Background: Microplastics (MPs), which are smaller in size and difficult to degrade, can be easily ingested by marine life and enter mammals through the food chain. Our previous study demonstrated that following acute exposure to MPs, the serum testosterone content reduced and sperm quality declined, resulting in male reproductive dysfunction in mice. However, the toxic effect of long-term exposure to MPs at environmental exposure levels on the reproductive system of mammals remains unclear. Results: In vivo, mice were given drinking water containing 100 μg/L and 1000 μg/L polystyrene MPs (PS-MPs) with particle sizes of 0.5 μm, 4 μm, and 10 μm for 180 consecutive days. We observed alterations in testicular morphology and reductions in testosterone, LH and FSH contents in serum. In addition, the viability of sperm was declined and the rate of sperm abnormality was increased following exposure to PS-MPs. The expression of steroidogenic enzymes and StAR was downregulated in testis tissues. In vitro, we used primary Leydig cells to explore the underlying mechanism of the decrease in testosterone induced by PS-MPs. First, we discovered that PS-MPs attached to and became internalized by Leydig cells. And then we found that the contents of testosterone in the supernatant declined. Meanwhile, LHR, steroidogenic enzymes and StAR were downregulated with concentration-dependent on PS-MPs. We also confirmed that PS-MPs decreased StAR expression by inhibiting activation of the AC/cAMP/PKA pathway. Moreover, the overexpression of LHR alleviated the reduction in StAR and steroidogenic enzymes levels, and finally alleviated the reduction in testosterone induced by PS-MPs. Conclusions: PS-MPs exposure resulted in alterations in testicular histology, abnormal spermatogenesis, and interference of serum hormone secretion in mice. PS-MPs induced a reduction in testosterone level through downregulation of the LH-mediated LHR/cAMP/PKA/StAR pathway. In summary, our study showed that chronic exposure to PS-MPs resulted in toxicity of male reproduction under environmental exposure levels, and these potential risks may ring alarm bells of public health. Graphical

Microcystin-leucine arginine (MC-LR) is a kind of toxin produced by cyanobacterial, resulting in decrease of testosterone levels in serum and leading to impaired spermatogenesis. Gonadotropin-releasing hormone (GnRH) neurons play crucial roles in the regulation of testosterone release. Meanwhile, it has been demonstrated that MC-LR is capable of entering the GnRH neurons and inducing apoptosis. Nevertheless, the molecular mechanism of MC-LR induced apoptosis of GnRH neurons remains elusive. In present study, we found that MC-LR inhibited the cell viability of GT1-7 cells. In addition, we discovered apoptosis of GnRH neurons and GT1-7 cells treated with MC-LR. And increased intracellular ROS production and the release of intracellular Ca²⁺ were all observed following exposure to MC-LR. Furthermore, we also found the endoplasmic reticulum stress (ERs) and autophagy were activated by MC-LR. Additionally, pretreatment of the ERs inhibitor (4-Phenyl butyric acid) reduced the apoptotic rate of GT1-7 cells comparing with MC-LR exposure alone. Comparing with MC-LR treatment alone, apoptotic cell death was increased by pretreatment of GT1-7 cells with an autophagy inhibitor (3-methyladenine). Together, our data implicated that the treatment of MC-LR induced the apoptosis of GnRH neurons by activating the ERs resulting in a decrease of serum testosterone level in mice. Autophagy is a protective cellular process which was activated by ER stress and thus protected cells from apoptosis upon MC-LR exposure.

Background: Diffuse large B-cell lymphoma (DLBCL), the most common B-cell non-Hodgkin lymphoma, remains challenging because more than one-third of patients fail to achieve durable remission with frontline therapy; therefore, a systematic and comprehensive understanding of its underlying biology is essential to improve risk stratification and treatment outcomes. Methods: Based on 30 glycolysis-related genes selected from 72 candidates in the MSigDB database, we comprehensively evaluated glycolysis-related modification patterns in 562 DLBCL samples and analyzed their associations with immune cell infiltration and patient prognosis in the tumor microenvironment (TME). In vivo, we identified three immune subtypes in DLBCL mouse models and accessed their correlation with glycolytsis-related patterns and outcomes using histopathological evaluation (H&E) staining, Kaplan–Meier survival analysis, Western blotting, and immunohistochemistry. Results: Four distinct glycolysis modification patterns were identified, which correlated with three immune subtypes: immune-inflamed, immune-desert, and immune-excluded. The immune-inflamed subtype, characterized by prominent immune infiltration, was associated with favorable survival. In contrast, the immune-excluded subtype, defined by stromal activation, did not confer a survival advantage. The immune-desert subtype, marked by a lack of immune infiltration, was linked to poor survival outcomes. Finally, using the DLBCL mouse model, we validated these three immune subtypes and demonstrated their corresponding associations with glycolytic patterns and prognosis. Conclusions: Our work demonstrated that glycolysis-related modification patterns have correlations with the immune cell infiltration within the TME of DLBCL and that distinct glycolytic states are associated with different clinical outcomes. These findings provide a framework for improved prognostic stratification and may inform new therapeutic decision-making in DLBCL.

Hemophagocytic lymphohistiocytosis (HLH) is a common and highly fatal hyperinflammatory syndrome characterized by the aberrant activation of macrophages. To date, there is a lack of targeted therapies for HLH. It is validated that macrophages in HLH efficiently phagocytose anti‐CD41‐platelets (anti‐CD41‐PLTs) from immune thrombocytopenia (ITP) patients in previous research. Hence, the pathological mechanisms of ITP are mimicked and anti‐CD41‐PLTs are utilized to load the macrophage‐toxic drug VP16 to construct macrophage‐targetable engineered platelets anti‐CD41‐PLT‐VP16, which is a novel targeted therapy against HLH. Both in vitro and in vivo studies demonstrate that anti‐CD41‐PLT‐VP16 has excellent targeting and pro‐macrophage apoptotic effects. In HLH model mice, anti‐CD41‐PLT‐VP16 prevents hemophagocytosis and inhibits the cytokine storm. Mechanistic studies reveal that anti‐CD41‐PLT‐VP16 increases the cytotoxicity of VP16, facilitating precise intervention in macrophages. Furthermore, it operates as a strategic “besieger” in diminishing hyperinflammation syndrome, which can indirectly prevent the abnormal activation of T cells and NK cells and reduce the Ab‐dependent cell‐mediated cytotoxicity effect. The first platelet‐based clinical trial is ongoing. The results show that after treatment with anti‐CD41‐PLT‐VP16, HLH patients have a threefold increase in the overall response rate compared to patients receiving conventional chemotherapy. In conclusion, anti‐CD41‐PLT‐VP16 provides a general insight into hyperinflammation syndrome and offers a novel clinical therapeutic strategy for HLH.