ABSTRACT
We previously demonstrated that glycyrrhizin (GL) suppressed inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer (CC). In this study, we found an accumulation of regulatory T cells (Tregs) in the spleen and suppression by GL in model mice. ICR mice were divided into four groups: Control, GL, CC, and GL-treated CC (CC+GL), and were sacrificed 20 weeks after AOM/DSS treatment. We measured spleen weight, areas of white and red pulp, and CD8+ T cells (cytotoxic T lymphocytes, CTL), and CD11c-positive cells (dendritic cells) in splenic tissues and forkhead box protein 3 (FoxP3)-positive cells (Tregs) in colorectal and splenic tissues. In all cases, the CC group showed a significant increase compared with those in Control group, and GL administration significantly attenuated this increase. These results indicate that Tregs accumulated in the spleen may participate in inflammation-related carcinogenesis by suppressing CTL. We also suggest that GL which binds to high-mobility group box 1 (HMGB1), suppresses carcinogenesis with decreasing Tregs in the spleen. Furthermore, there was an expression of FoxP3 in cancer cells, indicating that it may be involved in the malignant transformation of cancer cells.
Subject(s)
Azoxymethane , Colorectal Neoplasms , Dextran Sulfate , Forkhead Transcription Factors , Glycyrrhizic Acid , Spleen , T-Lymphocytes, Regulatory , Animals , Glycyrrhizic Acid/pharmacology , Forkhead Transcription Factors/metabolism , Spleen/metabolism , Spleen/pathology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/drug therapy , Mice , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Mice, Inbred ICR , Male , Immunohistochemistry , HMGB1 Protein/metabolismABSTRACT
Obesity is an emerging public health problem. Chronic low-grade inflammation is considered a major promotor of obesity-induced secondary diseases such as cardiovascular and fatty liver disease, type 2 diabetes mellitus, and several cancer entities. Most preliminary studies on obesity-induced immune responses have been conducted in male rodents. Sex-specific differences between men and women in obesity-induced immune dysregulation have not yet been fully outlined but are highly relevant to optimizing prevention strategies for overweight-associated complications. In this study, we fed C57BL/6 female vs. male mice with either standard chow or an obesity-inducing diet (OD). Blood and spleen immune cells were isolated and analyzed by flow cytometry. Lean control mice showed no sex bias in systemic and splenic immune cell composition, whereas the immune responses to obesity were significantly distinct between female and male mice. While immune cell alterations in male OD mice were characterized by a significant reduction in T cells and an increase in myeloid-derived suppressor cells (MDSC), female OD mice displayed preserved T cell numbers. The sex-dependent differences in obesity-induced T cell dysregulation were associated with varying susceptibility to body weight gain and fatty liver disease: Male mice showed significantly more hepatic inflammation and histopathological stigmata of fatty liver in comparison to female OD mice. Our findings indicate that sex impacts susceptibility to obesity-induced T cell dysregulation, which might explain sex-dependent different incidences in the development of obesity-associated secondary diseases. These results provide novel insights into the understanding of obesity-induced chronic inflammation from a sex-specific perspective. Given that most nutrition, exercise, and therapeutic recommendations for the prevention of obesity-associated comorbidities do not differentiate between men and women, the data of this study are clinically relevant and should be taken into consideration in future trials and treatment strategies.
Subject(s)
Mice, Inbred C57BL , Obesity , T-Lymphocytes , Animals , Obesity/immunology , Obesity/complications , Obesity/etiology , Female , Male , Mice , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Diet, High-Fat/adverse effects , Sex Factors , Spleen/immunology , Spleen/pathology , Sex Characteristics , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Fatty Liver/etiology , Fatty Liver/immunology , Fatty Liver/pathology , Inflammation/immunology , Inflammation/pathology , Inflammation/etiologyABSTRACT
PURPOSE: Type 1 diabetes (T1DM) is a chronic metabolic disorder that can cause damage to multiple organs including the spleen. Sole insulin therapy is not satisfactory. This study aims to investigate the effects and mechanisms of combined treatment with insulin and N-acetylcysteine (NAC) on spleen damage in T1DM canines, in order to identify drugs that may better assist patients in the management of diabetes and its complications. METHODS: The canine model of T1DM was established by intravenous injection of alloxan (ALX) and streptozotocin (STZ). The therapeutic effects of insulin and NAC were evaluated by clinical manifestations, spleen protein and mRNA expression. RESULTS: The results indicate that the combined treatment of insulin and NAC can alleviate hyperglycemia and hematologic abnormalities, improve splenic histopathological changes, prevent fibrous tissue proliferation, and glycogen deposition. In addition, we observed that this combination treatment significantly suppressed the protein expression of p-P65/P65 (17.6 %, P < 0.05), NLRP3 (46.8 %, P < 0.05), and p-P38/P38 (37.1 %, P < 0.05) induced by T1DM when compared to insulin treatment alone. Moreover, it also significantly decreased the mRNA expression of TLR4 (45.0 %, P < 0.01), TNF-α (30.3 %, P < 0.05), and NLRP3 (43.3 %, P < 0.05). CONCLUSIONS: This combination has the potential to mitigate splenic inflammatory injury in T1DM canines by suppressing the activation of MAPKs-NF-κB pathway and pyroptosis. These findings provide a reference for the treatment strategies of diabetes and its complications.
Subject(s)
Acetylcysteine , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 1 , Drug Therapy, Combination , Insulin , NF-kappa B , Pyroptosis , Signal Transduction , Spleen , Animals , Dogs , Acetylcysteine/pharmacology , Acetylcysteine/therapeutic use , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/drug therapy , NF-kappa B/metabolism , Pyroptosis/drug effects , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Signal Transduction/drug effects , Male , Spleen/drug effects , Spleen/pathology , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Splenic Diseases/drug therapy , Splenic Diseases/etiology , Splenic Diseases/complications , MAP Kinase Signaling System/drug effectsABSTRACT
BACKGROUND: Liver stiffness (LS) measurement with two-dimensional shear wave elastography (2D-SWE) correlates with the degree of liver fibrosis and thus indirectly reflects liver function reserve. The size of the spleen increases due to tissue proliferation, fibrosis, and portal vein congestion, which can indirectly reflect the situation of liver fibrosis/cirrhosis. It was reported that the size of the spleen was related to posthepatectomy liver failure (PHLF). So far, there has been no study combining 2D-SWE measurements of LS with spleen size to predict PHLF. This prospective study aimed to investigate the utility of 2D-SWE assessing LS and spleen area (SPA) for the prediction of PHLF in hepatocellular carcinoma (HCC) patients and to develop a risk prediction model. AIM: To investigate the utility of 2D-SWE assessing LS and SPA for the prediction of PHLF in HCC patients and to develop a risk prediction model. METHODS: This was a multicenter observational study prospectively analyzing patients who underwent hepatectomy from October 2020 to March 2022. Within 1 wk before partial hepatectomy, ultrasound examination was performed to measure LS and SPA, and blood was drawn to evaluate the patient's liver function and other conditions. Least absolute shrinkage and selection operator logistic regression and multivariate logistic regression analysis was applied to identify independent predictors of PHLF and develop a nomogram. Nomogram performance was validated further. The diagnostic performance of the nomogram was evaluated with receiver operating characteristic curve compared with the conventional models, including the model for end-stage liver disease (MELD) score and the albumin-bilirubin (ALBI) score. RESULTS: A total of 562 HCC patients undergoing hepatectomy (500 in the training cohort and 62 in the validation cohort) were enrolled in this study. The independent predictors of PHLF were LS, SPA, range of resection, blood loss, international normalized ratio, and total bilirubin. Better diagnostic performance of the nomogram was obtained in the training [area under receiver operating characteristic curve (AUC): 0.833; 95% confidence interval (95%CI): 0.792-0.873; sensitivity: 83.1%; specificity: 73.5%] and validation (AUC: 0.802; 95%CI: 0.684-0.920; sensitivity: 95.5%; specificity: 52.5%) cohorts compared with the MELD score and the ALBI score. CONCLUSION: This PHLF nomogram, mainly based on LS by 2D-SWE and SPA, was useful in predicting PHLF in HCC patients and presented better than MELD score and ALBI score.
Subject(s)
Carcinoma, Hepatocellular , Elasticity Imaging Techniques , Hepatectomy , Liver Failure , Liver Neoplasms , Liver , Nomograms , Spleen , Humans , Hepatectomy/adverse effects , Male , Female , Middle Aged , Elasticity Imaging Techniques/methods , Liver Neoplasms/surgery , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/pathology , Prospective Studies , Carcinoma, Hepatocellular/surgery , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/pathology , Liver/diagnostic imaging , Liver/surgery , Liver/pathology , Spleen/diagnostic imaging , Spleen/pathology , Spleen/surgery , Liver Failure/etiology , Aged , Postoperative Complications/etiology , Postoperative Complications/diagnostic imaging , Risk Assessment/methods , Predictive Value of Tests , Organ Size , Adult , ROC Curve , Liver Cirrhosis/diagnostic imaging , Liver Cirrhosis/surgery , Liver Cirrhosis/pathology , Liver Cirrhosis/complicationsABSTRACT
Since its identification in the vitreous humour of the eye and laboratory biosynthesis, hyaluronic acid (HA) has been a vital component in several pharmaceutical, nutritional, medicinal, and cosmetic uses. However, little is known about its potential toxicological impacts on aquatic inhabitants. Herein, we investigated the hematological response of Clarias gariepinus to nominal doses of HA. To achieve this objective, 72 adult fish were randomly and evenly distributed into four groups: control, low-dose (0.5 mg/l HA), medium-dose (10 mg/l HA), and high-dose (100 mg/l HA) groups for two weeks each during both the exposure and recovery periods. The findings confirmed presence of anemia, neutrophilia, leucopoenia, lymphopenia, and eosinophilia at the end of exposure to HA. In addition, poikilocytosis and a variety of cytomorphological disturbances were observed. Dose-dependent histological alterations in spleen morphology were observed in the exposed groups. After HA removal from the aquarium for 2 weeks, the groups exposed to the two highest doses still exhibited a notable decline in red blood cell count, hemoglobin concentration, mean corpuscular hemoglobin concentration, and an increase in mean corpuscular volume. Additionally, there was a significant rise in neutrophils, eosinophils, cell alterations, and nuclear abnormalities percentages, along with a decrease in monocytes, coupled with a dose-dependent decrease in lymphocytes. Furthermore, only the highest dose of HA in the recovered groups continued to cause a significant increase in white blood cells. White blood cells remained lower, and the proportion of apoptotic RBCs remained higher in the high-dose group. The persistence of most of the haematological and histological disorders even after recovery period indicates a failure of physiological compensatory mechanisms to overcome the HA-associated problems or insufficient duration of recovery. Thus, these findings encourage the inclusion of this new hazardous agent in the biomonitoring program and provide a specific pattern of hematological profile in HA-challenged fish. Further experiments are highly warranted to explore other toxicological hazards of HA using dose/time window protocols.
Subject(s)
Catfishes , Hyaluronic Acid , Spleen , Animals , Hyaluronic Acid/blood , Spleen/drug effects , Spleen/pathology , Dose-Response Relationship, DrugABSTRACT
This study evaluated the use of F-18 fluorodeoxyglucose (FDG) PET/CT imaging to differentiate between scrub typhus and systemic lupus erythematosus (SLE) in patients presenting with lymphadenopathy. We carried out a retrospective analysis of 18 scrub typhus patients and seven SLE patients, using various imaging parameters, including lymph node size, spleen and liver lengths, the distance between the two farthest lesions (Dmax), and assessments of glucose metabolism. On FDG PET images, we measured the maximum standardized uptake value (SUVmax) of the lymph nodes, spleen, and liver and the mean standardized uptake value (SUVmean) of the liver and spleen. The Dmax values of scrub typhus patients were significantly longer than those of SLE patients, indicating that lymphadenopathy is more generalized in the patients with scrub typhus. The SUVmax values for the lymph node, spleen, and liver were also higher in patients with scrub typhus, while the SUVmean of the liver and spleen did not differ between the two groups. This study is the first to compare FDG PET/CT images between these two conditions, suggesting the potential of this imaging modality to provide critical diagnostic distinctions.
Subject(s)
Fluorodeoxyglucose F18 , Lupus Erythematosus, Systemic , Positron Emission Tomography Computed Tomography , Scrub Typhus , Humans , Scrub Typhus/diagnostic imaging , Lupus Erythematosus, Systemic/diagnostic imaging , Lupus Erythematosus, Systemic/complications , Positron Emission Tomography Computed Tomography/methods , Female , Male , Middle Aged , Adult , Retrospective Studies , Aged , Lymph Nodes/diagnostic imaging , Lymph Nodes/pathology , Spleen/diagnostic imaging , Spleen/pathology , Liver/diagnostic imaging , Liver/pathology , Liver/metabolism , Diagnosis, Differential , Radiopharmaceuticals , Young AdultABSTRACT
Co-infections are a common reality but understanding how the immune system responds in this context is complex and can be unpredictable. Heligmosomoides bakeri (parasitic roundworm, previously Heligmosomoides polygyrus) and Toxoplasma gondii (protozoan parasite) are well studied organisms that stimulate a characteristic Th2 and Th1 response, respectively. Several studies have demonstrated reduced inflammatory cytokine responses in animals co-infected with such organisms. However, while general cytokine signatures have been examined, the impact of the different cytokine producing lymphocytes on parasite control/clearance is not fully understood. We investigated five different lymphocyte populations (NK, NKT, γδ T, CD4+ T and CD8+ T cells), five organs (small intestine, Peyer's patches, mesenteric lymph nodes, spleen and liver), and 4 cytokines (IFN©, IL-4, IL-10 and IL-13) at two different time points (days 5 and 10 post T. gondii infection). We found that co-infected animals had significantly higher mortality than either single infection. This was accompanied by transient and local changes in parasite loads and cytokine profiles. Despite the early changes in lymphocyte and cytokine profiles, severe intestinal pathology in co-infected mice likely contributed to early mortality due to significant damage by both parasites in the small intestine. Our work demonstrates the importance of taking a broad view during infection research, studying multiple cell types, organs/tissues and time points to link and/or uncouple immunological from pathological findings. Our results provide insights into how co-infection with parasites stimulating different arms of the immune system can lead to drastic changes in infection dynamics.
Subject(s)
Coinfection , Cytokines , Nematospiroides dubius , Toxoplasma , Animals , Coinfection/immunology , Coinfection/parasitology , Toxoplasma/immunology , Mice , Cytokines/metabolism , Nematospiroides dubius/immunology , Strongylida Infections/immunology , Strongylida Infections/parasitology , Strongylida Infections/mortality , Toxoplasmosis/immunology , Toxoplasmosis/mortality , Toxoplasmosis/complications , Female , Toxoplasmosis, Animal/immunology , Toxoplasmosis, Animal/mortality , Toxoplasmosis, Animal/parasitology , Spleen/immunology , Spleen/pathology , Spleen/parasitology , Parasite Load , Lymphoid Tissue/immunology , Lymphoid Tissue/pathology , Lymphoid Tissue/parasitologyABSTRACT
Animal models are an important tool in the research of chronic autoimmune diseases, like systemic lupus erythematosus (SLE). MRL-Faslpr mice are one of different lupus models that develop spontaneously an SLE-like disease with autoantibodies and immune complex deposition that leads into damage of different organs. In contrast to human SLE, both sexes of MRL-Faslpr mice develop a similar autoimmune disease. Due to the sex bias in human and the delayed disease progression in male MRL-Faslpr mice, the majority of studies have been performed in female mice. To determine the suitability of male MRL-Faslpr mice for SLE research, especially with regard to the 3 R-principle and animal welfare, analyses of phenotype, inflammation and damage with focus on kidney and spleen were performed in mice of both sexes. Female mice developed lymphadenopathy and skin lesions earlier as males. At an age of 3.5 month, more immune cells infiltrated kidney and spleen in females compared to males. At the age of 5 months, however, substantially less sex-specific differences were detected. Since other studies have shown differences between both sexes on other manifestations like autoimmune pancreatitis and Sjögren syndrome in MRL-Faslpr mice, the use of male mice as part of 3 R-principle and animal welfare must be carefully considered.
Subject(s)
Disease Models, Animal , Kidney , Lupus Erythematosus, Systemic , Mice, Inbred MRL lpr , Animals , Female , Male , Mice , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/pathology , Kidney/pathology , Kidney/immunology , Inflammation/immunology , Inflammation/pathology , Sex Factors , Spleen/immunology , Spleen/pathology , Humans , Sex Characteristics , Autoantibodies/immunologyABSTRACT
Per- and polyfluoroalkyl substances (PFAS) are a large group of synthetic surfactants of over 12,000 compounds that are incorporated into numerous products for their chemical and physical properties. Studies have associated PFAS with adverse health effects. Although there is a high potential for dermal exposure, these studies are lacking. The present study evaluated the systemic and immunotoxicity of subchronic 28- or 10-days of dermal exposure, respectively, to PFHpS (0.3125-2.5% or 7.82-62.5 mg/kg/dose) or PFOS (0.5% or 12.5 mg/kg/dose) in a murine model. Elevated levels of PFHpS were detected in the serum and urine, suggesting that absorption is occurring through the dermal route. PFHpS induced significantly increased relative liver weight, significantly decreased relative spleen and thymus weight, altered serum chemistries, and altered histopathology. Additionally, PFHpS significantly reduced the humoral immune response and altered immune subsets in the spleen, suggesting immunosuppression. Gene expression changes were observed in the liver, skin, and spleen of genes involved in fatty acid metabolism, necrosis, and inflammation. Immune-cell phenotyping identified significant decreases in B-cells and CD11b+ monocyte and/or macrophages in the spleen along with decreases in eosinophils and dendritic cells in the skin. These findings support PFHpS absorption through the skin leading to liver damage and immune suppression.
Subject(s)
Alkanesulfonic Acids , Fluorocarbons , Animals , Fluorocarbons/toxicity , Fluorocarbons/administration & dosage , Mice , Alkanesulfonic Acids/toxicity , Alkanesulfonic Acids/administration & dosage , Female , Humans , Spleen/drug effects , Spleen/immunology , Spleen/pathology , Sulfonic Acids/toxicity , Sulfonic Acids/administration & dosage , Administration, Topical , Liver/drug effects , Liver/immunology , Liver/pathology , Male , Skin/drug effects , Skin/immunology , Skin/pathologyABSTRACT
BACKGROUND: The authors aimed to use preoperative computed tomography images to develop a radiomic nomogram to select patients who would benefit from spleen-preserving splenic hilar (No.10) lymphadenectomy (SPSHL). METHODS: A pooled analysis of three distinct prospective studies was performed. The splenic hilar lymph node (SHLN) ratio (sLNR) was established as the quotient of the number of metastatic SHLN to the total number of SHLN. Radiomic features reflecting the phenotypes of the primary tumor (RS1) and SHLN region (RS2) were extracted and used as predictive factors for sLNR. RESULTS: This study included 733 patients: 301 in the D2 group and 432 in the D2+No.10 group. The optimal sLNR cutoff value was set at 0.4, and the D2+No.10 group was divided into three groups: sLNR=0, sLNR ≤0.4, and sLNR >0.4. Patients in the D2+No. 10 group were randomly divided into the training ( n =302) and validation ( n =130) cohorts. The AUCs value of the nomogram, including RS1 and RS2, were 0.952 in the training cohort and 0.888 in the validation cohort. The entire cohort was divided into three groups based on the nomogram scores: low, moderate, and high SHLN metastasis burden groups (LMB, MMB, and HMB, respectively). A similar 5-year OS rate was found between the D2 and D2+No. 10 groups in the LMB and HMB groups. In the MMB group, the 5-year OS of the D2+No. 10 group (73.4%) was significantly higher than that of the D2 group (37.6%) ( P <0.001). CONCLUSIONS: The nomogram showed good predictive ability for distinguishing patients with various SHLN metastasis burdens. It can accurately identify patients who would benefit from SPSHL.
Subject(s)
Lymph Node Excision , Nomograms , Tomography, X-Ray Computed , Humans , Male , Female , Middle Aged , Prospective Studies , Aged , Spleen/diagnostic imaging , Spleen/surgery , Spleen/pathology , Adult , Lymphatic Metastasis/diagnostic imaging , Lymph Nodes/pathology , Lymph Nodes/diagnostic imaging , Lymph Nodes/surgery , RadiomicsABSTRACT
The thymus, where T lymphocytes develop and mature, is sensitive to insults such as tissue ischemia or injury. The insults can cause thymic atrophy and compromise T-cell development, potentially impairing adaptive immunity. The objective of this study was to investigate whether myocardial infarction (MI) induces thymic injury to impair T lymphopoiesis and to uncover the underlying mechanisms. When compared with sham controls, MI mice at day 7 post-MI exhibited smaller thymus, lower cellularity, as well as less thymocytes at different developmental stages, indicative of T-lymphopoiesis impairment following MI. Accordingly, the spleen of MI mice has less T cells and recent thymic emigrants (RTEs), implying that the thymus of MI mice releases fewer mature thymocytes than sham controls. Interestingly, the secretory function of splenic T cells was not affected by MI. Further experiments showed that the reduction of thymocytes in MI mice was due to increased thymocyte apoptosis. Removal of adrenal glands by adrenalectomy (ADX) prevented MI-induced thymic injury and dysfunction, whereas corticosterone supplementation in ADX + MI mice reinduced thymic injury and dysfunction, indicating that glucocorticoids mediate thymic damage triggered by MI. Eosinophils play essential roles in thymic regeneration postirradiation, and eosinophil-deficient mice exhibit impaired thymic recovery after sublethal irradiation. Interestingly, the thymus was fully regenerated in both wild-type and eosinophil-deficient mice at day 14 post-MI, suggesting that eosinophils are not critical for thymus regeneration post-MI. In conclusion, our study demonstrates that MI-induced glucocorticoids trigger thymocyte apoptosis and impair T lymphopoiesis, resulting in less mature thymocyte release to the spleen.NEW & NOTEWORTHY The thymus is essential for maintaining whole body T-cell output. Thymic injury can adversely affect T lymphopoiesis and T-cell immune response. This study demonstrates that MI induces thymocyte apoptosis and compromises T lymphopoiesis, resulting in fewer releases of mature thymocytes to the spleen. This process is mediated by glucocorticoids secreted by adrenal glands. Therefore, targeting glucocorticoids represents a novel approach to attenuate post-MI thymic injury.
Subject(s)
Adrenalectomy , Apoptosis , Lymphopoiesis , Mice, Inbred C57BL , Myocardial Infarction , Thymus Gland , Animals , Thymus Gland/pathology , Thymus Gland/immunology , Thymus Gland/drug effects , Myocardial Infarction/pathology , Myocardial Infarction/metabolism , Myocardial Infarction/immunology , Myocardial Infarction/physiopathology , Male , Thymocytes/metabolism , Thymocytes/pathology , Thymocytes/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Glucocorticoids/pharmacology , Eosinophils/metabolism , Eosinophils/immunology , Spleen/immunology , Spleen/metabolism , Spleen/pathology , Disease Models, Animal , Mice , Corticosterone/bloodABSTRACT
Mitochondrial dysfunction has been increasingly recognized as a trigger for systemic lupus erythematosus (SLE). Recent bioinformatics studies have suggested Fam210b as a significant candidate for the classification and therapeutic targeting of SLE. To experimentally prove the role of Fam210b in SLE, we constructed Fam210b knockout (Fam210b-/-) mice using the CRISPR-Cas9 method. We found that approximately 15.68% of Fam210b-/- mice spontaneously developed lupus-like autoimmunity, which was characterized by skin ulcerations, splenomegaly, and an increase in anti-double-stranded DNA (anti-dsDNA) IgG antibodies and anti-nuclear antibodies(ANA). Single-cell sequencing showed that Fam210b was mainly expressed in erythroid cells. Critically, the knockout of Fam210b resulted in abnormal erythrocyte differentiation and development in the spleens of mice. Concurrently, the spleens exhibited an increased number of CD71+ erythroid cells, along with elevated levels of reactive oxygen species (ROS) in the erythrocytes. The co-culture of CD71+ erythroid cells and lymphocytes resulted in lymphocyte activation and promoted dsDNA and IgG production. In summary, Fam210b knockout leads to a low probability of lupus-like symptoms in mice through the overproduction of ROS in CD71+ erythroid cells. Thus, Fam210b reduction may serve as a novel key marker that triggers the development of SLE.
Subject(s)
Lupus Erythematosus, Systemic , Mice, Knockout , Animals , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/metabolism , Lupus Erythematosus, Systemic/pathology , Mice , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Reactive Oxygen Species/metabolism , Antibodies, Antinuclear , Mitochondrial Membranes/metabolism , Erythroid Cells/metabolism , Erythroid Cells/pathology , Disease Models, Animal , Immunoglobulin G/metabolism , Mice, Inbred C57BL , Spleen/metabolism , Spleen/pathology , Membrane Proteins/genetics , Membrane Proteins/metabolism , FemaleABSTRACT
Marek's disease virus (MDV) is an oncogenic alphaherpesvirus that causes deadly lymphomas in chickens. In chickens, up to 50% of all peripheral T cells are gamma delta (γδ) T cells. Until now, their role in MDV pathogenesis and tumor formation remains poorly understood. To investigate the role of γδ T cells in MDV pathogenesis, we infected recently generated γδ T cell knockout chickens with very virulent MDV. Strikingly, disease and tumor incidence were highly increased in the absence of γδ T cells, indicating that γδ T cells play an important role in the immune response against MDV. In the absence of γδ T cells, virus replication was drastically increased in the thymus and spleen, which are potential sites of T cell transformation. Taken together, our data provide the first evidence that γδ T cells play an important role in the pathogenesis and tumor formation of this highly oncogenic herpesvirus.IMPORTANCEGamma delta (γδ) T cells are the most abundant T cells in chickens, but their role in fighting pathogens remains poorly understood. Marek's disease virus (MDV) is an important veterinary pathogen, that causes one of the most frequent cancers in animals and is used as a model for virus-induced tumor formation. Our study revealed that γδ T cells play a crucial role in combating MDV, as disease and tumor incidence drastically increased in the absence of these cells. γδ T cells restricted virus replication in the key lymphoid organs, thereby decreasing the likelihood of causing tumors and disease. This study provides novel insights into the role of γδ T cells in the pathogenesis of this highly oncogenic virus.
Subject(s)
Chickens , Herpesvirus 2, Gallid , Marek Disease , Virus Replication , Animals , Chickens/virology , Marek Disease/virology , Marek Disease/immunology , Herpesvirus 2, Gallid/pathogenicity , Herpesvirus 2, Gallid/immunology , Herpesvirus 2, Gallid/genetics , Spleen/immunology , Spleen/virology , Spleen/pathology , Receptors, Antigen, T-Cell, gamma-delta/immunology , Receptors, Antigen, T-Cell, gamma-delta/genetics , Intraepithelial Lymphocytes/immunology , Thymus Gland/immunology , Thymus Gland/virology , Thymus Gland/pathology , T-Lymphocytes/immunology , Poultry Diseases/virology , Poultry Diseases/immunologyABSTRACT
BACKGROUND: Atypical/Nor98 scrapie (AS) is an idiopathic infectious prion disease affecting sheep and goats. Recent findings suggest that zoonotic prions from classical bovine spongiform encephalopathy (C-BSE) may copropagate with atypical/Nor98 prions in AS sheep brains. Investigating the risk AS poses to humans is crucial. METHODS: To assess the risk of sheep/goat-to-human transmission of AS, we serially inoculated brain tissue from field and laboratory isolates into transgenic mice overexpressing human prion protein (Met129 allele). We studied clinical outcomes as well as presence of prions in brains and spleens. RESULTS: No transmission occurred on the primary passage, with no clinical disease or pathological prion protein in brains and spleens. On subsequent passages, 1 isolate gradually adapted, manifesting as prions with a phenotype resembling those causing MM1-type sporadic Creutzfeldt-Jakob disease in humans. However, further characterization using in vivo and in vitro techniques confirmed both prion agents as different strains, revealing a case of phenotypic convergence. Importantly, no C-BSE prions emerged in these mice, especially in the spleen, which is more permissive than the brain for C-BSE cross-species transmission. CONCLUSIONS: The results obtained suggest a low zoonotic potential for AS. Rare adaptation may allow the emergence of prions phenotypically resembling those spontaneously forming in humans.
Subject(s)
Brain , Creutzfeldt-Jakob Syndrome , Goats , Mice, Transgenic , Prions , Scrapie , Zoonoses , Animals , Creutzfeldt-Jakob Syndrome/transmission , Creutzfeldt-Jakob Syndrome/pathology , Creutzfeldt-Jakob Syndrome/metabolism , Humans , Scrapie/transmission , Scrapie/pathology , Mice , Zoonoses/transmission , Brain/pathology , Brain/metabolism , Sheep , Cattle , Prions/metabolism , Phenotype , Spleen/pathology , Encephalopathy, Bovine Spongiform/transmission , Encephalopathy, Bovine Spongiform/pathology , Encephalopathy, Bovine Spongiform/metabolism , Goat Diseases/transmission , Goat Diseases/pathology , Disease Models, AnimalABSTRACT
Fluconazole (FCZ), an antifungal from the azole family, causes several detrimental effects in fish. In recent times, there has been a notable surge in interest regarding the utilization of Moringa oleifera (Mo) as a dietary antioxidant. This research aimed to evaluate the potential protective effects of dietary Moringa oleifera (MO) against the adverse impacts of fluconazole in the African catfish (Clarias gariepinus). The fish were allocated into four groups as follows: a control group fed a basal diet, an FCZ - exposed (200 ng/L) fed basal diet, 1% MO fed through basal diet, and an FCZ-exposed (200 ng/L) and 1% MO fed through basal diet fed group. The results showed that FCZ exposure decreased superoxide dismutase, total antioxidant capacity, and acetylcholine esterase levels. On the other hand, FCZ exposure increased malonaldehyde and cortisol levels as compared to control (P < 0.05). FCZ caused immunosuppressive effects in C. gariepinus as revealed by lower immunity indices (lysozyme and phagocytic activity and immunoglobulin level) and increased cytokine levels (IL-6 IL-1ß). Histological examination of the spleen from fish exposed to FCZ showed several splenic changes. We conclude that dietary MO supplementation has the potential to alleviate the oxidative stress, restore immune response balance, and mitigate histological damage induced by FCZ exposure, thus positioning MO as an immunostimulant in C. gariepinus when administered alongside FCZ.
Subject(s)
Animal Feed , Catfishes , Diet , Dietary Supplements , Fluconazole , Moringa oleifera , Spleen , Animals , Moringa oleifera/chemistry , Spleen/drug effects , Spleen/pathology , Fluconazole/pharmacology , Fluconazole/administration & dosage , Diet/veterinary , Animal Feed/analysis , Antifungal Agents/administration & dosage , Antifungal Agents/pharmacology , Antioxidants/pharmacology , Superoxide Dismutase/metabolismSubject(s)
Hemangioma , Microfilariae , Splenic Neoplasms , Humans , Hemangioma/pathology , Hemangioma/diagnostic imaging , Splenic Neoplasms/pathology , Splenic Neoplasms/diagnosis , Microfilariae/isolation & purification , Animals , Spleen/pathology , Spleen/diagnostic imaging , Spleen/parasitology , Microscopy , Male , Histocytochemistry , Filariasis/diagnosis , Filariasis/parasitologyABSTRACT
BACKGROUND AND AIM: The spleen has an essential role in immune responses regulation and is considered the biggest peripheral immune organ. Citicoline is used for various brain disorders management. This study aimed to examine the using possibility of citicoline to treat γ-radiation-induced splenic inflammation in rats. MATERIALS AND METHODS: Eighteen male albino rats were classified into: Group 1 (control) animals were kept as control. Group 2 (γ-radiation) animals were total-body γ-irradiated with 6 Gy. Group 3 (γ-radiation + citicoline) rats were γ-irradiated with 6 Gy, then injected intraperitoneally with citicoline (300 mg/kg/d) 5 min after irradiation for one week. Levels of TNF-α, IL-1ß, iNOS, NF-κB, JAK2, and STAT3 were determined in spleen tissue, along with histopathological examination. RESULTS: Rats exposure to gamma-radiation led to elevation in splenic TNF-α, IL-1ß, NF-κB, iNOS, JAK2, and STAT3 levels significantly. Treatment with citicoline after gamma-radiation exposure improved this elevation, and modulated gamma-radiation-induced histopathological alterations. CONCLUSIONS: This data showed that citicoline inhibited γ-radiation-induced splenic inflammation via suppressing NF-κB and JAK2/STAT3 signaling pathways in spleen tissue.
Subject(s)
Cytidine Diphosphate Choline , Gamma Rays , Signal Transduction , Spleen , Animals , Gamma Rays/adverse effects , Male , Spleen/drug effects , Spleen/radiation effects , Spleen/pathology , Spleen/immunology , Rats , Signal Transduction/drug effects , Signal Transduction/radiation effects , Cytidine Diphosphate Choline/pharmacology , Inflammation/drug therapy , NF-kappa B/metabolism , Whole-Body IrradiationABSTRACT
The objective of this study was to investigate spleen pathology and immune cell subset alterations in mice exposed to acute and chronic restraint stress over various timeframes. A deeper understanding of stress-induced spleen injuries can provide new insights into the mechanisms underlying stress-induced disorders. C57BL/6N mice were restrained for different durations (1, 3, 7, 14 and 21 days) for 6-8 h daily. The control mice were observed at the same time points. Post restraint, behavioural experiments were conducted to assess spleen weight, gross morphology and microscopic histological changes. Immunohistochemical staining was used to detect changes in glucocorticoid receptor (GR) expression, immune cell subsets and cell proliferation in response to stress. Our analysis revealed significant behavioural abnormalities in the stressed mice. In particular, there was an increase in the nuclear expression of GR beginning on Day 3, and it peaked on Day 14. The spleens of stressed mice displayed a reduction in size, disordered internal tissue structure and reduced cell proliferation. NK cells and M2-type macrophages exhibited immune cell subset alterations under stress, whereas T or B cells remained unaltered. Restraint stress can lead to pathomorphological alterations in spleen morphology, cell proliferation and immune cell counts in mice. These findings suggest that stress-induced pathological changes can disrupt immune regulation during stress.
Subject(s)
Mice, Inbred C57BL , Receptors, Glucocorticoid , Restraint, Physical , Spleen , Stress, Psychological , Animals , Spleen/pathology , Spleen/metabolism , Receptors, Glucocorticoid/metabolism , Mice , Male , Stress, Psychological/immunology , Cell Proliferation , Time Factors , Killer Cells, Natural/immunology , Stress, Physiological , Macrophages/immunology , Macrophages/metabolismABSTRACT
RATIONALE: Sclerosing angiomatoid nodular transformation (SANT) of the spleen is an uncommon benign vascular lesion with an obscure etiology. It predominantly affects middle-aged women and presents with nonspecific clinical signs, making preoperative diagnosis challenging. The definitive diagnosis of SANT relies on pathological examination following splenectomy. This study aims to contribute to the understanding of SANT by presenting a case series and reviewing the literature to highlight the clinical presentation, diagnostic challenges, and treatment outcomes. PATIENT CONCERNS: In this retrospective study, we analyzed the clinical data of 3 patients with confirmed SANT admitted from November 2013 to October 2023. The cases include a 25-year-old male, a 15-year-old female, and a 39-year-old male, each with a splenic mass. DIAGNOSES AND INTERVENTIONS: All of the three cases were treated by laparoscopic splenectomy (LS). Pathological examination confirmed SANT in all cases. OUTCOMES: No recurrence or metastasis was observed during a 10-year follow-up for the first 2 cases, and the third case showed no abnormalities at 2 months postoperatively. Despite its rarity, SANT is a significant condition due to its potential for misdiagnosis and the importance of distinguishing it from malignant lesions. The study underscores the utility of LS as a safe and effective treatment option. LESSONS: SANT is a rare benign tumor of the spleen, and the preoperative diagnosis of whom is challenging. LS is a safe and effective treatment for SANT, with satisfactory surgical outcomes and favorable long-term prognosis on follow-up. The study contributes to the limited body of research on this rare condition and calls for larger studies to validate these findings and improve clinical management.
Subject(s)
Splenectomy , Splenic Neoplasms , Humans , Male , Adult , Female , Splenectomy/methods , Adolescent , Splenic Neoplasms/pathology , Splenic Neoplasms/surgery , Splenic Neoplasms/diagnosis , Spleen/pathology , Histiocytoma, Benign Fibrous/pathology , Histiocytoma, Benign Fibrous/surgery , Histiocytoma, Benign Fibrous/diagnosis , Retrospective Studies , Laparoscopy/methods , Diagnosis, Differential , Splenic Diseases/surgery , Splenic Diseases/pathology , Splenic Diseases/diagnosisABSTRACT
The continuously expanding field of Alzheimer's disease (AD) research is now beginning to defocus the brain to take a more systemic approach to the disease, as alterations in the peripheral organs could be related to disease progression. One emerging hypothesis is organ involvement in the process of Aß clearance. In the present work, we aimed to examine the status and involvement of the kidney as a key organ for waste elimination and the spleen, which is in charge of filtering the blood and producing lymphocytes, and their influence on AD. The results showed morphological and structural changes due to acute amyloidosis in the kidney (glomeruli area) and spleen (red pulp area and red/white pulp ratio) together with reduced antioxidant defense activity (GPx) in 16-month-old male and female 3xTg-AD mice when compared to their age- and sex-matched non-transgenic (NTg) counterparts. All these alterations correlated with the anxious-like behavioral phenotype of this mouse model. In addition, forced isolation, a cause of psychological stress, had a negative effect by intensifying genotype differences and causing differences to appear in NTg animals. This study further supports the relevance of a more integrative view of the complex interplay between systems in aging, especially at advanced stages of Alzheimer's disease.