Serotonin signalling in cancer: Emerging mechanisms and therapeutic opportunities.

BACKGROUND: Serotonin (5-hydroxytryptamine) is a multifunctional bioamine serving as a neurotransmitter, peripheral hormone and mitogen in the vertebrate system. It has pleiotropic activities in central nervous system and gastrointestinal function via an orchestrated action of serotonergic elements, particularly serotonin receptor-mediated signalling cascades. The mitogenic properties of serotonin have garnered recognition for years and have been exploited for repurposing serotonergic-targeted drugs in cancer therapy. However, emerging conflicting findings necessitate a more comprehensive elucidation of serotonin's role in cancer pathogenesis. MAIN BODY AND CONCLUSION: Here, we provide an overview of the biosynthesis, metabolism and action modes of serotonin. We summarise our current knowledge regarding the effects of the peripheral serotonergic system on tumourigenesis, with a specific emphasis on its immunomodulatory activities in human cancers. We also discuss the dual roles of serotonin in tumour pathogenesis and elucidate the potential of serotonergic drugs, some of which display favourable safety profiles and impressive efficacy in clinical trials, as a promising avenue in cancer treatment. KEY POINTS: Primary synthesis and metabolic routes of peripheral 5-hydroxytryptamine in the gastrointestinal tract. Advanced research has established a strong association between the serotonergic components and carcinogenic mechanisms. The interplay between serotonergic signalling and the immune system within the tumour microenvironment orchestrates antitumour immune responses. Serotonergic-targeted drugs offer valuable clinical options for cancer therapy.

DZ2002 alleviates corneal angiogenesis and inflammation in rodent models of dry eye disease via regulating STAT3-PI3K-Akt-NF-κB pathway.

Dry eye disease (DED) is a prevalent ocular disorder with a multifactorial etiology. The pre-angiogenic and pre-inflammatory milieu of the ocular surface plays a critical role in its pathogenesis. DZ2002 is a reversible type III S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, which has shown excellent anti-inflammatory and immunosuppressive activities in vivo and in vitro. In this study, we evaluated the therapeutic potential of DZ2002 in rodent models of DED. SCOP-induced dry eye models were established in female rats and mice, while BAC-induced dry eye model was established in female rats. DZ2002 was administered as eye drops (0.25%, 1%) four times daily (20 µL per eye) for 7 or 14 consecutive days. We showed that topical application of DZ2002 concentration-dependently reduced corneal neovascularization and corneal opacity, as well as alleviated conjunctival irritation in both DED models. Furthermore, we observed that DZ2002 treatment decreased the expression of genes associated with angiogenesis and the levels of inflammation in the cornea and conjunctiva. Moreover, DZ2002 treatment in the BAC-induced DED model abolished the activation of the STAT3-PI3K-Akt-NF-κB pathways in corneal tissues. We also found that DZ2002 significantly inhibited the proliferation, migration, and tube formation of human umbilical endothelial cells (HUVECs) while downregulating the activation of the STAT3-PI3K-Akt-NF-κB pathway. These results suggest that DZ2002 exerts a therapeutic effect on corneal angiogenesis in DED, potentially by preventing the upregulation of the STAT3-PI3K-Akt-NF-κB pathways. Collectively, DZ2002 is a promising candidate for ophthalmic therapy, particularly in treating DED.

Research Note: Isolation and immunomodulatory activity of bursal peptide, a novel peptide from avian immune system developments.

The bursa of Fabricius (BF) is pivotal for B lymphocyte ontogenesis. In the present investigation, a novel bursal peptide, designated BP7, was extracted from BF and was found to stimulate colony-forming unit pre-B (CFU pre-B) formation at various concentrations (1 µg/mL, P < 0.05; 5 µg/mL, P < 0.05; 25 µg/mL, P < 0.05). Moreover, BP7 modulated B cell differentiation pathways. The immunoregulatory potential of BP7 was further assessed in avian and murine models subjected to immunization with inactivated avian influenza virus (AIV, H9N2 subtype). BP7 significantly augmented AIV-specific antibody levels (Prime immunization: 5 mg/kg, P < 0.05; Boost immunization: 0.4, 1, and 5 mg/kg, P < 0.05) and cytokine secretion in the avian model (IL-4 and IFN-γ: 0.4, 1, and 5 mg/kg, P < 0.05). Similarly, in the murine model, AIV-specific antibody levels (Prime and Boost immunization: 0.4, 1, and 5 mg/kg, P < 0.05) and cytokine production (IL-4 and IFN-γ: 0.4, 1, and 5 mg/kg, P < 0.05) were notably enhanced. This study offers novel insights into the mechanisms underlying B cell maturation and holds implications for future immunopharmacological interventions.

Graphene-Based Material-Mediated Immunomodulation in Tissue Engineering and Regeneration: Mechanism and Significance.

Tissue engineering and regenerative medicine hold promise for improving or even restoring the function of damaged organs. Graphene-based materials (GBMs) have become a key player in biomaterials applied to tissue engineering and regenerative medicine. A series of cellular and molecular events, which affect the outcome of tissue regeneration, occur after GBMs are implanted into the body. The immunomodulatory function of GBMs is considered to be a key factor influencing tissue regeneration. This review introduces the applications of GBMs in bone, neural, skin, and cardiovascular tissue engineering, emphasizing that the immunomodulatory functions of GBMs significantly improve tissue regeneration. This review focuses on summarizing and discussing the mechanisms by which GBMs mediate the sequential regulation of the innate immune cell inflammatory response. During the process of tissue healing, multiple immune responses, such as the inflammatory response, foreign body reaction, tissue fibrosis, and biodegradation of GBMs, are interrelated and influential. We discuss the regulation of these immune responses by GBMs, as well as the immune cells and related immunomodulatory mechanisms involved. Finally, we summarize the limitations in the immunomodulatory strategies of GBMs and ideas for optimizing GBM applications in tissue engineering. This review demonstrates the significance and related mechanism of the immunomodulatory function of GBM application in tissue engineering; more importantly, it contributes insights into the design of GBMs to enhance wound healing and tissue regeneration in tissue engineering.

Transcriptomic and Metabolomic Changes Reveal the Immunomodulatory Function of Casein Phosphopeptide-Selenium Chelate in Beagle Dogs.

Casein phosphopeptide-selenium chelate (CPP-Se) is an organic compound produced by the chelation of casein phosphopeptide with selenium. This compound showed the ability to modulate canine immune response in our previous study; but its effect on the peripheral blood transcriptome and serum metabolome was unknown. This study aims to reveal the potential mechanism behind the immunomodulatory function of CPP-Se. We have identified 341 differentially expressed genes (DEGs) in CPP-Se groups as compared to the control group which comprised 110 up-regulated and 231 down-regulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis found that DEGs were mainly involved in immune-related signaling pathways. Moreover, the immune-related DEGs and hub genes were identified. Similarly, metabolomics identified 53 differentially expressed metabolites (DEMs) in the CPP-Se group, of which 17 were up-regulated and 36 were down-regulated. The pathways mainly enriched by DEMs were primary bile acid biosynthesis, tryptophan metabolism, and other amino acids metabolic pathways. Combined analysis of transcriptomic and metabolomic data showed that the DEGs and DEMs were commonly enriched in fatty acid biosynthesis, pyrimidine metabolism, glutathione metabolism, and glycerolipid metabolic pathways. Taken together, our findings provided a theoretical basis for further understanding of the immunomodulatory function of CPP-Se as well as a scientific reference for the future use of CPP-Se in pet foods as a dietary supplement to modulate the immunity.

HMGB1 is a promising therapeutic target for asthma.

High-mobility group box protein 1 (HMGB1) is a non-histone deoxyribonucleic acid-binding nuclear protein. In physiological state it is involved in gene transctioripn regulation and cell replication, differentiation and maturation. HMGB1 is actively secreted into the extracellular space in the form of intracellular vesicles, upon stimulation of inflammation and infection, by monocytes, macrophages, dendritic cells (DCs), and other immune cells, and can also be passively released by necrotic or injured cells. After binding with the corresponding receptors, HMGB1 can activate the downstream substrate and trigger a series of biological effects. HMGB1 was mainly dependent on toll-like re ceptors (TLR) 2 and 4, and receptors for advanced glycation end products (RAGE) to trigger intracellular signal transduction, and mediate innate and adoptive immune responses. Besides these, studies have reported the participation of TLR3, TLR9, T-cell immunoglobulin mucin (TIM) 3, CD24, anti-N-methyl-D-aspartate receptor (NMDAR) in Th2 inflammatory response, eosinophilic airway inflammation, and airway hyperresponsiveness, mediated by HMGB1 in asthma. Both clinical and experimental studies suggested that HMGB1 was involved in the pathogenesis of asthma probably by regulating the downstream signaling pathways via corresponding receptors. This article reviews the role of HMGB1 in pathogenesis of asthma, and provides a new theoretical basis for the diagnosis and treatment of asthma.

The hematopoietic cytokine Astakine play a vital role in hemocyte proliferation and innate immunity in Scylla paramamosain.

Astakine may induce hematopoietic response in crustaceans, as it is necessary for hemocyte proliferation. In this study, we produced the recombinant Scylla paramamosain Astakine (rspAstakine) and assessed its immunomodulatory function. We analyzed its amino acid sequences and generated a three-dimensional model, then ligand binding sites and enzyme commission of spAstakine were predicted. The rspAstakine was identified at 21.3 kDa by Western blot and liquid chromatography-mass spectrometry. The results showed that rspAstakine induced proliferation of hemocytes in mud crab in vivo and in vitro. The expression of immune-related genes was up-regulated after rspAstakine treatment, similarly to the immunity-related parameters, activities of superoxide dismutase, phenoloxidase, lysozyme, and peroxidase. Additionally, the intracellular content of reactive oxygen species was higher in the rspAstakine treatment group than PBS group. The rspAstakine also enhanced the rate of phagocytosis, while reduced the apoptosis rate of hemocytes after Vibrio alginolyticus infection. The mortalities of the V. alginolyticus only group and rspAstakine + V. alginolyticus group were 83.3 % and 58.3 %, respectively, which illustrated that rspAstakine plays a protective role against V. alginolyticus infection in S. paramamosain. Our results demonstrate the potential of Astakine to enhance the proliferation and immunomodulatory function of hemocytes in crustaceans.

Single-cell RNA sequencing reveals the potential mechanism of heterogeneity of immunomodulatory properties of foreskin and umbilical cord mesenchymal stromal cells.

BACKGROUND: Mesenchymal stromal cells (MSCs) are heterogeneous populations. Heterogeneity exists within the same tissue and between different tissues. Some studies have found enormous heterogeneity in immunomodulatory function among MSCs derived from different tissues. Moreover, the underlying mechanism of heterogeneity in immunomodulatory abilities is still unclear. METHODS: Foreskin mesenchymal stromal cells (FSMSCs) and human umbilical cord mesenchymal stromal cells (HuMSCs) were isolated and cultured until the third passage. According to the International Association for Cell Therapy standard, we confirmed the cell type. Then, FSMSCs and HuMSCs were cocultured with human peripheral blood mononuclear cells (PBMCs) stimulated by lipopolysaccharide (LPS) in vitro. Furthermore, the supernatant was sampled for an enzyme-linked immunosorbent assay to investigate the secretion of IL-1ß, IL-6, IL-10, TNF-α, and TGF-ß1. Finally, we performed single-cell RNA sequencing (scRNA-seq) of FSMSCs and HuMSCs. RESULTS: We successfully identified FSMSCs and HuMSCs as MSCs. When cocultured with LPS pretreated PBMCs, FSMSCs and HuMSCs could effectively reduced the secretion of IL-1ß and TNF-α. However, FSMSCs stimulated the PBMCs to secrete more IL-10, TGF-ß1, and IL-6. Furthermore, 4 cell subsets were identified from integrated scRNA-seq data, including proliferative MSCs (MKI67+, CD146low+, NG2+, PDGFRB-), pericytes (CD146high+, PDGFRB+, MKI67-, CD31-, CD45-, CD34-), immune MSCs (CXCL12high+, PTGIShigh+, PDGFRB+, CD146-, MKI67-) and progenitor proliferative MSCs (CXCL12low+, PTGISlow+, PDGFRB+, CD146-, MKI67-). Among them, we found that immune MSCs with strengthened transcriptional activity were similar to pericytes with regard to the degree of differentiated. Various of immune-related genes, gene sets, and regulons were also enriched in immune MSCs. Moreover, immune MSCs were determined to be close to other cell subsets in cell-cell communication analysis. Finally, we found that the proportion of immune MSCs in foreskin tissue was highest when comparing the subset compositions of MSCs derived from different tissues. CONCLUSIONS: FSMSCs show better immunomodulatory capacity than HuMSCs in vitro. Moreover, immune MSCs may play a vital role in the heterogeneity of immunoregulatory properties. This study provides new insights suggesting that immune MSCs can be isolated to exert stable immunoregulatory functions without being limited by the heterogeneity of MSCs derived from different tissues.

[Comparative study of Astragali Radix Praeparata cum Melle and Hedysari Radix Praeparata cum Melle on spleen Qi deficiency rats].

This Radix study cum aims Melle to explore(HRPM)the on efficacy spleen differences deficiency between syndrome.modeling Astragali A Radix of Praeparata110cum rats Melle were(ARPM)randomized fatigue),and into rats Hedysari a Praeparata(n qi total irregular HRPM male diet,SD diarrhea,control were(n Yiqi=10)the=100).Pill group fied and model a modeling group,group Buzhong After(BYP)(through ARPM and the HRPM-H),classimedium-dose into(ARPM-M raised group,and high-dose(ARPM-H each and Rats BYP and under HRPM-M),normal and low-dose and(ARPM-L in and group HRPM-L)were groups,continuously10rats induced.were in group.the in group the were18.9,control given group were g·kg~(-1)conditions while those the the model Rats respectively in18.912.6,BYP kg~(-1)water extract,decoction those in ARPM/HRPM-H,the-M,dosage lasted and of-L groups treated the with control and model6.3group g·rewere motilin determined m L·kg~(-1)·day~(-1).days.of dose Spleen ARPM/HRPM of in water.morning,The at the10Rats spleen in index group thymus and index ceived equal calculated.(MTL),distilled tissue administration to15observe Then the and Routine of each group D-xylose,were was(IL-2),the subjected HE stainingγ(IFN-γ),lower to the pathological changes.(IgA),blood gastric indexes,mucosa index,interleukin-2group.interferon group immunoglobulin of A and spleen pepsin index,of in Ig A,IL-2spleen IFN-γ,control each MTL,levels Rats pepsin the in model(P<0.01),had higher levels routine(P<0.01),blood and indexes,more thymus lesions D-xylose,the and in index,level decreased HRPM-L of IL-2severe compared spleen with than the those model in group.thymus group.that(P<0.05group,P<0.01)index administration thymus groups Ig A or spleen as that and in spleen routine Except index,spleen the Ig A,index,group and were in in ARPM-M model group,group,index,indexes,P<0.01)and thymus MTL index,those in ARPM-L insignificantly Ig A,different pepsin from other those in the the blood index,compared IFN-γ,group,(P<0.05The D-xylose,model MTL,spleen and lesions high-dose in each administration administration groups group increased relieved.blood or comparison as of with HRPM in as the folARPM and the effect in and were white and result than ARPM and is of lows:(P stronger<0.05),of medium-dose high-dose HRPM HRPM on IL-2cell high-dose of(WBC)and count medium-dose the HRPM and corresponding doses than IFN-γmore ARPM the obvious effect(P<0.05of on evident(P<0.05of impact P<0.01),on low-dose between the on corresponD-xylose P<0.01),doses ding MTL doses than Meanwhile,in of or more high-dose,and medium-dose,difference HRPM the and indexes.corresponding there of ARPM in or IL-2no levels in the HRPM-L effect and two groups,on but conclusion,other the both functions IFN-γwas group no was difference more the than recovery that of the and ARPM-H between(IL-2,P<0.01;ARPM-L recovery HRPM the IFN-γ,P<0.05).HRPM-H and obvious therapeutic in rats group qi In ARPM dose have are certain equivalent,effects on with spleen function deficiency.the Specifically,is the better difference immunomodulatory of two at g·low kg~(-1).and but the promote immunomodulatory the of former rats significantly ARPM.than that between of the later two at in the dose>18.9HRPM promotion can of better digestion digestion absorption and may absorption due of than The immunoregulation and be to the difference in clinical medication.

Thymic endocrinology Part-1.

The concept of thymic endocrinology describes a bidirectional effect: the thymic hormones which circulate and significantly affect the immunomodulatory function of the body and the action of the other hormones derived from the pituitary, adrenal, gonads and thyroid gland on the thymocytes, thymic epithelial cells and the thymic stromal cells. Apart from this there is also an extensive paracrine and autocrine endocrine signal network within the Intra-thymic environment involving interleukins and thymic peptides. This review attempts to delve into the understanding of this intrinsic relationship between the thymus gland and the endocrine system at large.

Antibacterial activity of four recombinant carbohydrate recognition domain proteins identified from the kuruma shrimp Marsupenaeus japonicus.

The carbohydrate recognition domain (CRD) is the key component of C-type lectins (CTLs) with the capacity to recognize and eliminate invading pathogens. Herein, the recombinant proteins of four CRDs identified from the kuruma shrimp, Marsupenaeus japonicus, were produced and purified by an Escherichia coli expression system and affinity chromatography. Bacterial binding and antibacterial assays showed that the four CRDs displayed various bacterial binding and antibacterial activities against different bacteria. Among the four recombinant CRDs, His-CRD2-3 exhibited the broadest spectrum of bacterial binding and antibacterial activities against gram-negative bacteria (Vibrio parahaemolyticus, V. alginolyticus and V. harveyi) and gram-positive bacteria (Staphylococcus aureus and Micrococcus lysodeikticus). Moreover, the four recombinant CRDs showed different capacities to regulate the expression of several immune effector genes (MjCTL3, MjCTL4, MjCTL, Mjily and Mjsty), among which His-CRD2-3 displayed broader and stronger inductive effects on these immune effector genes. This study indicated that the four CRDs participated in immune defense by binding and killing bacteria and regulating the transcription of other immune effector genes. In addition, our results suggested that His-CRD2-3 might be a promising agent for the prevention and treatment of bacteriosis.

Nitrogen-Doped Multiwalled Carbon Nanotubes Enhance Bone Remodeling through Immunomodulatory Functions.

It has been reported that multiwalled carbon nanotubes (MWCNTs) can reportedly positively affect growth and differentiation of bone-related cells and therefore offer great potential in biomedical applications. To overcome negative immune responses that limit their application, specific doping and functionalization can improve their biocompatibility. Here, we demonstrated that nitrogen-doped carboxylate-functionalized MWCNTs (N-MWCNTs) enhance bone remodeling both in vitro and in vivo with excellent biocompatibility, via stimulation of both bone resorption and formation. We revealed that 0.2 µg/mL N-MWCNTs not only increase the transcription of osteoblastogenic and osteoclastogenic genes but also up-regulate the activities of both TRAP and AKP in the differentiation of bone marrow stromal cells (BMSCs). Additionally, intramuscular administration of N-MWCNTs at a dosage of 1.0 mg/kg body weight enhances bone mineral density and bone mass content in mice, as well as induces potentiated degree of TRAP- and ARS-positive staining in the femur. The positive regulation of N-MWCNTs on bone remodeling is initiated by macrophage phagocytosis, which induces altered production of inflammatory cytokines by immune response pathways, and consequently up-regulates IL1α, IL10, and IL16. These cytokines collectively regulate the central osteoclastogenic transcription factor NFATc1 and osteoblastogenic BMP signaling, the suppression of which confirmed that these factors respectively participate in N-MWCNT-mediated regulation of osteoclastic and osteoblastic bone marrow stem cell activities. These results suggest that N-MWCNTs can be readily generalized for use as biomaterials in bone tissue engineering for metabolic bone disorders.

Immunomodulatory Function of Vitamin D and Its Role in Autoimmune Thyroid Disease.

Vitamin D is one of the most important nutrients required by the human body. It is a steroid hormone that plays an important role in regulating calcium and phosphorus metabolism, and bone health. Epidemiological studies have revealed a close correlation between vitamin D and many common chronic diseases. Additionally, vitamin D has recently been shown to act as an immunomodulatory hormone, and, accordingly, vitamin D deficiency was uncovered as a risk factor for autoimmune thyroid diseases, although the underlying mechanisms are still unknown. It is therefore necessary to disclose the role and mechanism of action of vitamin D in the occurrence and development of autoimmune thyroid diseases. This knowledge will help design intervention and early treatment strategies for patients with autoimmune thyroid diseases who present with low levels of vitamin D.

Comparative study of Astragali Radix Praeparata cum Melle and Hedysari Radix Praeparata cum Melle on spleen Qi deficiency rats / 中国中药杂志

This Radix study cum aims Melle to explore(HRPM)the on efficacy spleen differences deficiency between syndrome.modeling Astragali A Radix of Praeparata110cum rats Melle were(ARPM)randomized fatigue),and into rats Hedysari a Praeparata(n qi total irregular HRPM male diet,SD diarrhea,control were(n Yiqi=10)the=100).Pill group fied and model a modeling group,group Buzhong After(BYP)(through ARPM and the HRPM-H),classimedium-dose into(ARPM-M raised group,and high-dose(ARPM-H each and Rats BYP and under HRPM-M),normal and low-dose and(ARPM-L in and group HRPM-L)were groups,continuously10rats induced.were in group.the in group the were18.9,control given group were g·kg~(-1)conditions while those the the model Rats respectively in18.912.6,BYP kg~(-1)water extract,decoction those in ARPM/HRPM-H,the-M,dosage lasted and of-L groups treated the with control and model6.3group g·rewere motilin determined m L·kg~(-1)·day~(-1).days.of dose Spleen ARPM/HRPM of in water.morning,The at the10Rats spleen in index group thymus and index ceived equal calculated.(MTL),distilled tissue administration to15observe Then the and Routine of each group D-xylose,were was(IL-2),the subjected HE stainingγ(IFN-γ),lower to the pathological changes.(IgA),blood gastric indexes,mucosa index,interleukin-2group.interferon group immunoglobulin of A and spleen pepsin index,of in Ig A,IL-2spleen IFN-γ,control each MTL,levels Rats pepsin the in model(P<0.01),had higher levels routine(P<0.01),blood and indexes,more thymus lesions D-xylose,the and in index,level decreased HRPM-L of IL-2severe compared spleen with than the those model in group.thymus group.that(P<0.05group,P<0.01)index administration thymus groups Ig A or spleen as that and in spleen routine Except index,spleen the Ig A,index,group and were in in ARPM-M model group,group,index,indexes,P<0.01)and thymus MTL index,those in ARPM-L insignificantly Ig A,different pepsin from other those in the the blood index,compared IFN-γ,group,(P<0.05The D-xylose,model MTL,spleen and lesions high-dose in each administration administration groups group increased relieved.blood or comparison as of with HRPM in as the folARPM and the effect in and were white and result than ARPM and is of lows:(P stronger<0.05),of medium-dose high-dose HRPM HRPM on IL-2cell high-dose of(WBC)and count medium-dose the HRPM and corresponding doses than IFN-γmore ARPM the obvious effect(P<0.05of on evident(P<0.05of impact P<0.01),on low-dose between the on corresponD-xylose P<0.01),doses ding MTL doses than Meanwhile,in of or more high-dose,and medium-dose,difference HRPM the and indexes.corresponding there of ARPM in or IL-2no levels in the HRPM-L effect and two groups,on but conclusion,other the both functions IFN-γwas group no was difference more the than recovery that of the and ARPM-H between(IL-2,P<0.01;ARPM-L recovery HRPM the IFN-γ,P<0.05).HRPM-H and obvious therapeutic in rats group qi In ARPM dose have are certain equivalent,effects on with spleen function deficiency.the Specifically,is the better difference immunomodulatory of two at g·low kg~(-1).and but the promote immunomodulatory the of former rats significantly ARPM.than that between of the later two at in the dose>18.9HRPM promotion can of better digestion digestion absorption and may absorption due of than The immunoregulation and be to the difference in clinical medication.

Effects of probiotic litchi juice on immunomodulatory function and gut microbiota in mice.

Development new functional foods containing probiotics had gained much attention during the past two decades. In this study, probiotic litchi juice was developed, and its effects on immunomodulatory function and gut microbiota were evaluated. Firstly, the litchi juice was fermented with Lactobacillus casei, which increased total phenolic, total flavone, and exopolysaccharide contents of the litchi juice. Hence, the immunomodulatory influence of fermented litchi juice (FL) was investigated in cyclophosphamide-induced mice. The results showed that FL enhanced immune organs indexes (spleen, thymus) and antioxidant capacity, improved the secretions of cytokines (IL-2, IL-6) and immunoglobulins (IgA, IgG, SIgA), and protected the intestinal tract. Finally, the effect of FL on gut microbiota was analyzed by high-throughput sequencing analysis. The changes in the relative abundance of dominant microbe were investigated at phylum and genus levels, respectively. After treatment with FL, the relative abundance of Firmicutes phylum was dramatically increased, as well as the genera of Faecalibaculum, Lactobacillus, and Akkermansia. These findings indicated that probiotic litchi juice could alleviate immune dysfunction and modify gut microbiota structure of mice, which provide a potential functional food to improve the host health.

Zn-Incorporated TiO2 Nanotube Surface Improves Osteogenesis Ability Through Influencing Immunomodulatory Function of Macrophages.

PURPOSE: Zinc (Zn), an essential trace element in the body, has stable chemical properties, excellent osteogenic ability and moderate immunomodulatory property. In the present study, a Zn-incorporated TiO2 nanotube (TNT) was fabricated on titanium (Ti) implant material. We aimed to evaluate the influence of nano-scale topography and Zn on behaviors of murine RAW 264.7 macrophages. Moreover, the effects of Zn-incorporated TNT surface-regulated macrophages on the behaviors and osteogenic differentiation of murine MC3T3-E1 osteoblasts were also investigated. METHODS: TNT coatings were firstly fabricated on a pure Ti surface using anodic oxidation, and then nano-scale Zn particles were incorporated onto TNTs by the hydrothermal method. Surface topography, chemical composition, roughness, hydrophilicity, Zn release pattern and protein adsorption ability of the Zn-incorporated TiO2 nanotube surface were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS), surface profiler, contact angle test, Zn release test and protein adsorption test. The cell behaviors and both pro-inflammatory (M1) and pro-regenerative (M2) marker gene and protein levels in macrophages cultured on Zn-incorporated TNTs surfaces with different TNT diameters were detected. The supernatants of macrophages were extracted and preserved as conditioned medium (CM). Furthermore, the behaviors and osteogenic properties of osteoblasts cultured in CM on various surfaces were evaluated. RESULTS: The release profile of Zn on Zn-incorporated TNT surfaces revealed a controlled release pattern. Macrophages cultured on Zn-incorporated TNT surfaces displayed enhanced gene and protein expression of M2 markers, and M1 markers were moderately inhibited, compared with the LPS group (the inflammation model). When cultured in CM, osteoblasts cultured on Zn-incorporated TNTs showed strengthened cell proliferation, adhesion, osteogenesis-related gene expression, alkaline phosphatase activity and extracellular mineralization, compared with their TNT counterparts and the Ti group. CONCLUSION: This study suggests that the application of Zn-incorporated TNT surfaces may establish an osteogenic microenvironment and accelerate bone formation. It provided a promising strategy of Ti surface modification for a better applicable prospect.

Cloning, characterization and tissue-specific expression of the antimicrobial peptide hepcidin from caspian trout (Salmo caspius) and the antibacterial activity of the synthetic peptide.

Antimicrobial peptides have a wide range of antimicrobial activity and widely occur in different organisms including mollusks, crustaceans and vertebrates. Hepcidins are a group of cysteine-rich antimicrobial peptides that are active against a variety of pathogens including gram-positive and gram-negative bacteria, as well as viruses. In this study, the hepcidin gene of Caspian trout (CtHep) was identified and characterized. Our results showed that CtHep cDNA has a 267-bp Open Reading Frame (ORF), which is translated to 88 amino acids. The CtHep was classified in the HAMP1 class of hepcidins. Comparison of DNA and cDNA sequences showed that CtHep has 3 exons and 2 introns. The signal, prodomain and mature part of CtHep have 24, 39 and 25 amino acids, respectively. The mature peptide has a molecular weight of 2881.43 Da and a theoretical isoelectric point of 8.53. The expression of CtHep mRNA was detected in different tissues of healthy and infected fish. CtHep expression in the liver, head kidney, spleen and skin was significantly enhanced after bacterial challenge. Expression of CtHep in different embryonic development stages was also substantial. Antibacterial activity of synthetic CtHep peptides was investigated against a number of Gram-positive and Gram-negative bacteria. CtHep inhibited some pathogenic bacteria such as Streptococcus iniae and Aeromonas hydrophila. In the in vivo experiment, CtHep upregulated the cytokines IL-6 and TNF-α in both kidney and spleen tissues after 24 h of the peptide injection. In conclusion, our study showed that CtHep plays an important role in the immune system of Caspian trout and also in the embryonic stages. Moreover, CtHep peptide has a potential to be used as an antimicrobial therapeutic agent as well as an immunostimulant in aquaculture.

Lactoferrin: Major Physiological Functions and Applications.

Lactoferrin (lactotransferrin; Lf) is an iron-binding glycoprotein and one of the most important bioactivators in milk and other external secretions. It has numerous biological roles, including the regulation of iron absorption and modulation of immune responses, and has anti-microbial, anti-viral, antioxidant, anti-cancer, and anti-inflammatory activities. Lf regulates the quantity of iron absorbed in the intestine via its role in iron transport and can also chelate iron, directly or indirectly. Notably, it has been used as an adjuvant therapy for some intestinal diseases. It is now used in nutraceuticalsupplemented infant formula and other food products. This article reviews the content, distribution, physiologic functions and current applications of Lf, and aims to shed light on future prospects for additional applications of Lf.

Evaluation of the immunogenicity of human iPS cell-derived neural stem/progenitor cells in vitro.

To achieve the goal of a first-in-human trial for human induced pluripotent stem cell (hiPSC)-based transplantation for the treatment of various diseases, allogeneic human leukocyte antigen (HLA)-matched hiPSC cell banks represent a realistic tool from the perspective of quality control and cost performance. Furthermore, considering the limited therapeutic time-window for acute injuries, including neurotraumatic injuries, an iPS cell bank is of potential interest. However, due to the relatively immunoprivileged environment of the central nervous system, it is unclear whether HLA matching is required in hiPSC-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation for the treatment of neurodegenerative diseases and neurotraumatic injuries. In this study, we evaluated the significance of HLA matching in hiPSC-NS/PC transplantation by performing modified mixed lymphocyte reaction (MLR) assays with hiPSC-NS/PCs. Compared to fetus-derived NS/PCs, the expression levels of human leukocyte antigen-antigen D related (HLA-DR) and co-stimulatory molecules on hiPSC-NS/PCs were significantly low, even with the addition of tumor necrosis factor-α (TNFα) and/or interferon-γ (IFNγ) to mimic the inflammatory environment surrounding transplanted hiPSC-NS/PCs in injured tissues. Interestingly, both the allogeneic HLA-matched and the HLA-mismatched responses were similarly low in the modified MLR assay. Furthermore, the autologous response was also similar to the allogeneic response. hiPSC-NS/PCs suppressed the proliferative responses of allogeneic HLA-mismatched peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner. Thus, the low antigen-presenting function and immunosuppressive effects of hiPSC-NS/PCs result in a depressed immune response, even in an allogeneic HLA-mismatched setting. It is crucial to verify whether these in vitro results are reproducible in a clinical setting.

Antimicrobial Peptides: An Introduction.

The "golden era" of antibiotic discovery has long passed, but the need for new antibiotics has never been greater due to the emerging threat of antibiotic resistance. This urgency to develop new antibiotics has motivated researchers to find new methods to combat pathogenic microorganisms resulting in a surge of research focused around antimicrobial peptides (AMPs; also termed host defense peptides) and their potential as therapeutics. During the past few decades, more than 2000 AMPs have been identified from a diverse range of organisms (animals, fungi, plants, and bacteria). While these AMPs share a number of common features and a limited number of structural motifs; their sequences, activities, and targets differ considerably. In addition to their antimicrobial effects, AMPs can also exhibit immunomodulatory, anti-biofilm, and anticancer activities. These diverse functions have spurred tremendous interest in research aimed at understanding the activity of AMPs, and various protocols have been described to assess different aspects of AMP function including screening and evaluating the activities of natural and synthetic AMPs, measuring interactions with membranes, optimizing peptide function, and scaling up peptide production. Here, we provide a general overview of AMPs and introduce some of the methodologies that have been used to advance AMP research.