Search Results (820)

Fumonisin B1 (FB1) is a prevalent mycotoxin in moldy grains and feeds, highly toxic to livestock and compromising product quality while threatening food safety. Poultry exhibit low susceptibility to FB1, but the underlying tolerance mechanisms remain unclear. Traditional 3D chicken intestinal organoid models cannot simulate direct interaction between the epithelial monolayer and FB1, limiting the study of FB1–chicken intestinal crosstalk. Here, we established a 2D chicken intestinal organoid monolayer model, derived from intestinal crypts of 18-day-old specific pathogen-free chicken embryos, to systematically explore poultry’s resistance mechanisms against FB1. Using this model, we compared FB1-induced effects with those in a porcine intestinal epithelial cell model. Results showed that FB1 exposure did not reduce transepithelial electrical resistance, induce abnormal expression of tight junction genes, or cause significant fluctuations in inflammatory factor levels in chicken intestinal organoid monolayers. Mechanistically, FB1 enhances chicken intestinal stem cell function by activating the Wnt/β-catenin pathway, thereby promoting epithelial regeneration and renewal to increase FB1 resistance and decrease toxin sensitivity in chickens. This study reveals a strategy for enhancing FB1 tolerance in poultry by promoting intestinal stem cell function, providing a new perspective for developing mycotoxin prevention and control strategies. Full article

Primary podocytopathies, including minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), are caused by a circulating factor or factors injurious to the podocyte. An immunologic origin seems likely based on responsiveness to corticosteroids or other immunosuppressive agents, including calcineurin inhibitors targeting T-cells and rituximab targeting B-cells. Potential non-antibody-mediated circulating factors have been identified, including cardiotrophin-like cytokine 1, soluble urokinase plasminogen activator receptor, and angiopoietin-like 4, among others. More recent research supports a primary antibody pathogenesis, with anti-nephrin antibodies found in a significant percentage of cases. Such antibodies also predict recurrence after transplantation. Other potential antigenic targets besides nephrin include annexin, the proteosome, podocin, and CD40. Additionally, high-resolution confocal microscopy has identified punctate immunoglobulin deposits along the slit diaphragm and podocyte cell body that may or may not colocalize with abnormal punctate nephrin staining and may correlate with detectable circulating antibodies. The success of rituximab in observational studies in both native kidneys and transplants supports a primary role for autoantibodies. We discuss in detail the data supporting putative non-antibody circulating factors, as well as the recent data supporting antibody pathogenesis, which may provide some clues on treating the individual patient. Full article

Long COVID (LC), also known as post-acute sequelae of COVID-19 infection (PASC), is a heterogeneous and debilitating chronic disease that currently affects 10 to 20 million people in the U.S. and over 420 million people globally. With no approved treatments, the long-term global health and economic impact of chronic LC remains high and growing. LC affects children, adolescents, and healthy adults and is characterized by over 200 diverse symptoms that persist for months to years after the acute COVID-19 infection is resolved. These symptoms target twelve major organ systems, causing dyspnea, vascular damage, cognitive impairments (“brain fog”), physical and mental fatigue, anxiety, and depression. This heterogeneity of LC symptoms, along with the lack of specific biomarkers and diagnostic tests, presents a significant challenge to the development of LC treatments. While several biological abnormalities have emerged as potential drivers of LC, a causative factor in a large subset of patients with LC, involves reservoirs of virus and/or viral RNA (vRNA) that persist months to years in multiple organs driving chronic inflammation, respiratory, muscular, cognitive, and cardiovascular damages, and provide continuous viral antigenic stimuli that overstimulate and exhaust CD4⁺ and CD8⁺ T cells. In this review, we (i) shed light on persisting virus and vRNA reservoirs detected, either directly (from biopsy, blood, stool, and autopsy samples) or indirectly through virus-specific B and T cell responses, in patients with LC and their association with the chronic symptomatology of LC; (ii) explore potential mechanisms of inflammation, immune evasion, and immune overstimulation in LC; (iii) review animal models of virus reservoirs in LC; (iv) discuss potential T cell immunotherapeutic strategies to reduce or eliminate persistent virus reservoirs, which would mitigate chronic inflammation and alleviate symptom severity in patients with LC. Full article

Metabolic reprogramming has recently been recognized as related to immune disorders in ulcerative colitis (UC), but the specific metabolic pathways and genes involved remain unclear. Here, Mendelian randomization confirmed that mannose and mannonate exhibited a negative causal relationship with UC, and that the immune cell phenotype HLA DR on CD33dim HLA DR+ CD11b− mediated the effect of mannonate on UC. Bulk RNA sequencing data revealed that mannose metabolism abnormity is critical for driving the innate and acquired immune response. A well-performing diagnostic model related to mannose metabolism was constructed using SVM analysis, achieving an AUC-ROC value of 0.987 in the training set and an AUC-ROC value of 0.899 in the validation set. Single-cell analysis revealed that epithelial cells in which the mannose metabolism pathway was inactivated demonstrated increased intercell communication with myeloid cells, T cells, and B cells. In vitro experiments confirmed that KHK and AKR1B10 were suppressed under inflammatory stimulation, which may hinder mannose-related metabolism. This study elucidates the protective role of mannose metabolism in UC and provides a novel gene signature for diagnosis and treatment. Full article

Obesity is a major global health issue associated with an increased risk of early-onset metabolic disorders and chronic inflammation. Identifying the epigenetic mechanisms that contribute to obesity-related metabolic and inflammatory dysregulation is crucial for developing effective prevention and treatment strategies. This pilot study aimed to investigate the effects of obesity on the expression of microRNAs (miRNAs) related to metabolic disorders in human peripheral blood mononuclear cells from metabolically healthy obese subjects and non-obese controls. Differentially expressed miRNAs in TaqMan human miRNA arrays were quantified using quantitative PCR. To validate the robustness and generalizability of our findings, we performed cross-validation using the publicly available GSE155096 dataset. The expression of miR-145-5p was significantly increased (4.913-fold change) in obese individuals compared to the non-obese control group. Two miRNAs, miR-27b-3p and miR-17-5p, were downregulated 2.207- and 1.448-fold, respectively, approaching significance. A positive correlation was established between miR-145-5p and free triiodothyronine, eosinophils, and vitamin D. A cross-validation analysis confirmed the direction of change for these key miRNAs. The data suggest that miR-145-5p, miR-27b-3p, and miR-17-5p could be implicated in the progression of obesity in causing metabolic abnormalities, clarifying how molecular factors cause the metabolic deregulation associated with obesity. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social/communication deficits and behavioral abnormalities, with neuronal apoptosis and immune-inflammatory dysregulation implicated in its pathogenesis. Marine-derived polysaccharides, particularly those from Enteromorpha prolifera (PEPs), exhibit neuroprotective and anti-inflammatory properties—yet their therapeutic potential for ASD remains unexplored. Major monosaccharide components of PEPs were identified as rhamnose, xylose, glucose, glucuronic acid, galactose, and ribose through ion chromatography analysis. Infrared spectroscopy confirmed PEPs as pyranose-type polysaccharides with α-glycosidic bonds and uronic acids, while gel permeation chromatography showed a predominant molecular weight of 3.813 kDa (83.919%). To explore the therapeutic potential of PEPs in ASD, a comprehensive method combining network pharmacology, molecular docking, and in vitro validation was conducted. A total of 235 ASD-related target proteins were predicted, with enrichment analyses indicating significant involvement in pathways such as neuroactive ligand–receptor interaction and the MAPK signaling pathway. In vitro assays using valproic acid (VPA)-induced HT22 neuronal cells showed that PEPs significantly attenuated apoptosis. Western blot analysis further confirmed the downregulation of HSP90AA1, cleaved CASP3/pro-CASP3, p-NF-κB1/NF-κB1, p-AKT1/AKT, and p-mTOR/mTOR, as well as the upregulation of IκBα after PEPs treatment. These findings suggest that PEPs exert neuroprotective effects through the modulation of apoptosis and inflammation-related signaling pathways, supporting their potential as a promising candidate for further study in ASD. Full article

Objectives: This study focuses on the regulatory mechanism of Schisandrin B (Sch B) on the lipid metabolism and apoptosis of AML-12 liver cells, with a particular emphasis on its potential therapeutic effect and mechanism of action in preventing and treating metabolic-associated fatty liver disease (MAFLD) by activating the PPARγ signaling pathway. Methods: An MAFLD cell model was established by inducing AML-12 cells with a mixture of oleic acid (OA) and palmitic acid (PA) (2:1). AML-12 cells were divided into a control group, a model group, and 20 μM and 40 μM Sch B groups. The cells were lysed and prepared into the cell suspension, then the cell suspension was centrifuged to obtain its supernatant, and the levels of total cholesterol (TC), triglycerides (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in the supernatant were detected according to the instructions of the kits. Effects of Sch B on the pathological changes of AML-12 cells were observed by Oil Red O staining. The key targets were screened through network pharmacology, and relevant targets were verified through molecular docking simulation. The activity of PPARγ was detected using a dual luciferase reporter plasmid, and the level of cell apoptosis was detected using the Annexin V-FITC/PI double staining method. The Western blot method was used to analyze the expression of genes related to lipid metabolism and apoptosis pathways. Results: Sch B could regulate lipid metabolism disorders in OA+PA-induced MAFLD cell model. The activation of PPARγ-PCK1/Aspase is a key step in the action of Sch B, which can effectively block fatty acid synthesis, improve fatty acid oxidation, and reduce lipid droplet aggregation in liver cells, thereby alleviating lipid metabolism abnormalities in the MAFLD cell model and inhibiting cell apoptosis. Conclusions: This finding may lay an important theoretical foundation and open a new research direction for the deep development and application of Schisandra chinensis. Full article

Background/Objectives: Angioimmunoblastic T-cell lymphoma (AITL) is a rare peripheral T-cell lymphoma of follicular helper T-cell (TFH) origin, often associated with immune dysregulation and EBV-positive B-cell proliferation. Kaposi sarcoma (KS) is a vascular neoplasm caused by human herpesvirus 8 (HHV-8), typically arising in immunocompromised individuals. The synchronous occurrence of AITL and KS in HIV-negative patients is exceptionally rare, with only three cases previously reported worldwide. Case Presentation: We describe an 81-year-old HIV-negative Korean woman presenting with progressive generalized edema and dyspnea. Imaging revealed multifocal lymphadenopathy. Excisional biopsy of the inguinal lymph node showed two distinct but adjacent neoplastic processes. The AITL component demonstrated a polymorphous infiltrate of atypical TFH cells expressing CD3, CD4, CD10, PD-1, and Bcl-6, with monoclonal TCR-γ rearrangement and TET2 and RHOA mutations. The KS component comprised spindle cells with slit-like vascular spaces, red blood cell extravasation, and immunoreactivity for HHV-8, CD31, CD34, and ERG. The findings were consistent with a collision tumor. Despite supportive care, the patient’s condition deteriorated, and she was discharged with palliative care. Discussion: The coexistence of AITL and KS in an HIV-negative setting raises important pathogenetic considerations. AITL is characterized by profound immune dysregulation, with depletion of normal T-cell subsets, abnormal B-cell activation, and cytokine milieu changes that may favor latent viral reactivation. This immunologic environment may permit HHV-8 reactivation, thereby facilitating the development of KS even in the absence of overt immunodeficiency due to HIV infection. Our findings support the hypothesis that AITL-related immune dysfunction may create a permissive niche for HHV-8-driven neoplasia. Conclusions: This is the first reported case in Asia and the fourth worldwide of a collision tumor comprising AITL and KS in an HIV-negative patI dient. The case suggests that AITL-associated immune dysregulation may facilitate HHV-8 reactivation and KS development even in the absence of HIV infection. Awareness of this association is critical for accurate diagnosis and optimal patient management. Full article

Brain tumors usually appear as masses formed by localized abnormal cell proliferation. Although complete removal of tumors is an ideal treatment goal, this process faces many challenges due to the aggressive nature of malignant tumors and the need to protect normal brain tissue. Therefore, early diagnosis is crucial to mitigate the harm posed by brain tumors. In this study, the classification accuracy is improved by improving the ResNet50 model. Specifically, the image is preprocessed and enhanced firstly, and the image is denoised by fractional calculus; then, transfer learning technology is adopted, the ECA attention mechanism is introduced, the convolutional layer in the residual block is optimized, and the multi-scale convolutional layer is fused. These optimization measures not only enhance the model’s ability to grasp the overall details but also improve its ability to recognize micro and macro features. This allows the model to understand data features more comprehensively and process image details more efficiently, thereby improving processing accuracy. In addition, the improved ResNet50 model is combined with EfficientNetB0 to further optimize performance and improve classification accuracy by utilizing EfficientNetB0’s efficient feature extraction capabilities through feature fusion. In this study, we used a brain tumor image dataset containing 5712 training images and 1311 validation images. The optimized ResNet50 model achieves a verification accuracy of 98.78%, which is 3.51% higher than the original model, and the Kappa value is also increased by 4.7%. At the same time, the lightweight design of the EfficientNetB0 improves performance while reducing uptime. These improvements can help diagnose brain tumors earlier and more accurately, thereby improving patient outcomes and survival rates. Full article

Diffuse large B-cell lymphoma (DLBCL) is a molecular and clinical heterogenous entity, and, over the past 30 years, many efforts have been made in trying to dissect this diverseness and identify biomarkers capable of efficiently stratifying DLBCL patients and spotting the ones showing a worse clinical outcome. Despite the achievement in this research field, only a few biomarkers have been validated and introduced in a clinical setting. Among those, approximately 5–15% of DLBCL cases harbor MYC gene translocations, often involving immunoglobulin genes as a translocation partner, and concomitant point mutations, correlating with a poor response to standard therapies. However, given the difficulty in detecting these abnormalities requiring specialized techniques and high-quality specimens, the use of metabolomics (i.e., the study of small metabolites in body fluids and tissues) can offer a useful alternative for the identification of high-risk DLBCL patients. Amino acids (AAs) are metabolites essential in the process of tumorigenesis and can increase immune escape and drug resistance. Therefore, we review the use of metabolomics to improve the diagnosis and prognosis in DLBCL patients in relation to the MYC role in the regulation of amino acid metabolism, as these metabolites may be used as potential biomarkers in a clinical environment. Full article

This study investigated the complexity of neurotransmitter-related gene regulation in peripheral blood mononuclear cells (PBMCs) of patients with obsessive–compulsive disorder (OCD), aiming to identify clinically relevant molecular markers. We analyzed three key genes: SLC6A4 (serotonin transporter), MAOB (monoamine oxidase B, a dopamine-degrading enzyme), and COMT (catechol-O-methyltransferase, a dopamine/norepinephrine metabolizing enzyme). OCD patients exhibited significant downregulation of SLC6A4 and MAOB, accompanied by upregulation of MB-COMT. The contrasting expression of MAOB and MB-COMT suggests a dysregulated compensatory mechanism in dopamine homeostasis, which contributes to clinical heterogeneity and variability in treatment for OCD. Epigenetic analysis revealed that downregulation of SLC6A4 was associated with hypermethylation of the gene promoter, demonstrating the critical role of epigenetic mechanisms in neurotransmitter system dysregulation. Moreover, gene–gene correlations identified distinctive molecular expression patterns that reliably discriminated OCD patients from healthy individuals, proposing their potential as peripheral biomarkers. In conclusion, serotonergic and dopaminergic abnormalities characterize OCD, where epigenetic regulation contributes to gene dysregulation. The identified molecular signatures may explain the inefficiency of treatments and support biomarker-guided clinical approaches. Given that peripheral gene regulation and core neurotransmitter systems are similar, this study contributes to the biological picture of OCD, indicating the accuracy of diagnoses and treatments. Full article

The mechanisms underlying the abnormal activation of microglia affecting cognitive function under high-altitude hypobaric hypoxia (HAHH) have not been fully elucidated. This study aims to investigate the effects of HAHH on the expression of the receptor for advanced glycation end-products (RAGE) in hippocampal microglia of mice and to explore the role of RAGE inhibitors in alleviating HAHH-induced microglial inflammation and cognitive impairment. Mice were exposed to HAHH via a multi-environment simulation chamber, and RNA sequencing, qPCR, WB, flow cytometry and immunohistochemistry showed that HAHH exposome significantly increased RAGE expression in hippocampal microglia of mice (p < 0.001 vs. normoxia), which was closely related to microglial neuroinflammatory responses. RAGE inhibitor (FPS-ZM1) alleviated HAHH-induced microglial inflammation (TNF-α decreased by 64%, p < 0.001; CD86⁺ cells decreased by 42%, p < 0.001) and improved cognitive function in mice (Y-maze novel arm time: 28.08 ± 5.14 s vs. hypoxia 19.67 ± 4.68 s, p = 0.016; NORT recognition index: 0.52 ± 0.05 vs. hypoxia 0.33 ± 0.07, p < 0.001). Mechanistic studies revealed that RAGE inhibitors reduced microglial inflammation by inhibiting the MAPK pathway and decreasing nuclear translocation of NF-κB p65. Furthermore, high-mobility group box 1 (HMGB1) expression increased under hypoxic conditions (p < 0.001 vs. normoxia) and positively regulated RAGE expression. HMGB1 inhibitors reduced RAGE expression and attenuated HAHH-induced microglial inflammation. Overall, the HAHH exposome induces microglial inflammation via the HMGB1-RAGE-NF-κB pathway. RAGE and HMGB1 inhibitors may serve as novel therapeutic strategies to mitigate HAHH-induced cognitive impairment, providing a theoretical basis for the treatment of cognitive impairment. Full article

Excessive osteoclast activity in bone remodeling can lead to an imbalance between bone resorption and formation, a common occurrence in abnormal bone metabolic diseases. This research investigates the effect of Coptidis rhizoma water extract (CRW) on osteoclastogenesis provoked by RANKL in vitro and bone destruction mediated by ovariectomy (OVX) in vivo. CRW, prepared from dried Coptidis rhizoma (CR), was analyzed for its active compounds—coptisine and berberine—using HPLC analysis. CRW markedly decreased the size and number of TRAP-positive multinucleated cells (TRAP⁺ MNCs), suppressed F-actin ring formation, and diminished bone resorption in RANKL-treated cultures. In the early phase of differentiation, CRW suppressed the phosphorylation of MAPKs p38, JNK, and ERK, as well as NF-κB p65, Iκ-Bα, and Akt. CRW also down-regulated RANKL-mediated induction of c-Fos and NFATc1 and attenuated the activation of NFATc1- dependent genes, such as OSCAR, ATP6V0D2, ACP5 (TRAP), OC-STAMP, DC-STAMP, CTSK (cathepsin K), CALCR (calcitonin receptor), and MMP-9. In ovariectomized rats, micro-CT and histological analyses showed that CRW alleviated femoral bone destruction. These findings indicate that CRW restrains osteoclast differentiation and function and may have therapeutic potential for disorders driven by excessive osteoclast activity. Full article

Chimeric antigen receptor (CAR) T-cell infusion has led to improved outcomes in patients with B-lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma. The spectrum of post-CAR T-cell hematolymphoid abnormalities is expanding, although they remain under-recognized. Pathologists play a key role in characterizing hematolymphoid proliferation after CAR T-cell therapy. This review presents clinical and pathologic findings of common hematolymphoid proliferation after CAR T-cell therapy, illustrated by selected cases. A review of the literature is presented in the context of individual cases, and our current understanding of the pathomechanism is discussed. Infused CAR T-cells undergo a series of four phases: distribution, expansion, contraction, and persistence. In the expansion phase, transient peripheral blood lymphocytosis occurs, reaching a peak two weeks post-infusion. Delayed contraction of CAR T-cells may give rise to hemophagocytic lymphohistiocytosis-like syndrome. Immune effector cell-associated enterocolitis presents in the persistence phase, about 3–6 months after infusion. Pathologic findings include a T-cell infiltrate in the intestinal mucosa and changes resembling graft versus host disease (GVHD). This entity requires differentiation from infections and from T-cell neoplasms, including those derived from CAR T-cells. Secondary myeloid malignancies follow the same pathways as therapy-related myeloid neoplasm but present with a shorter median latency. It is essential for pathologists to recognize post-CAR T-cell hematolymphoid proliferation to support clinical decision making in a high-risk patient population. Full article

Background: Primary thyroid lymphoma (PTL) is an uncommon malignancy that predominantly affects women in their sixth or seventh decade. It is strongly associated with chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) and other autoimmune conditions. The hallmark clinical feature is a rapidly enlarging thyroid mass, which can quickly cause compressive symptoms such as dysphagia, hoarseness, and dyspnoea. Timely recognition and treatment are essential. [¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([¹⁸F]FDG-PET/CT) plays a central role in the diagnosis, staging, response assessment, prognostication, and surveillance of high-grade lymphomas, significantly influencing clinical management. Case presentation: We report the case of a woman in her sixties with a history of multinodular goitre but without an autoimmune background, who presented with a large left-sided cervical mass that had rapidly enlarged over approximately two months. Laboratory tests, fine-needle aspiration (FNA), and [¹⁸F]FDG-PET/CT revealed abnormal cytology and a highly hypermetabolic necrotic left thyroid mass, without extra-thyroidal disease, suggestive of lymphoma. Definitive biopsy with immunohistochemistry confirmed a high-grade B-cell lymphoma, positive for CD5 and demonstrating triple expression of Bcl2, Bcl6, and c-Myc. The patient underwent chemotherapy, achieving a marked morphometabolic response after two cycles, consolidated after four cycles. Conclusions: This rare case highlights the importance of considering PTL in the differential diagnosis of an isolated, rapidly enlarging thyroid mass, regardless of prior Hashimoto’s thyroiditis. Early diagnosis and timely treatment are crucial to improve patient outcomes. Full article