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Background MLN4924 is a novel small molecule inhibitor of neddylation. During clinical trials, it has demonstrated promising therapeutic efficacy in hematological malignancies, lung cancer, and colon cancer. MLN4924 possesses anti-inflammatory properties and promotes cardiomyocyte autophagy. Given that atherosclerosis is an inflammatory disease in which autophagy and cellular senescence are key factors, we hypothesize that MLN4924 may exert a regulatory effect on the progression of atherosclerosis, warranting further investigation. The formation of foam cells plays a critical role in the development of atherosclerosis. Methods We evaluated the effects of MLN4924 on the mRNA and protein expressions of scavenger receptor genes in macrophages and genes associated with the senescence-associated secretory phenotype (SASP). Oil Red O staining, Dil-ox-LDL uptake staining and cellular β-galactosidase staining were employed to assess the impacts of MLN4924 on the transformation of macrophages into foam cells and the senescence of macrophages. LC3 immunofluorescence staining, RT-qPCR and western blot were utilized to detect the regulatory effects of MLN4924 on macrophage autophagy. RNA sequencing (RNA-seq) and untargeted metabolomics analysis was carried out to evaluate the regulatory effects of MLN4924 on the transcriptome of macrophages and key metabolites. Results Our findings indicate that MLN4924 significantly downregulates the expressions of scavenger receptors such as CD36, SR-A1, SR-B1, and LOX-1, while upregulating genes associated with cholesterol efflux, including ABCA1 and ABCG1. Additionally, MLN4924 inhibits macrophage senescence and suppresses the expressions of SASP factors. The mechanism by which MLN4924 exerts these effects likely involves enhancing autophagy, thereby mitigating atherosclerotic progression. Furthermore, we conducted transcriptomic and metabolomic analyses to explore the effects of MLN4924 on macrophage transcriptome and metabolic phenotypes. Pathway enrichment analyses reveal significant enrichment of differentially expressed genes in the PI3K-AKT signaling pathway. Conclusions We confirmed that MLN4924 inhibits AKT phosphorylation, thereby suppressing its activation and further inhibits GSK-3β phosphorylation. Moreover, MLN4924 regulates the mRNA levels of multiple genes and modulates metabolite production. These findings demonstrate that MLN4924 could inhibit the formation of foam cells, justifying further in-depth research.

SummaryDysfunction of natural killer (NK) cells is associated with poor prognosis in hepatocellular carcinoma (HCC). We explored the phenotypic and functional characteristics of peripheral blood NK cells in HCC patients following sorafenib treatment.Peripheral blood samples were collected from 60 HCC patients in a single centre (2015~2017) and 45 healthy donors. The percentage and cytoplasmic granule production of NK cells were analysed. Subset proportions were evaluated for their associations with the modified Response Evaluation Criteria in Solid Tumors (mRECIST), time to progression, and median overall survival (OS).Compared with baseline, the percentages of total and CD56dimCD16+ NK cells increased after two months of treatment, while the percentage of CD56brightCD16− NK cells decreased, leading to a dramatically reduced ratio of CD56bright and CD56dim NK cells (ratiobri/dim). Patients with low ratiobri/dim exhibited better mRECIST responses and longer median OS than those with high ratiobri/dim. The expression levels of granzyme B and perforin in total NK cells and in both subsets of cells were increased after treatment.This study showed that sorafenib could affect the proportions and functions of peripheral CD56brightCD16− and CD56dimCD16+ NK cells, which was associated with the outcomes including OS of HCC patients.

Background/Objectives: Influenza A virus (IAV) infection triggers robust inflammation and acute lung injury. Andrographolide, a primary active compound from Andrographis paniculata, can mitigate IAV-induced inflammation; however, its precise mechanisms remain poorly elucidated. This study aimed to define its host-directed protective effects and molecular mechanisms. Methods: We used a lethal IAV (H1N1, PR8) model in BALB/c mice and infected A549 cells. Survival, lung pathology, cytokines, and viral titers were measured. Lung RNA sequencing identified dysregulated signaling pathways. PI3K/AKT and pyroptosis pro-teins were analyzed by Western blot. The PI3K/AKT axis was functionally validated with the AKT inhibitor in vivo and AKT1 siRNA in vitro. Results: Andrographolide improved survival, attenuated body weight loss, and reduced lung pathology and inflammatory cytokine levels in IAV-infected mice, without exhibiting direct antiviral activity. Consistent with the in vivo findings, andrographolide enhanced cell viability and suppressed cytokine secretion in infected cells. RNA sequencing revealed marked upregulation of the PI3K/AKT signaling pathway in the lungs of treated mice, as confirmed by increased PI3K and AKT phosphorylation. Furthermore, andrographolide downregulated the expression of key pyroptosis-executing proteins, including cleaved caspase-3 and the gasdermin E (GSDME) N-terminal fragment. These protective effects were substantially abrogated by an AKT inhibitor and AKT1 siRNA. Conclusions: These findings reveal a novel host-directed mechanism by which andrographolide alleviates IAV-induced immunopathology by activating the PI3K/AKT pathway, thereby suppressing caspase-3/GSDME-dependent pyroptosis. Thus, this axis represents a promising target for controlling excessive inflammation in severe influenza.

Non-small-cell lung cancer (NSCLC) represents most of lung cancers, is often diagnosed at an advanced metastatic stage. Therefore, exploring the mechanisms underlying metastasis is key to understanding the development of NSCLC. The expression of B cell receptor-associated protein 31 (BCAP31), calreticulin, glucose-regulated protein 78, and glucose-regulated protein 94 were analyzed using immunohistochemical staining of 360 NSCLC patients. It resulted that the high-level expression of the four proteins, but particularly BCAP31, predicted inferior overall survival. What’s more, BCAP31 was closely associated with histological grade and p53 status, which was verified by seven cohorts of NSCLC transcript microarray datasets. Then, three NSCLC cell lines were transfected to observe behavior changes BCAP31 caused, we found the fluctuation of BCAP31 significantly influenced the migration, invasion of NSCLC cells. To identify the pathway utilized by BCAP31, Gene Set Enrichment Analysis was firstly performed, showing Akt/m-TOR/p70S6K pathway was the significant one, which was verified by immunofluorescence, kinase phosphorylation and cellular behavioral observations. Finally, the data of label-free mass spectroscopy implied that BCAP31 plays a role in a fundamental biological process. This study provides the first demonstration of BCAP31 as a novel prognostic factor related to metastasis and suggests a new therapeutic strategy for NSCLC.

With the large number of atypical cases in the mpox outbreak, which was classified as a global health emergency by the World Health Organization (WHO) on 23 July 2022, rapid diagnosis of mpox and diseases with similar symptoms to mpox such as chickenpox and respiratory infectious diseases in the early stages of viral infection is key to controlling the spread of the outbreak. In this study, antibodies against the monkeypox virus A29L protein were efficiently and rapidly identified by combining rapid mRNA immunization with high-throughput sequencing of individual B cells. We obtained eight antibodies with a high affinity for A29L validated by ELISA, which were was used as the basis for developing an ultrasensitive fluorescent immunochromatographic assay based on multilayer quantum dot nanobeads (SiTQD-ICA). The SiTQD-ICA biosensor utilizing M53 and M78 antibodies showed high sensitivity and stability of detection: A29L was detected within 20 min, with a minimum detection limit of 5 pg/mL. A specificity test showed that the method was non-cross-reactive with chickenpox or common respiratory pathogens and can be used for early and rapid diagnosis of monkeypox virus infection by antigen detection. This antibody identification method can also be used for rapid acquisition of monoclonal antibodies in early outbreaks of other infectious diseases for various studies.

Hepatic intercellular communication is the driving force for the progression of chronic Hepatitis B virus (CHB)‐associated hepatopathologies, with the dynamic molecular mechanisms largely unknown. Combining scRNA‐seq and spatial transcriptomic analysis, the kinetic landscape of the liver microenvironment across time and space in AAV‐HBV mice, which develop from inflammation to ultimately hepatocellular carcinoma is generated. Kupffer cells (KCs), originally resided within the peri‐portal area, are persistently recruited to the HBV‐enriched peri‐central region via increased CXCL9 produced by endothelial cells, facilitating the interaction between KCs and HBV+ hepatocytes to induce LXRα deficiency‐mediated lipid metabolism disorders (LMD) in KCs. In turn, KCs with LMD elicited cancer stem cell formation from HBV+ hepatocytes via Stat3 pathway, activated by the chemokine network within the crosstalk. Moreover, miR‐155‐mediated post‐transcriptional regulation and ASGR1‐dependent degradation collaboratively regulated LXRα downregulation in KCs. LXRα deficiency in KCs is also detected in the tumor tissues of HBV+ patients compared to that of the normal and tumor‐adjacent tissue. Importantly, LXRα upregulation in KCs constrained fibrosis and cancer stem cell formation. For the first time, the role of KC zonation in disease progression has been revealed, highlighting LXRα in KCs as a promising target for the early intervention in the transition from CHB‐induced inflammation to cancer. By profiling the spatiotemporal hepatic landscape of CHB mouse models, the originally peri‐portal localized KCs migrated to the peri‐central in a CXCL9‐CXCR3‐dependent manner, facilitating their interaction with HBV+ hepatocytes. The interaction promoted LMD in KCs through ASGR1‐induced LXRα degradation, which, in turn, induced CSC formation via Stat3 activation in hepatocytes. LXRα agonists constrained CHB‐induced fibrosis and CSC formation.

Hepatocellular carcinoma (HCC) patients are mostly diagnosed at an advanced stage, resulting in systemic therapy and poor prognosis. Therefore, the identification of a novel treatment target for HCC is important. B-cell receptor-associated protein 31 (BAP31) has been identified as a cancer/testis antigen; however, BAP31 function and mechanism of action in HCC remain unclear. In this study, BAP31 was demonstrated to be upregulated in HCC and correlated with the clinical stage. BAP31 overexpression promoted HCC cell proliferation and colony formation in vitro and tumor growth in vivo . RNA-sequence (RNA-seq) analysis demonstrated that serpin family E member 2 (SERPINE2) was downregulated in BAP31-knockdown HCC cells. Coimmunoprecipitation and immunofluorescence assays demonstrated that BAP31 directly binds to SERPINE2. The inhibition of SERPINE2 significantly decreased the BAP31-induced cell proliferation and colony formation of HCC cells and phosphorylation of Erk1/2 and p38. Moreover, multiplex immunohistochemistry staining of the HCC tissue microarray showed positive associations between the expression levels of BAP31, SERPINE2, its downstream gene LRP1, and a tumor proliferation marker, Ki-67. The administration of anti-BAP31 antibody significantly inhibited HCC cell xenograft tumor growth in vivo . Thus, these findings suggest that BAP31 promotes tumor cell proliferation by stabilizing SERPINE2 and can serve as a promising candidate therapeutic target for HCC.

Background: The continuous clinical use of cisplatin is prevented by gastrointestinal toxicity. Methods: Cisplatin was used to treat THP-1-derived macrophages to see its differential effects on different subtypes of macrophages. Wild-type and Gsdme−/− mice models were used to examine the effect of cisplatin and metformin on intestinal inflammation in vivo. The effect of GSDME on macrophage polarization was further confirmed by GSDME knockdown. Results: We found that M2 macrophages, with more cell blebbing and GSDME cleavage, were more sensitive to cisplatin-induced pyroptosis than M1 macrophages. Cisplatin was capable of enhancing the M1 phenotype, which was reversed by GSDME knockdown. GSDME contributed to M1 polarization and GSDME knockdown promoted M2 phenotype via STAT6 activation. Reduced intestinal inflammation and increased M2 macrophage numbers was detected in cisplatin-treated GSDME-knockout mice. Furthermore, metformin alleviated cisplatin-induced intestinal inflammation by reducing M2 pyroptosis and enhancing M2 phenotype through GSDME inhibition. Conclusion: This is the first study to reveal the non-pyroptotic role of GSDME in macrophage polarization, revealing that metformin could be used in combination with cisplatin to reduce intestinal toxicity.

Chronic Hepatitis B virus (CHB) infection is a global health challenge, causing damage ranging from hepatitis to cirrhosis and hepatocellular carcinoma. In our study, single-cell RNA sequencing (scRNA-seq) analysis was performed in livers from mice models with chronic inflammation induced by CHB infection and we found that endothelial cells (ECs) exhibited the largest number of differentially expressed genes (DEGs) among all ten cell types. NF-κB signaling was activated in ECs to induce cell dysfunction and subsequent hepatic inflammation, which might be mediated by the interaction of macrophage-derived and cholangiocyte-derived VISFATIN/Nampt signaling. Moreover, we divided ECs into three subclusters, including periportal ECs (EC_Z1), midzonal ECs (EC_Z2), and pericentral ECs (EC_Z3) according to hepatic zonation. Functional analysis suggested that pericentral ECs and midzonal ECs, instead of periportal ECs, were more vulnerable to HBV infection, as the VISFATIN/Nampt- NF-κB axis was mainly altered in these two subpopulations. Interestingly, pericentral ECs showed increasing communication with macrophages and cholangiocytes via the Nampt-Insr and Nampt-Itga5/Itgb1 axis upon CHB infection, which contribute to angiogenesis and vascular capillarization. Additionally, ECs, especially pericentral ECs, showed a close connection with nature killer (NK) cells and T cells via the Cxcl6-Cxcr6 axis, which is involved in shaping the microenvironment in CHB mice livers. Thus, our study described the heterogeneity and functional alterations of three subclusters in ECs. We revealed the potential role of VISFATIN/Nampt signaling in modulating ECs characteristics and related hepatic inflammation, and EC-derived chemokine Cxcl16 in shaping NK and T cell recruitment, providing key insights into the multifunctionality of ECs in CHB-associated pathologies.

The depletion of phosphorus resources and the problem of environmental pollution are driving the advancement of traditional methods for wastewater treatment. Researchers have taken an interest in microalgae-based processes, which offer a sustainable approach by effectively converting phosphorus into biomass. To improve the environment and make better use of waste phosphorus resources, the efficiency of phosphorus removal by microalgae must be increased. Therefore, studying the mechanisms of phosphorus uptake by microalgae cells is valuable. This review outlines the typical microalgae systems used for phosphorus removal from wastewater. It summarizes the procedures of phosphorus surface adsorption, membrane transport, and intercellular utilization by microalgae. Additionally, this work analyzed the phenomena of excess phosphorus uptake and emerging organic phosphorus uptake by microalgae. Furthermore, the article examines the primary external factors that affect phosphorous removal. Lastly, this review proposes utilizing microalgal biomass phosphorus in fertilizer and transition metal phosphide catalysts. This review provides innovative approaches for removing phosphorus from wastewater and applying microalgal biomass phosphorus. Article highlights The treatment of P-contained wastewater by microalgae systems is summarized. Possible phosphorus metabolism pathways in microalgae are described. The uptake and utilization of organophosphorus by microalgae was highlighted. The application of microalgal biomass phosphorus in catalysts is discussed.