteristics of the entire cohort demonstrate a strong and significant correlation of elevated blood CD16+ cell counts and natural killer activity with early tumor progression and death due to melanoma. Favorable prognosis is associated with monocyte capacity to produce tumor necrosis factor (TNF), and polymorphonuclear leukocyte formylmethionyl-leucylphenylalanine-inducible superoxide release. This study reveals several new immunological correlates of tumor progression and lethal outcome in resected high-risk melanoma. It demonstrates that the depressed IL-1, TNF, and IFNγ release associated with melanoma may be mitigated by treatment with OK-432. This study has defined treatment and dose response patterns of immunomodulation associated with one of the most complex immunological agents yet evaluated in phase IB trials, in a well-defined population of high-risk patients with resected melanoma. [ABSTRACT FROM AUTHOR]

Immunostimulants are gradually being used in the prevention and treatment of recurrent respiratory tract infections in susceptible children, but their drug effects have not been quantified. The purpose of this study was to confirm the efficacy of immunostimulants in the prevention and treatment of recurrent respiratory tract infections in susceptible children. A model-based meta-analysis was used to describe the time course of placebo and immunostimulants in the prevention of respiratory tract infections in children. The cumulative number of respiratory tract infections was used as an indicator of efficacy. A meta-analysis was used to analyze the incidence of drug-related adverse events. Fourteen articles with 2400 pediatric subjects were finally included in the analysis. The results showed that the cumulative number of respiratory tract infections increased linearly with time, with the incidence of respiratory tract infections in the placebo group being 0.65 (95% confidence interval [CI], 0.55-0.75) per month. OM-85 BV and pidotimod reduced the incidence of respiratory tract infections by 0.21 (95%CI, 0.16-0.26) and 0.19 (95%CI, 0.17-0.21) compared to placebo per month, respectively. Pidotimod and OM-85 BV can effectively reduce the incidence of respiratory tract infections in susceptible children, with no significant increase in the incidence of drug-related adverse events when compared with placebo (risk ratio values were 1.07 [95%CI, 0.66-1.71] and 1.31 [95%CI, 0.54-3.19], respectively). This study provides quantitative support for the application of immunostimulants for the prevention of recurrent respiratory tract infections in children., (© 2021, The American College of Clinical Pharmacology.)

Stimulation of the fish immune system using immunostimulants is an environmentally friendly strategy to minimize bacterial outbreaks in aquaculture. Different biological and synthetic immunostimulants can enhance non-specific innate immune responses by directly activating immune cells. An example are Bacillus spp., known for their immunostimulatory effects, although the exact mechanisms by which Bacillus spp. offer protection against diseases remains to be elucidated. Furthermore, most studies have focused on Bacillus spp. cells, while the immunostimulant effect of their extracellular metabolome, known to harbour biologically important metabolites, including antimicrobial molecules, has been scarcely evaluated. Here, we evaluated the in vitro immune-modulatory properties of extracellular extracts of three Bacillus spp. strains (B. subtilis FI314, B. vezelensis FI436 and B. pumilus FI464), previously isolated from fish-guts and characterized for their in vitro and in vivo antimicrobial activity against a wide range of fish pathogens. Bacillus spp. extracellular extracts did not affect immune cells viability, but remarkably increased pathogens' phagocytosis when seabream head-kidney leukocytes were challenged with Vibrio anguillarum and Edwardsiella tarda. All extracts significantly increased the engulfment of bacterial pathogens 1 h post-infection. Cells stimulated with the extracellular extracts showed an up-regulation of the expression of immune-relevant genes associated with inflammation, including IL-1β, IL-6, and COX-2. In cells challenged with E. tarda, FI314 extracellular extract significantly increased the expression of IL-1β, IL-6, and COX-2, while FI436 and FI464 significantly increased IL-6 expression. The results of this study revealed that the extracellular molecules from Bacillus spp. fish isolates improved the in vitro response of gilthead seabream immune cells and are thus promising candidates to act as immunostimulants, helping fish fight diseases., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Autoimmune hepatitis is a chronic liver disease harboring an autoimmune basis and progressive character. Despite still obscurity in etiology and pathogenesis, some evidence supports the importance of sustaining the immune system. Vitamin D is a lipo-soluble vitamin, which has been identified as decreased in our body. It is often due to the daily habit change and decrease of individual sun exposure due to the increase of the ultraviolet-induced potential melanocytic transformation. Here, we emphasize the importance of vitamin D supplementation in patients affected with liver disease., Competing Interests: Conflict-of-interest statement: No conflicts of interest with regard to this manuscript exist., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Cobia ( Rachycentron canadum ) is a marine fish of high economic value that grows at a fast rate. However, intensive fish farming has led to disease outbreaks in cobia cultures, which is highly costly to the industry. The impact of infectious diseases on cobia production has led to the inappropriate and increased use of chemicals and antibiotics, which negatively affects the environment and human health and promotes the spread of drug-resistant pathogens. Hence, prophylactic measurements, such as the use of immunomodulators, are required to improve the health of cultured animals against pathogens. In this study, we examined the effects of Sarcodia suiae water extract (SSWE) in cobia in vitro and in vivo . We found that treatment with SSWE could significantly increase the expression of cytokines (e.g., IL-1β , IL-6 , IL-10 , IL-12 , and TNF-α ) and chemokines (e.g., IL-8 ) in primary cultured head kidney leukocytes. Intraperitoneal injection of SSWE (20 μg/g body weight) promoted higher expression of IL-6 , IL-8 , IL-10 , IL-12 , chemokines (e.g., CC1 ), and antibodies (e.g., IgT ) in head kidney and spleen tissues of the fish compared with other dose levels. Additionally, we describe for the second time (only after India) of the isolation of Photobacterium damselae subsp. damselae ( Phdd ) from a deadly epizootic in cage-farmed cobia. An intraperitoneal inoculation of SSWE before Phdd challenge showed that SSWE treatment could delay the onset of mortality of cobia. Finally, fish that received SSWE intraperitoneally before infection with Phdd exhibited elevated expression of Th1-type cytokines, namely, IL-8 , IL-12 , TNF-α , and IFN-γ . At the same time, the expression of Th2-related factors (such as IL-10 in the head kidney, and IgM and IgT in the spleen) were lower for the fish that received SSWE instead of PBS before the Phdd challenge. The results indicate that SSWE treatment facilitates the induction of Th1-type cytokines in cobia to fight against Phdd infection and has the potential to be used as an immunostimulant and vaccine adjuvant for fish., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Nan, Chiu, Tseng and Lee.)

The review considers liposomes as systems of substantial interest as adjuvant carriers in vaccinology due to their versatility and maximal biocompatibility. Research and development on the use of liposomes and lipid nanoparticles to create subunit vaccines for the prevention and treatment of infectious diseases has been going on for several decades. In recent years, the area has seen serious progress due to the improvement of the technology of industrial production of various high-grade lipids suitable for parenteral administration and the emergence of new technologies and equipment for the production of liposomal preparations. When developing vaccines, it is necessary to take into account how the body's immune system (innate and adaptive immunity) functions. The review briefly describes some of the fundamental mechanisms underlying the mobilization of immunity when encountering an antigen, as well as the influence of liposome carriers on the processes of internalization of antigens by immunocompetent cells and ways of immune response induction. The results of the studies on the interactions of liposomes with antigen-presenting cells in function of the liposome size, charge, and phase state of the bilayer, which depends on the lipid composition, are often contradictory and should be verified in each specific case. The introduction of immunostimulant components into the composition of liposomal vaccine complexes-ligands of the pathogen-associated molecular pattern receptors-permits modulation of the strength and type of the immune response. The review briefly discusses liposome-based vaccines approved for use in the clinic for the treatment and prevention of infectious diseases, including mRNA-loaded lipid nanoparticles. Examples of liposomal vaccines that undergo various stages of clinical trials are presented., Competing Interests: The authors declare they have no conflicts of interests., (© Pleiades Publishing, Ltd. 2022, ISSN 1990-7478, Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology, 2022, Vol. 16, No. 1, pp. 1–20. © Pleiades Publishing, Ltd., 2022.Russian Text © The Author(s), 2022, published in Biologicheskie Membrany, 2022, Vol. 39, No. 2, pp. 85–106.)

The gastrointestinal immune system plays an important role in immune homeostasis regulation. It regulates the symbiotic host-microbiome interactions by training and developing the host's innate and adaptive immunity. This interaction plays a vital role in host defence mechanisms and at the same time, balancing the endogenous perturbations of the host immune homeostasis. The fish gastrointestinal immune system is armed with intricate diffused gut-associated lymphoid tissues (GALTs) that establish tolerance toward the enormous commensal gut microbiome while preserving immune responses against the intrusion of enteric pathogens. A comprehensive understanding of the intestinal immune system is a prerequisite for developing an oral vaccine and immunostimulants in aquaculture, particularly in cultured fish species. In this review, we outline the remarkable features of gut immunity and the essential components of gut-associated lymphoid tissue. The mechanistic principles underlying the antigen absorption and uptake through the intestinal epithelial, and the subsequent immune activation through a series of molecular events are reviewed. The emphasis is on the significance of gut immunity in oral administration of immunoprophylactics, and the different potential adjuvants that circumvent intestinal immune tolerance. Comprehension of the intestinal immune system is pivotal for developing effective fish vaccines that can be delivered orally, which is less labour-intensive and could improve fish health and facilitate disease management in the aquaculture industry., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Yamamoto, Low, Loh and Chong.)

The use of yeasts as a dietary additive for fish can act as a source of nutrients and as an immunostimulant. This work aimed to evaluate the effects of the fermented biomass of the yeast Yarrowia lipolytica as a food additive on zootechnical and hematological parameters, and on immune response in the plasma and kidney of Nile Tilapia (Oreochromis niloticus). After supplementation with 3, 5, and 7% of the yeast biomass for 35 days, the blood and tissues of the animals of each experimental group were collected for analysis. The addition of this biomass in the feed promoted an improvement of zootechnical parameters in tilapia. There was also a rise in the number of neutrophils (groups with 3, 5, and 7%) and monocytes (group 3, 5, and 7%) compared with the control group. Moreover, there was an increase in the levels of lysozyme, myeloperoxidase, and nitrite/nitrate content in the blood of animals fed with yeast biomass. On the other hand, there were no observed alterations in survival and hematological parameters of animals fed with yeast biomass. In the analysis of the kidney, the addition of biomass in feed promoted an increase in levels of myeloperoxidase (group with 3%) but did not alter the levels of lysozyme and nitrite/nitrate content. In conclusion, this study demonstrated that Y. lipolytica had growth and immunostimulatory effects on Nile tilapia. These findings strongly suggest the potential application of a Y. lipolytica-based immunostimulant for tilapia aquaculture., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Viruses are abiotic obligate parasites utilizing complex mechanisms to hijack cellular machinery and reproduce, causing multiple harmful effects in the process. Viruses represent a growing global health concern; at the time of writing, COVID-19 has killed at least two million people around the world and devastated global economies. Lingering concern regarding the virus' prevalence yet hampers return to normalcy. While catastrophic in and of itself, COVID-19 further heralds in a new era of human-disease interaction characterized by the emergence of novel viruses from natural sources with heretofore unseen frequency. Due to deforestation, population growth, and climate change, we are encountering more viruses that can infect larger groups of people with greater ease and increasingly severe outcomes. The devastation of COVID-19 and forecasts of future human/disease interactions call for a creative reconsideration of global response to infectious disease. There is an urgent need for accessible, cost-effective antiviral (AV) drugs that can be mass-produced and widely distributed to large populations. Development of AV drugs should be informed by a thorough understanding of viral structure and function as well as human biology. To maximize efficacy, minimize cost, and reduce development of drug-resistance, these drugs would ideally operate through a varied set of mechanisms at multiple stages throughout the course of infection. Due to their abundance and diversity, natural compounds are ideal for such comprehensive therapeutic interventions. Promising sources of such drugs are found throughout nature; especially remarkable are the algae, a polyphyletic grouping of phototrophs that produce diverse bioactive compounds. While not much literature has been published on the subject, studies have shown that these compounds exert antiviral effects at different stages of viral pathogenesis. In this review, we follow the course of viral infection in the human body and evaluate the AV effects of algae-derived compounds at each stage. Specifically, we examine the AV activities of algae-derived compounds at the entry of viruses into the body, transport through the body via the lymph and blood, infection of target cells, and immune response. We discuss what is known about algae-derived compounds that may interfere with the infection pathways of SARS-CoV-2; and review which algae are promising sources for AV agents or AV precursors that, with further investigation, may yield life-saving drugs due to their diversity of mechanisms and exceptional pharmaceutical potential. [Display omitted] • COVID-19 and other novel viral diseases are a growing public health concern. • Microalgae, macroalgae, and cyanobacteria produce a wide array of antiviral compounds. • Algae-derived antivirals inhibit different viruses at various points during their replication. • Such multi-target therapies increase treatment efficacy and prevent drug-resistance. • Algae are a valuable source of potent bioactive compounds that may save many lives. [ABSTRACT FROM AUTHOR]

Microalgae are multifaceted photosynthetic microorganisms with emerging business potential. They are present ubiquitously in terrestrial and aquatic environments with rich species diversity and are capable of producing significant biomass. Traditionally, microalgal biomass is being used as food and feed in many countries around the globe. The production of microalgal-based bioactive compounds at an industrial scale through biotechnological interventions is gaining interest more recently. The present review provides a detailed overview of the key algal metabolites, which plays a crucial role in nutraceutical, functional foods, and animal/aquaculture feed industries. Bioactive compounds of microalgae known to exhibit antioxidant, antimicrobial, antitumor, and immunomodulatory effects were comprehensively reviewed. The potential microalgal species and biological extracts against human pathogens were also discussed. Further, current technologies involved in upstream and downstream bioprocessing including cultivation, harvesting, and cell disruption were documented. Establishing microalgae as an alternative supplement would complement the sustainable and environmental requirements in the framework of human health and well-being. [ABSTRACT FROM AUTHOR]

Infectious diseases represent a major cause of deaths worldwide. No vaccine or effective treatment exists nowadays, especially against intracellular pathogens. The increase in multiple drug and superbug antibiotic resistance strains, excessive medication, or misuse of drugs has prompted the search for other safe and effective alternatives. Consistent with this, adjuvants (Latin word "adjuvare": "help or aid") co-administered (Exo) in vaccines have emerged as a promising alternative to initiate and boost an innate, downstream signal that led to adaptative immune response. Nowadays, a promising model of strong immunogens and adjuvants at mucosal sites are the microbial bacterial toxins. Other adjuvants that are also used and might successfully replace aluminum salts in combination with nanotechnology are CpG-ODN, poly IC, type I IFNs, mRNA platforms. Therefore, in the present review, we focused to revisit the old to the new adjuvants compounds, the properties that make them friends in vaccine formulations against infectious diseases.

Yarrowia lipolytica has been widely used in food industry but scarcely explored as probiotics. Thus, the aims of this study were to characterize in vitro the probiotic potential, antioxidant capacity, and antimicrobial activity of the marine yeast Y. lipolytica D-1 and N-6 strains. Dietary administration effect was evaluated in vivo on immunological parameters in serum, skin-mucus, intestine, and fish leukocytes upon challenge with Vibrio parahaemolyticus. The results showed that Y. lipolytica D-1 and N-6 strains grew with NaCl or bile salts but were sensitive to low pH. Each of the Y. lipolytica strains had a distinctive antioxidant capacity and fatty acid profile, but their antimicrobial activity was similar against fish bacterial pathogens. Fish (Lutjanus peru) supplemented with Y. lipolytica strains showed normal intestinal morphology, high IgM levels, and antioxidant enzyme activities. Immune-related genes were modulated in fish fed Y. lipolytica in a strain-dependent fashion. In addition, leucocytes from fish fed Y. lipolytica challenged with V. parahaemolyticus increased innate immune and antioxidant parameters compared with the control groups. In conclusion, the marine yeast Y. lipolytica D-1 and N-6 strains may be potential probiotics for fish by exerting free-radical scavenging, antimicrobial activity, and improved immune-protective responses against V. parahaemolyticus infection., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)