1,25 dihydroxyvitamin D3-mediated effects on bovine innate immunity and on biofilm-forming Staphylococcus spp. isolated from cattle with mastitis.

Mastitis is one the most widespread and serious diseases in dairy cattle. Recurrent and chronic infections are often attributable to certain pathogenicity mechanisms in mastitis-causing pathogens such as Staphylococcus spp. These include growing in biofilm and invading cells, both of which make it possible to resist or evade antimicrobial therapies and the host's immune system. This study tested the effects of active vitamin D3 (i.e., calcitriol or 1,25-dihydroxyvitamin D3) on the internalization and phagocytosis of biofilm-forming Staphylococcus spp. isolated from animals with mastitis. Two established bovine cell lines were used: MAC-T (mammary epithelial cells) and BoMac (macrophages). Calcitriol (0-200 nM) did not affect the viability of MAC-T cells nor that of BoMac cells after 24 and 72 h. Concentrations of 0-100 mM for 24 h upregulated the expression of 24-hydroxylase in MAC-T cells, but did not alter that of VDR. Pre-treatment of the cells with calcitriol for 24 h decreased the internalization of S. aureus V329 into MAC-T cells (0-100 nM), and stimulated the phagocytosis of the same strain and of S. xylosus 4913 (0-10 nM). Calcitriol and two conditioned media, obtained by treating the cells with 25-200 nM of the metabolite for 24 h, were also assessed in terms of their antimicrobial and antibiofilm activity. Neither calcitriol by itself nor the conditioned media affected staphylococcal growth or biofilm formation (0-200 nM for 12 and 24 h, respectively). In contrast, the conditioned media (0-100 nM for 24 h) decreased the biomass of preformed non-aureus staphylococcal biofilms and killed the bacteria within them, without affecting metabolic activity. These effects may be mediated by reactive oxygen species and proteins with antimicrobial and/or antibiofilm activity. In short, calcitriol could make pathogens more accessible to antimicrobial therapies and enhance bacterial clearance by professional phagocytes. Moreover, it may modulate the host's endogenous defenses in the bovine udder and help combat preformed non-aureus staphylococcal biofilms (S. chromogenes 40, S. xylosus 4913, and/or S. haemolyticus 6). The findings confirm calcitriol's potential as an adjuvant to prevent and/or treat intramammary infections caused by Staphylococcus spp., which would in turn contribute to reducing antibiotic use on dairy farms.

Wogonin improves colitis by activating the AhR pathway to regulate the plasticity of ILC3/ILC1.

BACKGROUND: Intestinal barrier dysfunction caused by the disrupted balance of group 3 innate lymphoid cells (ILC3)/group 1 innate lymphoid cells (ILC1) is a significant feature in the pathogenesis of inflammatory bowel disease (IBD). Activation of aryl hydrocarbon receptor (AhR) signaling contributes to the maintenance of ILC3/ILC1 balance. Wogonin, a natural flavonoid from Scutellaria baicalensis Georgi, can repair intestinal mucosal damage of IBD. However, it remains unclear if wogonin can exert a therapeutic effect by activating the AhR pathway to regulate the plasticity of ILC3/ILC1. PURPOSE: In this study, we investigated the immunomodulatory effects of wogonin on IBD and its potential mechanisms in vitro and in vivo. STUDY DESIGN AND METHODS: Chronic colitis was induced by four cycles of 2 % DSS treatment in mice. 20 mg kg-1/day wogonin was administrated by oral gavage and mice were treated intraperitoneally with 10 mg kg-1/2 days CH223191 to block the AhR pathway. Colon tissues were processed for histopathological examination and evaluation of the epithelial barrier function by immunohistochemistry. The activation of the AhR pathway and the plasticity of ILC3/ILC1 were determined by western blot and flow cytometry. Then, we also detected the intestinal microflora and their metabolites by 16 s sequencing and non-targeted Metabolomics analysis. Furthermore, an in vitro culture system consisting of MNK3 cells and NCM460 cells, and a CETSA assay were performed to confirm the molecular mechanism. RESULTS: Wogonin ameliorated histological severity of the colon, decreased the secretion of inflammatory factors, and increased tight junction proteins in colitis mice. These effects are associated with the tendency of conversion from ILC3 to ILC1 prevented by wogonin, which was offset by AhR antagonist CH223191. In addition, wogonin exerted the curative effect by altering gut microbiota to produce metabolites such as Kynurenic acid, and 1H-Indole-3-carboxaldehyde as AhR endogenous ligands. In vitro data further verified that wogonin as an exogenous ligand directly binds to the structural domain of AhR by CETSA. Also, the supernatant of MNK-3 cells stimulated with wogonin enhanced expression of Occludin and Claudin1 in NCM460 cells induced by LPS. CONCLUSION: Cumulatively, our study illustrated that wogonin improved the outcomes of DSS-induced chronic colitis via regulating the plasticity of ILC3/ILC1. Its specific mechanism is to binding to AhR directly, and to activate the AhR pathway indirectly by altering the tryptophan metabolisms of gut microbiota.

The Dietary Intake of Carrot-Derived Rhamnogalacturonan-I Accelerates and Augments the Innate Immune and Anti-Viral Interferon Response to Rhinovirus Infection and Reduces Duration and Severity of Symptoms in Humans in a Randomized Trial.

Acute respiratory infections are an important health concern. Traditionally, polysaccharide-enriched extracts from plants, containing immunomodulatory rhamnogalacturonan-I (RG-1), were used prophylactically. We established the effects of dietary supplementation with carrot-derived RG-I (cRG-I, 0-0.3-1.5 g/day) in 177 healthy individuals (18-65 years) on symptoms following infection with rhinovirus strain 16 (RV16). Primary outcomes were changes in severity and duration of symptoms, and viral load in nasal lavage. Secondary outcomes were changes in innate immune and anti-viral responses, reflected by CXCL10 and CXCL8 levels and cell differentials in nasal lavage. In a nested cohort, exploratory transcriptome analysis was conducted on nasal epithelium. Intake of cRG-I was safe, well-tolerated and accelerated local cellular and humoral innate immune responses induced by RV16 infection, with the strongest effects at 1.5 g/d. At 0.3 g/d, a faster interferon-induced response, induction of the key anti-viral gene EIF2AK2, faster viral clearance, and reduced symptom severity (-20%) and duration (-25%) were observed. Anti-viral responses, viral clearance and symptom scores at 1.5 g/d were in between those of 0 and 0.3 g/d, suggesting a negative feedback loop preventing excessive interferon responses. Dietary intake of cRG-I accelerated innate immune and antiviral responses, and reduced symptoms of an acute respiratory viral infection.

A Bioactive Extract Rich in Triterpenic Acid and Polyphenols from Olea europaea Promotes Systemic Immunity and Protects Atlantic Salmon Smolts Against Furunculosis.

In the present study, the modulation of the transcriptional immune response (microarray analysis) in the head kidney (HK) of the anadromous fish Atlantic salmon (Salmo salar) fed a diet supplemented with an olive fruit extract (AQUOLIVE®) was evaluated. At the end of the trial (133 days), in order to investigate the immunomodulatory properties of the phytogenic tested against a bacterial infection, an in vivo challenge with Aeromonas salmonicida was performed. A total number of 1,027 differentially expressed genes (DEGs) (805 up- and 222 downregulated) were found when comparing the transcriptomic profiling of the HK from fish fed the control and AQUOLIVE® diets. The HK transcripteractome revealed an expression profile that mainly favored biological processes related to immunity. Particularly, the signaling of i-kappa B kinase/NF-kappa and the activation of leukocytes, such as granulocytes and neutrophils degranulation, were suggested to be the primary actors of the innate immune response promoted by the tested functional feed additive in the HK. Moreover, the bacterial challenge with A. salmonicida that lasted 12 days showed that the cumulative survival was higher in fish fed the AQUOLIVE® diet (96.9 ± 6.4%) than the control group (60.7 ± 13.5%). These results indicate that the dietary supplementation of AQUOLIVE® at the level of 0.15% enhanced the systemic immune response and reduced the A. salmonicida cumulative mortality in Atlantic salmon smolts.

Phosphodiesterase-4 Inhibition Reduces Cutaneous Inflammation and IL-1ß Expression in a Psoriasiform Mouse Model but Does Not Inhibit Inflammasome Activation.

Apremilast (Otezla®) is an oral small molecule phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet's disease. While PDE4 inhibition overall is mechanistically understood, the effect of apremilast on the innate immune response, particularly inflammasome activation, remains unknown. Here, we assessed the effect of apremilast in a psoriasis mouse model and primary human cells. Psoriatic lesion development in vivo was studied in K5.Stat3C transgenic mice treated with apremilast for 2 weeks, resulting in a moderate (2 mg/kg/day) to significant (6 mg/kg/day) resolution of inflamed plaques after 2-week treatment. Concomitantly, epidermal thickness dramatically decreased, the cutaneous immune cell infiltrate was reduced, and proinflammatory cytokines were significantly downregulated. Additionally, apremilast significantly inhibited lipopolysaccharide- or anti-CD3-induced expression of proinflammatory cytokines in peripheral mononuclear cells (PBMCs). Notably, inflammasome activation and secretion of IL-1ß were not inhibited by apremilast in PBMCs and in human primary keratinocytes. Collectively, apremilast effectively alleviated the psoriatic phenotype of K5.Stat3 transgenic mice, further substantiating PDE4 inhibitor-efficiency in targeting key clinical, histopathological and inflammatory features of psoriasis. Despite lacking direct effect on inflammasome activation, reduced priming of inflammasome components upon apremilast treatment reflected the indirect benefit of PDE4 inhibition in reducing inflammation.

Dietary Supplementation with Biobran/MGN-3 Increases Innate Resistance and Reduces the Incidence of Influenza-like Illnesses in Elderly Subjects: A Randomized, Double-Blind, Placebo-Controlled Pilot Clinical Trial.

Influenza-like illness (ILI) remains a major cause of severe mortality and morbidity in the elderly. Aging is associated with a decreased ability to sense pathogens and mount effective innate and adaptive immune responses, thus mandating the development of protective nutraceuticals. Biobran/MGN-3, an arabinoxylan from rice bran, has potent anti-aging and immunomodulatory effects, suggesting that it may be effective against ILI. The objective of the current study was to investigate the effect of Biobran/MGN-3 on ILI incidence, natural killer (NK) cell activity, and the expressions of RIG-1 (retinoic acid-inducible gene 1), MDA5 (melanoma differentiation-associated protein 5), and their downstream signaling genes ISG-15 (interferon-stimulated genes 15) and MX1 (myxovirus (influenza) resistance 1, interferon-inducible). A double-blind, placebo-controlled clinical trial included eighty healthy older adults over 55 years old, 40 males and 40 females, who received either a placebo or Biobran/MGN-3 (500 mg/day) for 3 months during known ILI seasonality (peak incidence) in Egypt. The incidence of ILI was confirmed clinically according to the WHO case definition criteria. Hematological, hepatic, and renal parameters were assessed in all subjects, while the activity of NK and NKT (natural killer T) cells was assessed in six randomly chosen subjects in each group by the degranulation assay. The effect of Biobran/MGN-3 on RIG-1 and MDA5, as well as downstream ISG15 and MX1, was assessed in BEAS-2B pulmonary epithelial cells using flow cytometry. The incidence rate and incidence density of ILI in the Biobran/MGN-3 group were 5.0% and 0.57 cases per 1000 person-days, respectively, compared to 22.5% and 2.95 cases per 1000 person-days in the placebo group. Furthermore, Biobran/MGN-3 ingestion significantly enhanced NK activity compared to the basal levels and to the placebo group. In addition, Biobran/MGN-3 significantly upregulated the expression levels of RIG-1, MDA5, ISG15, and MX1 in the human pulmonary epithelial BEAS-2B cell lines. No side effects were observed. Taken together, Biobran/MGN-3 supplementation enhanced the innate immune response of elderly subjects by upregulating the NK activity associated with reduction of ILI incidence. It also upregulated the intracellular RIG-1, MDA5, ISG15, and MX1 expression in pulmonary epithelial tissue cultures. Biobran/MGN-3 could be a novel agent with prophylactic effects against a wide spectrum of respiratory viral infections that warrants further investigation.

Results of Complex Immunopharmacological Analysis of the Mechanisms of Action of Bioregulation Agents.

Elucidation of the pharmacodynamic mechanisms of drugs capable of potentiating the effects of non-steroidal anti-inflammatory drugs is an important task. In this in vitro study, the ability of Traumeel S to influence the innate and acquired immunity was evaluated. Traumeel S was found to reduce activities of NADPH oxidase and neutrophil extracellular traps, as well as to evoke anti-inflammatory activity of lymphocyte subpopulations.

Vitamin D and COVID-19: An Overview of Recent Evidence.

The novel coronavirus severe acute respiratory syndrome (SARS-CoV-2) has progressed rapidly from an outbreak to a global pandemic, with new variants rapidly emerging. Coronavirus disease 2019 (COVID-19), the disease resulting from SARS-CoV-2 infection, can lead to multiorgan damage. Due to the extremely contagious and fatal nature of the virus, it has been a priority of medical research to find effective means of treatment. Amid this search, the role of vitamin D in modulating various aspects of the innate and adaptive immune system has been discussed. This review aims to consolidate the research surrounding the role of vitamin D in the treatment and prevention of COVID-19. While there are some conflicting results reported, the consensus is that vitamin D has a host of immunomodulatory effects which may be beneficial in the context of COVID-19 and that low levels of vitamin D can result in dysfunction of crucial antimicrobial effects, potentially contributing to poor prognosis. Studies also show that the effects of low vitamin D can be mitigated via supplementation, although the benefits of vitamin D supplementation in the treatment of COVID-19 remain controversial.

Modified BuShenYiQi formula alleviates experimental allergic asthma in mice by negative regulation of type 2 innate lymphoid cells and CD4+ type 9 helper T cells and the VIP-VPAC2 signalling pathway.

CONTEXT: Modified BuShenYiQi formula (M-BYF) is derived from BuShenYiQi formula, used for the treatment of allergic asthma. The exact effect and mechanism of M-BYF on the improvement of asthma remain unclear. OBJECTIVE: We investigated the mechanism underlying the therapeutic effect of M-BYF on allergic asthma. MATERIALS AND METHODS: The asthma model was established in female BALB/c mice that were sensitized and challenged with ovalbumin (OVA). Mice in the treated groups were orally treated once a day with M-BYF (7, 14 and 28 g/kg/d) or dexamethasone before OVA challenge. Control and Model group received saline. Pathophysiological abnormalities and percentages of lung type 2 innate lymphoid cells (ILC2s) and Th9 cells were measured. Expression levels of type 2 cytokines and transcription factors required for these cells function and differentiation were analysed. Expression of vasoactive intestinal polypeptide (VIP)-VPAC2 signalling pathway-related proteins, and percentages of VIP expressing (VIP+) cells and VPAC2, CD90 co-expressing (VPAC2+CD90+) cells were detected. RESULTS: M-BYF alleviated airway hyperresponsiveness, inflammation, mucus hypersecretion and collagen deposition in asthmatic mice. M-BYF down-regulated percentages of ILC2s and Th9 cells with lower expression of GATA3, PU.1 and IRF4, reduced IL-5, IL-13, IL-9 and VIP production. The decrease in the expression of VIP-VPAC2 signalling pathway and percentages of VIP+ cells, VPAC2+CD90+ cells were observed after M-BYF treatment. The LD50 value of M-BYF was higher than 90 g/kg. DISCUSSION AND CONCLUSIONS: M-BYF alleviated experimental asthma by negatively regulating ILC2s and Th9 cells and the VIP-VPAC2 signalling pathway. These findings provide the theoretical basis for future research of M-BYF in asthma patient population.

Predicting the herbal medicine triggering innate anti-tumor immunity from a system pharmacology perspective.

Although the main focus of immuno-oncology has been manipulating the adaptive immune system, tumor associated macrophages (TAMs) are the main infiltrating component in the tumor microenvironment (TME) and play a critical role in cancer progression. TAMs are mainly divided into two different subtypes: macrophages with antitumor or killing activity are called M1 while tumor-promoting or healing macrophages are named M2. Therefore, controlling the polarization of TAMs is an important strategy for cancer treatment, but there is no particularly effective means to regulate the polarization process. Here, combined systems pharmacology targets and pathways analysis strategy, we uncovered Scutellariae Radix (SR) has the potential to regulate TAMs polarization to inhibit the growth of non-small cell lung cancer (NSCLC). Firstly, systems pharmacology approach was used to reveal the active components of SR targeting macrophages in TME through compound target prediction and target-microenvironment phenotypic association analysis. Secondly, in vitro experiment verified that WBB (wogonin, baicalein and baicalin), major active ingredients of SR are significantly related to macrophages and survival, initiated macrophages programming to M1-like macrophages to promoted the apoptosis of tumor cells. Finally, we evidenced that WBB effectively inhibited tumor growth in LLC (Lewis lung carcinoma) tumor-bearing mice and increased the infiltration of M1-type macrophages in TME. Overall, the systems pharmacology strategy offers a paradigm to understand the mechanism of polypharmacology of natural products targeting TME.

Modulatory effects of laurel-leaf cistus (Cistus laurifolius) ethanolic extract on innate immune responses and disease resistance in common carp (Cyprinus carpio).

Medicinal herbs are used for growth promotion, disease control and other health benefits in aquaculture industry. Here, we examined the effect of dietary laurel-leaf cistus (Cistus laurifolius) ethanolic extract on growth performance, digestive enzyme activity, haematological profile and nonspecific immune responses in common carp (Cyprinus carpio). In addition, resistance against Aeromonas hydrophila infection was examined. Common carp was fed diets containing 0 (Control), 0.1 (CL0.1), 0.5 (CL0.5) and 1 (CL1) g kg-1 laurel-leaf cistus extract for 45 days. After 30 days, superoxide anion production (SAP) increased in CL0.1 and CL0.5 fish groups and at the end of the study all experimental fish groups had higher SAP compared to that of the control (P ˂ 0.05). Lysozyme activity (LA) was elevated in CL0.5 and CL1 treated groups on 30th day (P < 0.05), and this increase was only observed in C0.1 fish group at the end of study compared to control (P ˂ 0.05). Myeloperoxidase activity was significantly increased in CL0.5 and CL1 fish groups at the end of study. IL-1ßgene expression was significantly increased in treated fish in a dose-depended manner. Similar results were observed for transcription of IL-6 and IL-8 (P < 0.05). Anti-inflammatory cytokines, IL-10 and TGF-ß were highly up-regulated in the intestine and head kidney of CL treated fish groups compared to control (P < 0.05). At the end of experiment, significantly higher final body weight, weight gain, and specific growth rate were obtained in CL0.1 treated fish group compared to control. However, growth was negatively affected in CL1 fish group (P < 0.05). CL1 fish group had also a significantly higher FCR. Amylase activity was significantly increased in all experimental fish groups compared to control (P ˂ 0.05). Trypsin activity was decreased in CL0.1 and CL1 fish groups (P ˂ 0.05). WBC and RBC were significantly increased (P ˂ 0.05) in CL0.5 and CL1 fish groups, whereas haemoglobin, haematocrit, mean cell, mean cell haemoglobin contents were no significantly changed among control and treatment groups. Result of challenge test with A. hydrophila exhibited that survival rate in all treatment groups was significantly higher than that of control. These findings demonstrated that laurel-leaf cistus at 0.1 g kg-1 can be a suitable candidate for growth promotion, immune system induction and infection control in fish.

Therapeutic effect and immune mechanism of chitosan-gentamicin conjugate on Pacific white shrimp (Litopenaeus vannamei) infected with Vibrio parahaemolyticus.

To explore the disease resistance mechanism of chitosan conjugates, chitosan-gentamicin conjugate (CS-GT) was synthesized and systematically characterized, the immune mechanism of CS-GT on Litopenaeus vannamei infected with Vibrio parahaemolyticus was further explored. The results showed that imine groups in CS-GT were effectively reduced. Dietary supplementation of CS-GT can significantly increase the survival rate, total hemocyte counts, the antioxidant and immune related enzyme activity levels of shrimps (P < 0.05), which are all dose-dependent under the experimental conditions. In addition, CS-GT can protect the hepatopancreas from invading bacteria and alleviate inflammation. Particularly, CS-GT promotes the expressions of legumain (LGMN), lysosomal acid lipase (LIPA) and Niemann-Pick type C2 (NPC2) up-regulated. It is speculated that CS-GT may stimulate the lysosome to phagocytose pathogens more effectively. In conclusions, shrimps fed with CS-GT can produce immune response via lysosome and greatly improve the disease resistance to Vibrio parahaemolyticus.

Evaluation of Alpha-Ketoglutarate Supplementation on the Improvement of Intestinal Antioxidant Capacity and Immune Response in Songpu Mirror Carp (Cyprinus carpio) After Infection With Aeromonas hydrophila.

As an intermediate substance of the tricarboxylic acid cycle and a precursor substance of glutamic acid synthesis, the effect of alpha-ketoglutarate on growth and protein synthesis has been extensively studied. However, its prevention and treatment of pathogenic bacteria and its mechanism have not yet been noticed. To evaluate the effects of alpha-ketoglutarate on intestinal antioxidant capacity and immune response of Songpu mirror carp, a total of 360 fish with an average initial weight of 6.54 ± 0.08 g were fed diets containing alpha-ketoglutarate with 1% for 8 weeks. At the end of the feeding trial, the fish were challenged with Aeromonas hydrophila for 2 weeks. The results indicated that alpha-ketoglutarate supplementation significantly increased the survival rate of carp after infection with Aeromonas hydrophila (P < 0.05), and the contents of immune digestion enzymes including lysozyme, alkaline phosphatase and the concentration of complement C4 were markedly enhanced after alpha-ketoglutarate supplementation (P < 0.05). Also, appropriate alpha-ketoglutarate increased the activities of total antioxidant capacity and catalase and prevented the up-regulation in the mRNA expression levels of pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1ß, interleukin-6, and interleukin-8 (P < 0.05). Furthermore, the mRNA expression levels of toll-like receptor 4 (TLR4), and nuclear factor kappa-B (NF-κB) were strikingly increased after infection with Aeromonas hydrophila (P < 0.05), while the TLR4 was strikingly decreased with alpha-ketoglutarate supplementation (P < 0.05). Moreover, the mRNA expression levels of tight junctions including claudin-1, claudin-3, claudin-7, claudin-11 and myosin light chain kinases (MLCK) were upregulated after alpha-ketoglutarate supplementation (P < 0.05). In summary, the appropriate alpha-ketoglutarate supplementation could increase survival rate, strengthen the intestinal enzyme immunosuppressive activities, antioxidant capacities and alleviate the intestinal inflammation, thereby promoting the intestinal immune responses and barrier functions of Songpu mirror carp via activating TLR4/MyD88/NF-κB and MLCK signaling pathways after infection with Aeromonas hydrophila.

Effects of Kumaizasa (Sasa senanensis) Leaf Extract on Innate Immune Regulation in HEK293 Cells and Macrophages.

BACKGROUND/AIM: We investigated the effect of Kumaizasa leaf extract (KLE) on innate immunity using the HEK293 and RAW 264.7 cell lines. MATERIALS AND METHODS: KLE, lipopolysaccharides (LPS), or KLE with LPS were added to RAW 264.7 cells. The TNF-α and IL-1ß mRNA expression was then quantified. The expression of MAPKs, NFĸB, TNF-α and IL-1ß proteins was also quantified. In addition, KLE was added to HEK293 cells and the IL-8 concentration was measured. RESULTS: In RAW 264.7 cells, KLE increased the levels of TNF-α and IL-1ß mRNA. By contrast, when KLE and LPS were added to RAW 264.7 cells, the increase in TNF-α and IL-1ß mRNA was ameliorated. Similarly, the expression of JNK and ERK proteins was reduced. The addition of KLE to HEK293 cells induced IL-8 production. CONCLUSION: Based on these results, a KLE-mediated mechanism may regulate immunity by suppressing the expression of JNK and ERK, which are involved in inflammatory signal transduction.

Beneficial Modulation of Lipid Mediator Biosynthesis in Innate Immune Cells by Antirheumatic Tripterygium wilfordii Glycosides.

Tripterygium wilfordii glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation and immune responses and are strongly linked to RA. The mechanism by which TWG affects LM networks in RA treatment remains elusive. Employing LM metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry revealed striking modulation of LM pathways by TWG in human monocyte-derived macrophage (MDM) phenotypes. In inflammatory M1-MDM, TWG (30 µg/mL) potently suppressed agonist-induced formation of 5-LOX products which was confirmed in human PMNL and traced back to direct inhibition of 5-LOX (IC50 = 2.9 µg/mL). TWG also efficiently blocked thromboxane formation in M1-MDM without inhibiting other prostanoids and COX enzymes. Importantly, in anti-inflammatory M2-MDM, TWG (30 µg/mL) induced pronounced formation of specialized pro-resolving mediators (SPM) and related 12/15-LOX-derived SPM precursors, without COX and 5-LOX activation. During MDM polarization, TWG (1 µg/mL) decreased the capacity to generate pro-inflammatory 5-LOX and COX products, cytokines and markers for M1 phenotypes. Together, suppression of pro-inflammatory LM but SPM induction may contribute to the antirheumatic properties of TWG.

Vascular Endothelial Growth Factor, a Key Modulator of the Anti-Tumor Immune Response.

During tumor growth, angiogenesis is required to ensure oxygen and nutrient transport to the tumor. Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and appears to be a key modulator of the anti-tumor immune response. Indeed, VEGF modulates innate and adaptive immune responses through direct interactions and indirectly by modulating protein expressions on endothelial cells or vascular permeability. The inhibition of the VEGF signaling pathway is clinically approved for the treatment of several cancers. Therapies targeting VEGF can modulate the tumor vasculature and the immune response. In this review, we discuss the roles of VEGF in the anti-tumor immune response. In addition, we summarize therapeutic strategies based on its inhibition, and their clinical approval.

YIV-906 potentiated anti-PD1 action against hepatocellular carcinoma by enhancing adaptive and innate immunity in the tumor microenvironment.

YIV-906 (PHY906) is a standardized botanical cancer drug candidate developed with a systems biology approach-inspired by a traditional Chinese herbal formulation, historically used to treat gastrointestinal symptoms including diarrhea, nausea and vomiting. In combination with chemotherapy and/or radiation therapy, preclinical and clinical results suggest that YIV-906 has the potential to prolong survival and improve quality of life for cancer patients. Here, we demonstrated that YIV-906 plus anti-PD1 could eradicate all Hepa 1-6 tumors in all tumor bearing mice. YIV-906 was found to have multiple mechanisms of action to enhance adaptive and innate immunity. In combination, YIV-906 reduced PD1 or counteracted PD-L1 induction caused by anti-PD1 which led to higher T-cell activation gene expression of the tumor. In addition, YIV-906 could reduce immune tolerance by modulating IDO activity and reducing monocytic MDSC of the tumor. The combination of anti-PD1 and YIV-906 generated acute inflammation in the tumor microenvironment with more M1-like macrophages. YIV-906 could potentiate the action of interferon gamma (IFNg) to increase M1-like macrophage polarization while inhibiting IL4 action to decrease M2 macrophage polarization. Flavonoids from YIV-906 were responsible for modulating IDO activity and potentiating IFNg action in M1-like macrophage polarization. In conclusion, YIV-906 could act as an immunomodulator and enhance the innate and adaptive immune response and potentiate anti-tumor activity for immunotherapies to treat cancer.

Hot water extract of Pleurotus pulmonarius stalk waste enhances innate immune response and immune-related gene expression in red hybrid tilapia Oreochromis sp. following challenge with pathogen-associated molecular patterns.

In aquaculture, commercial fish such as red hybrid tilapia are usually raised at high density to boost the production within a short period of time. This overcrowded environment, however, may cause stress to the cultured fish and increase susceptibility to infectious diseases. Antibiotics and chemotherapeutics are used by fish farmers to overcome these challenges, but this may increase the production cost. Studies have reported on the potential of mushroom polysaccharides that can act as immunostimulants to enhance the immune response and disease resistance in fish. In the current study, hot water extract (HWE) from mushroom stalk waste (MSW) was used to formulate fish feed and hence administered to red hybrid tilapia to observe the activation of immune system. Upon 30 days of feeding, the fish were challenged with pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides (LPS) and polyinosinic:polycytidylic acid (poly (I:C)) to mimic bacterial and viral infection, respectively. HWE supplementation promoted better feed utilisation in red hybrid tilapia although it did not increase the body weight gain and specific growth rate compared to the control diet. The innate immunological parameters such as phagocytic activity and respiratory burst activity were significantly higher in HWE-supplemented group than that of the control group following PAMPs challenges. HWE-supplemented diet also resulted in higher mRNA transcription of il1b and tnfa in midgut, spleen and head kidney at 1-day post PAMPs injection. Tlr3 exhibited the highest upregulation in the HWE fed fish injected with poly (I:C). At 3-days post PAMPs injection, both ighm and tcrb expression were upregulated significantly in the spleen and head kidney. Results showed that HWE supplementation enhances the immune responses of red hybrid tilapia and induced a higher serum bactericidal activity against S. agalactiae.

Modulation of growth, innate immunity, and disease resistance of Nile tilapia (Oreochromis niloticus) culture under biofloc system by supplementing pineapple peel powder and Lactobacillus plantarum.

Eight weeks feeding experiment was managed to evaluate the impacts of dietary addition of pineapple peel powder (PAPP) and Lactobacillus plantarum CR1T5 (LP) individual or mixed on growth performance, skin mucus and serum immunities, as well as disease resistance of Nile tilapia. Fish (average weight 20.91 ± 0.11 g) were fed four diets: Diet 1 (0 g kg-1 PAPP and 0 CFU g-1 L. plantarum, Diet 2 (10 g kg-1 PAPP), Diet 3 (108 CFU g-1L. plantarum), and Diet 4 (10 g kg-1 PAPP + 108 CFU g-1L. plantarum). Serum and mucus immune responses, as well as growth rate, were assessed every 4 weeks. Ten fish were chosen for the challenge test with Streptococcus agalactiae after 8 weeks post-feeding. The findings showed that PAPP and/or LP diets increased (P ≤ 0.05) growth performance, skin mucus, and serum immune responses. The best data were obtained in fish fed a mixture of PAPP and LP. Nevertheless, no variation (P > 0.05) was recorded between groups fed PAPP or LP. The relative survival percentage (RSP, %) in Diet 2, Diet 3, and Diet 4 was 46.15%, 50.0%, and 73.08%. Fish fed mixture of PAPP + LP recorded the best (P < 0.05) survival rate versus other treatments. The current findings recommended using a mixture of PAPP and LP as promising functional additives for aquaculture practice.

Amelioration of immune and digestive system through weed supplemented feed against Aeromonas hydrophila in Clarias gariepinus.

Aquaculture is one of the important globally growing industries. It serves as an important food source of protein for human beings. With the expanding demand for the fish and their products it has become extremely important to improve the aquaculture practices. Aquaculture in India has witnessed huge mortalities caused by bacteria, viruses, fungi, nematodes etc. Aquatic weeds plants are harmful for aquaculture in many ways. Present study is aimed to overcome the disease caused by Aeromonas hydrophila (fish pathogenic bacteria) through feed supplementation of two aquatic weed plants (Azolla pinnata and Ceratophyllum demersum). The fish were divided into 6 groups: experimental groups (fish fed on supplementary feed at 5% and 2.5% concentration for individual plant and challenged with bacteria), positive control (fish fed on non-supplemented feed and challenged with bacteria) and negative control (fish fed on non-supplementary feed and not challenged with bacteria). It was observed that supplemented feed enhanced both cell mediated and humoral immunity in fish. Therefore, we advocate that feed formulated with incorporation of Azolla pinnata and Ceratophyllum demersum leaf powder at 5% and 2.5% could be used to prevent disease caused by A. hydrophila or can be used to enhance fish health by boosting its immune system. The results of this study also showed an improved digestibility in fish fed on supplemented feed.