Long-Term Accumulation, Biological Effects and Toxicity of BSA-Coated Gold Nanoparticles in the Mouse Liver, Spleen, and Kidneys.

Introduction: Gold nanoparticles are promising candidates as vehicles for drug delivery systems and could be developed into effective anticancer treatments. However, concerns about their safety need to be identified, addressed, and satisfactorily answered. Although gold nanoparticles are considered biocompatible and nontoxic, most of the toxicology evidence originates from in vitro studies, which may not reflect the responses in complex living organisms. Methods: We used an animal model to study the long-term effects of 20 nm spherical AuNPs coated with bovine serum albumin. Mice received a 1 mg/kg single intravenous dose of nanoparticles, and the biodistribution and accumulation, as well as the organ changes caused by the nanoparticles, were characterized in the liver, spleen, and kidneys during 120 days. Results: The amount of nanoparticles in the organs remained high at 120 days compared with day 1, showing a 39% reduction in the liver, a 53% increase in the spleen, and a 150% increase in the kidneys. The biological effects of chronic nanoparticle exposure were associated with early inflammatory and fibrotic responses in the organs and were more pronounced in the kidneys, despite a negligible amount of nanoparticles found in renal tissues. Conclusion: Our data suggest, that although AuNPs belong to the safest nanomaterial platforms nowadays, due to their slow tissue elimination leading to long-term accumulation in the biological systems, they may induce toxic responses in the vital organs, and so understanding of their long-term biological impact is important to consider their potential therapeutic applications.

Immunological, histological and immunohistochemical alternations induced by zinc oxide nanoparticles and mureer plant in spleen albino rats with the prospective anti-inflammatory action of gallic acid.

The current study was proposed to evaluate the mortal impacts of either alone or mixed treatments of zinc oxide nanoparticles (ZnO NPs) and mureer or Senecio glaucus L. plant (SP) on spleen tissue via immunological and histological studies and to estimate the likely immunomodulatory effect of gallic acid (GA) for 30 days in rats. Rats were classified into eight groups with orally treated: Control, GA (100mg/kg), ZnO NPs (150mg/kg), SP (400mg/kg), GA+ZnO NPs (100,150mg/kg), GA+SP (100,400mg/kg), ZnONPs+SP (150,400mg/kg) and GA+ZnONPs+SP (100,150,400mg/kg). Interleukin-6 (IL-6) level was measured using an enzyme-linked immunoassay (ELISA). Also, the pro-apoptotic protein (caspase-3) expression was estimated using an immunohistochemistry assay. Our data revealed that ZnO NPs and SP triggered a significant increase in the levels of IL-6 and total lipids (TL) and the activity of lactate dehydrogenase (LDH), (p<0.001). Furthermore, they overexpressed caspase-3 and caused lymphoid depletion. They revealed that the immunotoxic outcome of mixed treatment was more than the outcome of the alone treatment. However, GA restored the spleen damage from these adverse results. Finally, this study indicated that ZnO NPs and SP might be immunotoxic and splenotoxic agents; however, GA may be displayed as an anti-inflammatory and splenic-protective agent.

[MPV17 inhibits iron overload-induced ferroptosis of splenic CD3+ T cells in mice by blocking ERK pathway].

Objective This work aimed to explore the effect of iron overload on splenic injury and the role of MPV17 in the ferroptosis of splenic CD3+ T cells from mice subjected to iron overload. Methods Mice were randomly divided into normal diet group, high-iron diet group, high-iron diet combined with Fer-1 treatment group, and high-iron diet combined with adenovirus harboring MPV17 injection group, with 5 mice in each group. After treatment for 8 weeks, mice spleens were harvested and fixed; Histological section and HE staining were performed to observe the structures of the spleens; Cell death of CD3+ T cells was detected by propidium iodide (PI) staining; The lipid peroxidation levels were detected by C11 BODIPY581/591 staining; The mRNA levels of Solute carrier family 7 member 11 (SLC7A11) and prostaglandin-endoperoxide synthase 2 (PTGS2) were detected by qPCR assays; The macrophage phenotype-switching (M1/M2) were detected by flow cytometry; The levels of TNF-α, IL-1ß and IL-6 were measured by ELISA assays. Moreover, high-iron diet combined with extracellular signal-regulated kinase (ERK) inhibitor treatment group, ERK agonist treatment group, ß-gal combined with ERK agonist treatment group, and MPV17 overexpression combined with ERK agonist treatment group were added. The protein levels of MPV17, glutathione peroxidase 4 (GPX4) and phosphorylated ERK (p-ERK) were detected by Western blot; The mitochondrial membrane potential was detected by JC-1 staining and flow cytometry. Results Compared with the normal diet group, the red pulps of the mice spleens from the high-iron diet group showed irregular structures and the white pulps were almost missing; Cell death, lipid peroxides, and the expression levels of SLC7A11 and PTGS2 increased; Both the ratio of M1 macrophages to M2 macrophages and the levels of inflammatory factors increased. Fer-1 treatment or overexpression of MPV17 in the high-iron diet mice group partially recovered the irregular structures of the spleens, reduced cell death and lipid peroxides in CD3+ T cells, and decreased the expression levels of SLC7A11 and PTGS2; The ratio of M1/M2 macrophages and the levels of inflammatory factors were decreased. High-iron diet decreased the protein levels of GPX4 while p-ERK were up-regulated. Inhibition of ERK partially recovered the protein levels of GPX4; ERK agonist decreased the protein levels of GPX4; MPV17 inhibited the ERK signaling and partially recovered the protein levels of GPX4 and the decreased mitochondrial membrane potential of CD3+ T induced by ERK activation. Conclusion Iron overload resulted in splenic injury and ferroptosis in the splenic CD3+ T cells; MPV17 prevented splenic injury and ferroptosis of splenic CD3+ T cells of the iron overload mice through blocking ERK signaling pathway.

Cadmium promoted LPS-induced inflammation through TLR4/IκBα/NFκ-B signaling by increasing ROS-mediated incomplete autophagy.

Cadmium (Cd) exposure is considered as non-infectious stressor to human and animal health. Recent studies suggest that the immunotoxicity of low dose Cd is not directly apparent, but disrupts the immune responses when infected with some bacteria or virus. But how Cd alters the adaptive immunity organ and cells remains unclear. In this study, we applied lipopolysaccharide (LPS, infectious stressor) to induced inflammation in spleen tissues and T cells, and investigated the effects after Cd exposure and the underlying mechanism. Cd exposure promoted LPS-induced the expressions of the inflammatory factors, induced abnormal initiation of autophagy, but blocked autophagic flux. The effects Cd exposure under LPS activation were reversed by the autophagy promoter Rapamycin. Under LPS activation conditions, Cd also induced oxidative stress by increasing the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and reducing total antioxidant capacity (T-AOC) activity. The increased superoxide dismutase (SOD) activity after Cd exposure might be a negative feedback or passive adaptive regulation of oxidative stress. Cd-increased autophagic flux inhibition and TNF-α expression were reversed by ROS scavenger α-tocopherol (TCP). Furthermore, under LPS activation condition, Cd promoted activation of toll-like receptor 4 (TLR4)/IκBα/NFκ-B signaling pathway and increased TLR4 protein stability, which were abolished by the pretreatment of Rapamycin. The present study confirmed that, by increasing ROS-mediated inhibiting autophagic degradation of TLR4, Cd promoted LPS-induced inflammation in spleen T cells. This study identified the mechanism of autophagy in Cd-aggravated immunotoxicity under infectious stress, which could arouse public attention to synergistic toxicity of Cd and bacterial or virus infection.

Comparative analysis of immunological changes following realgar and arsenic trioxide treatments in a murine model of myelodysplastic syndrome.

BACKGROUND: Myelodysplastic syndrome (MDS) is a prevalent hematological neoplastic disorder in clinics and its immunopathogenesis has garnered growing interest. Oral and intravenous arsenic agents have long been used to treat hematological malignancies. The main component of oral arsenic is realgar (arsenic disulfide), while arsenic trioxide is the main component of intravenous arsenic. METHODS: This study aimed to assess the effects of ATO and Realgar on the enhancement of peripheral blood, drug safety, and T cell immune status in the NUP98-HOXD13 (NHD13) mice model of MDS, specifically in the peripheral blood, spleen, and liver. RESULTS: The study findings indicate that realgar and arsenic trioxide (ATO) can improve peripheral hemogram in mice, whereas realgar promotes higher peripheral blood cell production than ATO. Furthermore, the clinical administration method and dose did not cause significant toxicity or side effects and thus can be considered safe. Coexistence and interconversion of hyperimmune function and immunosuppression in mice were also observed in this study. In addition, there were interactions between immune cells in the peripheral blood, spleen, and liver to regulate the immune balance of the body and activate immunity via T-cell activation. CONCLUSION: In summary, oral and intravenous arsenic agents are beneficial in improving peripheral hemogram and immunity in mice.

Yogurt Alleviates Cyclophosphamide-Induced Immunosuppression in Mice through D-Lactate.

Numerous studies have investigated the immunomodulatory effects of yogurt, but the underlying mechanism remained elusive. This study aimed to elucidate the alleviating properties of yogurt on immunosuppression and proposed the underlying mechanism was related to the metabolite D-lactate. In the healthy mice, we validated the safety of daily yogurt consumption (600 µL) or D-lactate (300 mg/kg). In immunosuppressed mice induced by cyclophosphamide (CTX), we evaluated the immune regulation of yogurt and D-lactate. The result showed that yogurt restored body weight, boosted immune organ index, repaired splenic tissue, recovered the severity of delayed-type hypersensitivity reactions and increased serum cytokines (IgA, IgG, IL-6, IFN-γ). Additionally, yogurt enhanced intestinal immune function by restoring the intestinal barrier and upregulating the abundance of Bifidobacterium and Lactobacillus. Further studies showed that D-lactate alleviated immunosuppression in mice mainly by promoting cellular immunity. D-lactate recovered body weight and organ development, elevated serum cytokines (IgA, IgG, IL-6, IFN-γ), enhanced splenic lymphocyte proliferation and increased the mRNA level of T-bet in splenic lymphocyte to bolster Th1 differentiation. Finally, CTX is a chemotherapeutic drug, thus, the application of yogurt and D-lactate in the tumor-bearing mouse model was initially explored. The results showed that both yogurt (600 µL) and D-lactate (300 mg/kg) reduced cyclophosphamide-induced immunosuppression without promoting tumor growth. Overall, this study evaluated the safety, immune efficacy and applicability of yogurt and D-lactate in regulating immunosuppression. It emphasized the potential of yogurt as a functional food for immune regulation, with D-lactate playing a crucial role in its immunomodulatory effects.

In vivo study of chelating agent-modified nano zero-valent iron: Biodistribution and toxicity in mice.

In this study, the distribution and toxicity of nanoscale zero valent iron (nZVI) and nZVIs coated with citric acid and sodium tripolyphosphate (CA-nZVI and STPP-nZVI) in mice were investigated. nZVIs were primarily found in the livers and spleens, followed by the lungs, hearts, and kidneys. Histologic analysis revealed no significant histopathologic abnormalities or lesions in all organs except the liver at 14th d gavage. nZVIs did not have a noticeable impact on the body weight of the mice or the weight of their organs. Compared with the control group, there were no significant changes in hematology indexes in the nZVIs groups. However, the nZVIs groups exhibited varying levels of elevation in alanine aminotransferase, aspartate aminotransferase, and creatinine, suggesting liver and kidney inflammation in mice. The up-regulation of Nuclear Factor erythroid 2-Related Factor 2 and Heme oxygenase 1 in the nZVIs groups may be a response to nZVIs-induced oxidative stress. Immunohistochemical analysis confirmed the inflammatory response induced by the three nZVI groups. Chelating agents did not have a significant impact on the distribution or toxicity of nZVIs in mice. This study contributes to a comprehensive and detailed insight into nZVI toxicity in the environmental field.

Determining toxicity of europium oxide nanoparticles in immune cell components and hematopoiesis in dominant organs in mice: Role of lysosomal fluid interaction.

Extensive application of rare earth element oxide nanoparticles (REE NPs) has raised a concern over the possible toxic health effects after human exposure. Once entering the body, REE NPs are primarily processed by phagocytes in particular macrophages and undergo biotic phosphate complexation in lysosomal compartment. Such biotransformation affects the target organs and in vivo fate of REE NPs after escaping the lysosomes. However, the immunomodulatory effects of intraphagolysosomal dissolved REE NPs remains insufficient. Here, europium oxide (Eu2O3) NPs were pre-incubated with phagolysosomal simulant fluid (PSF) to mimic the biotransformation of europium oxide (p-Eu2O3) NPs under acid phagolysosome conditions. We investigated the alteration in immune cell components and the hematopoiesis disturbance on adult mice after intravenous administration of Eu2O3 NPs and p-Eu2O3 NPs. Our results indicated that the liver and spleen were the main target organs for Eu2O3 NPs and p-Eu2O3 NPs. Eu2O3 NPs had a much higher accumulative potential in organs than p-Eu2O3 NPs. Eu2O3 NPs induced more alterations in immune cells in the spleen, while p-Eu2O3 NPs caused stronger response in the liver. Regarding hematopoietic disruption, Eu2O3 NPs reduced platelets (PLTs) in peripheral blood, which might be related to the inhibited erythrocyte differentiation in the spleen. By contrast, p-Eu2O3 NPs did not cause significant disturbance in peripheral PLTs. Our study demonstrated that the preincubation with PSF led to a distinct response in the immune system compared to the pristine REE NPs, suggesting that the potentially toxic effects induced by the release of NPs after phagocytosis should not be neglected, especially when evaluating the safety of NPs application in vivo.

Splenic Elemental Composition of Breast Cancer-Suffering Rats Supplemented with Pomegranate Seed Oil and Bitter Melon Extract.

The aim of this study was to investigate how dietary modifications with pomegranate seed oil (PSO) and bitter melon aqueous extract (BME) affect mineral content in the spleen of rats both under normal physiological conditions and with coexisting mammary tumorigenesis. The diet of Sprague-Dawley female rats was supplemented either with PSO or with BME, or with a combination for 21 weeks. A chemical carcinogen (7,12-dimethylbenz[a]anthracene) was applied intragastrically to induce mammary tumors. In the spleen of rats, the selected elements were determined with a quadrupole mass spectrometer with inductively coupled plasma ionization (ICP-MS). ANOVA was used to evaluate differences in elemental composition among experimental groups. Multivariate statistical methods were used to discover whether some subtle dependencies exist between experimental factors and thus influence the element content. Experimental factors affected the splenic levels of macroelements, except for potassium. Both diet modification and the cancerogenic process resulted in significant changes in the content of Fe, Se, Co, Cr, Ni, Al, Sr, Pb, Cd, B, and Tl in rat spleen. Chemometric analysis revealed the greatest impact of the ongoing carcinogenic process on the mineral composition of the spleen. The obtained results may contribute to a better understanding of peripheral immune organ functioning, especially during the neoplastic process, and thus may help develop anticancer prevention and treatment strategies.

Small Spleen Peptides (SSPs) Shape Dendritic Cell Differentiation through Modulation of Extracellular ATP Synthesis Profile.

Restoring peripheral immune tolerance is crucial for addressing autoimmune diseases. An ancient mechanism in maintaining the balance between inflammation and tolerance is the ratio of extracellular ATP (exATP) and adenosine. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs) in inhibiting psoriatic arthritis progression, even in the presence of the pro-inflammatory cytokine TNFα, by transforming dendritic cells (DCs) into tolerogenic cells and fostering regulatory Foxp3+ Treg cells. Here, we identified thymosins as the primary constituents of SSPs, but recombinant thymosin peptides were less efficient in inhibiting arthritis than SSPs. Since Tß4 is an ecto-ATPase-binding protein, we hypothesized that SSPs regulate exATP profiles. Real-time investigation of exATP levels in DCs revealed that tolerogenic stimulation led to robust de novo exATP synthesis followed by significant degradation, while immunogenic stimulation resulted in a less pronounced increase in exATP and less effective degradation. These contrasting exATP profiles were crucial in determining whether DCs entered an inflammatory or tolerogenic state, highlighting the significance of SSPs as natural regulators of peripheral immunological tolerance, with potential therapeutic benefits for autoimmune diseases. Finally, we demonstrated that the tolerogenic phenotype of SSPs is mainly influenced by adenosine receptors, and in vivo administration of SSPs inhibits psoriatic skin inflammation.

Augmentation of NK-cell activity and immunity by combined natural polyphenols and saccharides in vitro and in vivo.

Curcuma longa and Sargassum coreanum are commonly used in traditional pharmaceutical medicine to improve immune function in chronic diseases. The present study was designed to systematically elucidate the in vitro and in vivo immuno-enhancing effects of a combination of C. longa and S. coreanum extracts (CS) that contain polyphenols and saccharides as functional molecules in a cyclophosphamide (Cy)-induced model of immunosuppression. In primary splenocytes, we observed the ameliorative effects of CS on a Cy-induced immunosuppression model with low cytotoxicity and an optimal mixture procedure. CS treatment enhanced T- and B-cell proliferation, increased splenic natural killer-cell activity, and restored cytokine release. Wistar rats were orally administered low (30 mg/kg), intermediate (100 mg/kg), or high (300 mg/kg) doses of CS for four weeks, followed by oral administration of Cy (5 mg/kg) for four weeks. Compared with the vehicle group, low-, intermediate-, and high-dose CS treatment accelerated dose-dependent recovery of the serum level of tumor necrosis factor-α, interferon-γ, interleukin-2, and interleukin-12. These results suggest that CS treatment accelerates the amelioration of immune deficiency in Cy-treated primary splenocytes and rats, which supports considering it for immunity maintenance. Our findings provide experimental evidence for further research and clinical application in immunosuppressed patients.

The ameliorative effect on chemotherapy-induced injury and tumor immunosuppressive microenvironment of the polysaccharide from the rhizome of Menispermum dauricum DC.

Combined medication has attracted increasing attention as an important treatment option for tumors due to the serious adverse effects of chemotherapy. In this study, as a new therapy strategy, a combination treatment of MDP (a polysaccharide from the rhizome of Menispermum dauricum DC.) with cyclophosphamide (CTX) was investigated. The results showed that combination treatment with MDP and CTX exerted a significantly synergistic anti-tumor effect in Lewis tumor-bearing mice, improved CTX-induced emaciation and hair loss, as well as increased the number of leukocytes, erythrocytes, hemoglobin, and platelets in the peripheral blood. In addition, compared with CTX alone, the thymus index and spleen index of the MDP + CTX group were increased, the number of CD3 + T cells, CD8 + T cells, white blood cells and B cells in spleen also increased significantly. MDP could also ameliorate the increase in liver and kidney index caused by CTX. In the Lewis lung cancer model, MDP showed a certain degree of anti-tumor effects, which may be related to its promotion of tumor-associated macrophages (TAMs) to M1 phenotype polarisation, enhancement of the number of T cells in tumor tissues and promotion of Th cells in tumor tissues to Th1 phenotype polarisation, thus alleviating the immunosuppressive microenvironment in tumor tissues. This study laid the foundation for the development of MDP as a polysaccharide drug for the treatment or adjuvant therapy of tumors and has important significance for the further clinical application of polysaccharides.

Decreased Treg cells induced by bisphenol A is associated with up-regulation of PI3K/Akt/mTOR signaling pathway and Foxp3 DNA methylation in spleen of adolescent mice.

The current study aimed to explore whether bisphenol A (BPA) exposure aggravated the decrease in Tregs induced by ovalbumin (OVA) in adolescent female mouse models of asthma, and whether the process was associated with mTOR-mediated signaling pathways and DNA methylation levels. A total of 40 female C57BL/6 mice at the age of four weeks were used and divided into five groups after 1 week of domestication. Each group consisted of eight mice: the control group, OVA group, OVA + BPA (0.1 µg mL-1) group, OVA + BPA (0.2 µg mL-1) group, and OVA + BPA (0.4 µg mL-1) group. Results revealed that Foxp3 protein levels decreased in the spleens of mice exposed to BPA compared to those in the OVA group. After an elevation in BPA dose, the mRNAs of methyltransferases (Dnmt1, Dnmt3a, and Dnmt3b) were gradually upregulated. The mechanism was related to the activity of TLR4/NF-κB and PI3K/Akt/mTOR signaling pathways and the enhancement of Foxp3 DNA methylation. Our results, collectively, provided a new view for studying the mechanisms underlying BPA exposure-induced immune dysfunction. Investigation of the regulatory mechanisms of DNA methylation in the abnormal Th immune response caused by BPA exposure could help reveal the causes and molecular mechanisms underlying the high incidence of allergic diseases in children in recent years.

Splenic gene expression of cytokines at multiple time points following lipopolysaccharide challenge in layers.

OBJECTIVE: To investigate inflammatory responses to lipopolysaccharide (LPS) injection in layers. ANIMALS: 33 40-week-old laying hens were used. METHODS: 30 laying hens were divided into 2 groups: the first group was injected with 8 mg/kg LPS, while the second group was injected with sterile saline. At the start of the study, 3 birds served as a baseline and were used as the time 0 controls for both the saline and LPS-treated groups. Blood and spleen tissues were collected at 0 (before) and 1, 2, 3, 4, and 6 hours after injection. RESULTS: LPS administration increased splenic mRNA levels of IL-1ß, IL-2, IL-6, IL-8, IL-10, interferon-γ, and tumor necrosis factor-α (P < .001) and serum IL-6 levels (P < .01) compared to saline injection. The mRNA expression of most cytokine genes increased rapidly toward peak values within 2 hours after the LPS injection, and then the difference between the saline and LPS treatments got smaller as time went on; serum IL-6 reached its highest concentration 2 hours after LPS administration. The magnitude of LPS-induced upregulation of gene expression was the highest for IL-6, followed by IL-1ß and IL-8, and tumor necrosis factor-α was the least affected. CLINICAL RELEVANCE: The temporal and quantitative profile of these inflammatory mediators generated from this study provides valuable information in identifying the optimal time window and appropriate biomarkers for LPS-induced inflammation, which has significant implications in evaluating the effects of interventions on the immune system of chickens.

Xuanhusuo powder has an anti-breast cancer effect by inhibiting myeloid-derived suppressor cell differentiation in the spleen of mice through down-regulating granulocyte colony stimulating factor. / çŽ„èƒ¡ç´¢æ•£é€šè¿‡ä¸‹è°ƒç²’ç»†èƒžé›†è½åˆºæ¿€å› å­æŠ‘åˆ¶è„¾è„é«“æºæŠ‘åˆ¶ç»†èƒžåˆ†åŒ–å‘æŒ¥æŠ—ä¹³è ºç™Œä½œç”¨.

OBJECTIVES: To investigate the mechanism of Xuanhusuo powder (XHSP) inhibiting the differentiation of spleen myeloid-derived suppressor cells (MDSCs) in breast cancer mice. METHODS: Forty-eight BALB/c female mice aged 4-5 weeks were selected, 6 of them were in normal control group, while others were in tumor-bearing models established by orthotopic injection of 4T1 cells into the subcutaneous fat pad of the second pair of left mammary glands. The tumor-bearing mice were divided into granulocyte colony stimulating factor (G-CSF) control group, G-CSF knock-down group, model control group, XHSP small dose group, XHSP medium dose group, XHSP high dose group, and cyclophosphamide (CTX) group, with 6 mice in each group. G-CSF control group and G-CSF knock-down group were constructed by stably transfecting 4T1 cells established by shRNA lentivirus combined with puromycin selection. 48 h after the model was established, XHSP small, medium, high dose group were given 2, 4, 8 g·kg－1·d－1 intragastric administration once a day, respectively. CTX was given 30 mg/kg by intraperitoneal injection, once every other day. The other groups were given an equal volume of 0.5% hydroxymethylcellulose sodium. The drugs in each group were continuously administered for 25 d. Histological changes in spleen were observed by HE staining, the proportion of MDSCs subsets in the spleen were detected by flow cytometry, the co-expression of CD11b and Ly6G in the spleen was detected by immunofluorescence, and the concentration of G-CSF in peripheral blood was detected by ELISA. The spleen of tumor-bearing mice was co-cultured with 4T1 stably transfected cell lines in vitro, treated with XHSP (30 µg/mL) for 24 h, and the co-expression of CD11b and Ly6G in the spleen was detected by immunofluorescence. 4T1 cells were treated by XHSP (10, 30, 100 µg/mL) for 12 h. The mRNA level of G-CSF was detected by realtime RT-PCR. RESULTS: Compared with normal mice, the red pulp of the spleen in tumor-bearing mice was widened with megakaryocyte infiltration. The proportion of spleen polymorphonucleocyte-like MDSCs (PMN-MDSCs) was significantly increased (P<0.01) and the co-expression of CD11b and Ly6G was increased, and the concentration of G-CSF in peripheral blood was significantly increased (P<0.01). However, XHSP could significantly reduce the proportion of PMN-MDSCs (P<0.05) and the co-expression of CD11b and Ly6G in the spleen, down-regulate the mRNA level of G-CSF in 4T1 cells (P<0.01). The concentration of G-CSF in peripheral blood of tumor-bearing mice also decreased (P<0.05) and tumor volume was reduced and splenomegaly was improved (all P<0.05). CONCLUSIONS: XHSP may play an anti-breast cancer role by down-regulating G-CSF, negatively regulating the differentiation of MDSCs, and reconstruct the spleen myeloid microenvironment.

In Vitro and In Vivo Dendritic Cell Immune Stimulation Effect of Low Molecular Weight Fucoidan from New Zealand Undaria pinnatifida.

Low molecular weight fucoidan (LMWF) has been reported to have immunomodulation effects through the increase of the activation and function of macrophages. In this study, the regulating effect of LMWF from Undaria pinnatifida grown in New Zealand on dendritic cells (DCs) was investigated. We discovered that LMWF could stimulate DCs' maturation and migration, as well as CD4+ and CD8+ T cells' proliferation in vitro. We proved that this immune promoting activity is activated through TLR4 and its downstream MAPK and NF-κB signaling pathways. Further in vivo (mouse model) investigation showed that LMWF has a strong immunological boosting effect, such as facilitating the proliferation of immune cells and increasing the index of immune organs. These findings suggest that LMWF has a positive immunomodulatory effect and is a promising candidate to supplement cancer immunotherapy.

Immunomodulatory Effects of Pure Cylindrospermopsin in Rats Orally Exposed for 28 Days.

Cylindrospermopsin (CYN) is a ubiquitous cyanotoxin showing increasing incidence worldwide. CYN has been classified as a cytotoxin and, among its toxic effects, its immunotoxicity is scarcely studied. This work investigates for the first time the influence of oral CYN exposure (18.75; 37.5 and 75 µg/kg b.w./day, for 28 days) on the mRNA expression of selected interleukin (IL) genes (IL-1ß, IL-2, IL-6, Tumor Necrosis Factor alpha (TNF-α), Interferon gamma (IFN-γ)) in the thymus and the spleen of male and female rats, by quantitative real-time polymerase chain reaction (RT-qPCR). Moreover, their serum levels were also measured by a multiplex-bead-based immunoassay, and a histopathological study was performed. CYN produced immunomodulation mainly in the thymus of rats exposed to 75 µg CYN/kg b.w./day in both sexes. However, in the spleen only IL-1ß and IL-2 (males), and TNF-α and IFN-γ (females) expression was modified after CYN exposure. Only female rats exposed to 18.75 µg CYN/kg b.w./day showed a significant decrease in TNF-α serum levels. There were no significant differences in the weight or histopathology in the organs studied. Further research is needed to obtain a deeper view of the molecular mechanisms involved in CYN immunotoxicity and its consequences on long-term exposures.

Chicoric Acid Prevents Neuroinflammation and Neurodegeneration in a Mouse Parkinson's Disease Model: Immune Response and Transcriptome Profile of the Spleen and Colon.

Chicoric acid (CA), a polyphenolic acid compound extracted from chicory and echinacea, possesses antiviral, antioxidative and anti-inflammatory activities. Growing evidence supports the pivotal roles of brain-spleen and brain-gut axes in neurodegenerative diseases, including Parkinson's disease (PD), and the immune response of the spleen and colon is always the active participant in the pathogenesis and development of PD. In this study, we observe that CA prevented dopaminergic neuronal lesions, motor deficits and glial activation in PD mice, along with the increment in striatal brain-derived neurotrophic factor (BDNF), dopamine (DA) and 5-hydroxyindoleacetic acid (5-HT). Furthermore, CA reversed the level of interleukin-17(IL-17), interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-ß) of PD mice, implicating its regulatory effect on the immunological response of spleen and colon. Transcriptome analysis revealed that 22 genes in the spleen (21 upregulated and 1 downregulated) and 306 genes (190 upregulated and 116 downregulated) in the colon were significantly differentially expressed in CA-pretreated mice. These genes were functionally annotated with GSEA, GO and KEGG pathway enrichment, providing the potential target genes and molecular biological mechanisms for the modulation of CA on the spleen and gut in PD. Remarkably, CA restored some gene expressions to normal level. Our results highlighted that the neuroprotection of CA might be associated with the manipulation of CA on brain-spleen and brain-gut axes in PD.

Experimental Research on the Antitumor Effect of Human Gastric Cancer Cells Transplanted in Nude Mice Based on Deep Learning Combined with Spleen-Invigorating Chinese Medicine.

Gastric cancer is still the fifth most common malignant tumor in the world and has the fourth highest mortality rate in the world. Gastric cancer is difficult to treat because of its unobvious onset, low resection rate, and rapid deterioration. Therefore, humans have been working hard to combat gastric cancer. At present, the most commonly used treatment method is radiotherapy. However, this method will damage the normal tissues of the irradiated area while treating malignant tumor cells. It not only has side effects of damage to the patient's skin and mucous membranes but also needs high-rate radiotherapy and has high cost for chemotherapy. In order to solve these problems, it is necessary to find new treatment methods. This article proposes the use of Chinese medicine to invigorate the spleen to inhibit human gastric cancer cells. This article combines modern machine learning technology with traditional Chinese medicine and combines traditional Chinese medicine physiotherapy with Western medicine nude mouse transplantation experiments. The treatment of tumors in Chinese medicine is based on the theory of Chinese medicine and has different characteristics. Western medicine has the advantage of permanently injuring patients. The process of the experiment is to transplant human-derived gastric cancer cells into nude mice. After grouping treatments and obtaining comparative data, deep learning techniques are used to analyze the properties of Chinese medicines for strengthening the spleen and to compare the properties of Chinese medicines for strengthening the spleen. The experimental results showed that the tumor inhibition rate of mice using fluorouracil was 18%, the tumor inhibition rate of mice using low-dose Chinese medicine was 16%, and the tumor inhibition rate of mice using high-dose Chinese medicine reached 52%. 80 days after the experiment, the survival rate of mice using high-dose Chinese medicine is 100% higher than that of mice without treatment.

Traditional Patchouli essential oil modulates the host's immune responses and gut microbiota and exhibits potent anti-cancer effects in ApcMin /+ mice.

Patchouli Essential Oil (PEO) has been used as a scent for various healing purposes since the ancient Egyptian period. The primary source of the oil is Pogostemon cablin (PC), a medicinal plant for treating gastrointestinal symptoms. However, the pharmacological function has not been addressed. Here, we report the cancer prevention and gut microbiota (GM) modulating property of PEO and its derivatives patchouli alcohol (PA) and pogostone (PO) in the ApcMin /+ colorectal cancer mice model. We found that PEO, PA, and PO significantly reduced the tumor burden. At the same time, it strengthened the epithelial barrier, evidenced by substantially increasing the number of the goblet and Paneth cells and upregulation of tight junction and adhesion molecules. In addition, PEO, PA, and PO shifted M1 to M2 macrophage phenotypes and remodeled the inflammatory milieu of ApcMin /+ mice. We also found suppression of CD4+CD25+ and stimulation CD4+ CD8+ cells in the spleen, blood, mesenteric lymph nodes (MLNs), and Peyer's patches (PPs) of the treated mice. The composition of the gut microbiome of the drug-treated mice was distinct from the control mice. The drugs stimulated the short-chain fatty acids (SCFAs)-producers and the key SCFA-sensing receptors (GPR41, GPR43, and GPR109a). The activation of SCFAs/GPSs also triggered the alterations of PPAR-γ, PYY, and HSDCs signaling mediators in the treated mice. Our work showed that PEO and its derivatives exert potent anti-cancer effects by modulating gut microbiota and improving the intestinal microenvironment of the ApcMmin /+ mice.