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Exposure to environmental pollutants, including nanomaterials, has a significant impact on tumor progression. The increased demand for black phosphorus nanosheets (BPNSs), driven by their exceptional properties, raises concerns about potential environmental contamination. Assessing their toxicity on tumor growth is essential. Herein, we employed a range of biological techniques, including cytotoxicity measurement, bioinformatics tools, proteomics, target gene overexpression, Western blot analysis, and apoptosis detection, to investigate the toxicity of BPNSs across A549, HepG-2, MCF-7, and Caco-2 cell lines. Our results demonstrated that BPNSs downregulated the expression of ADIPOQ and its associated downstream pathways, such as AMP-activated protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (Nrf2), and other unidentified pathways. These downregulated pathways ultimately led to mitochondria-dependent apoptosis. Notably, the specific downstream pathways involved varied depending on the type of tumors. These insightful findings not only confirm the consistent inhibitory effects of BPNSs across different tumor cells, but also elucidate the cytotoxicity mechanisms of BPNSs in different tumors, providing valuable information for their safe application and health risk assessment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hinokiflavone (HF), a natural biflavonoid that possesses various biological activities, has reported that HF could be a pre-mRNA splicing modulator, whereas its underlying mechanisms remain elusive. In the present study, we identified HF as a potential MDM2 inhibitor. What's more, we found that HF suppressed mdm2 mRNA synthesis at the transcriptional level. Then, this MDM2 inhibition led in turn to increase p53 protein expression and activate p53 pathway, which could decrease the survival of HCT116 colon cells by G2/M phase arrest and apoptosis induction. Then, bioinformatics suggested that ESR1 was a predicted and potential target of HF. Finally, we used molecular docking and molecular dynamics simulation to demonstrate the binding patterns of HF and ESR1. To sum up, our study unearthed that HF was a feasible agent for MDM2 inhibitor through down-regulating mdm2 RNA level and activating p53 signaling pathway., Competing Interests: Declaration of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Drug resistance remains a major challenge in the current treatment of acute myeloid leukemia (AML). Finding specific molecules responsible for mediating drug resistance in AML contributes to the effective reversal of drug resistance. Recent studies have found that mitogen- and stress-activated protein kinase 1 (MSK1) is of great significance in the occurrence and development of tumors. In the current study, MSK1 was found highly expressed in drug-resistant AML patients. Heme oxygenase-1 (HO-1) has been previously validated to be associated with drug resistance in AML. Our study revealed a positive correlation between MSK1 and HO-1 in patient samples. In vitro experiments revealed that the sensitivity of AML cell lines THP-1 and U937 to cytarabine (Ara-C) significantly decreased after overexpression of MSK1. Meanwhile, downregulation of MSK1 by siRNA transfection or treatment of pharmacological inhibitor SB-747651A in AML cell lines and primary AML cells enhanced the sensitivity to Ara-C. Flow cytometry analysis showed that downregulation of MSK1 in AML cells accelerated apoptosis and arrested cell cycle progression in G0/G1 phase. However, the increased cell sensitivity induced by MSK1 downregulation was reversed by the induction of HO-1 inducer Hemin. Through further mechanism exploration, real-time PCR, immunofluorescence and Western blot analysis demonstrated that brahma related gene 1 (BRG1) was involved in the regulatory effect of MSK1 on HO-1. High expression of MSK1 could promote the resistance of AML through BRG1-mediated upregulation of HO-1. Downregulation of MSK1 enhanced the sensitivity of AML cells to Ara-C. Our findings provide novel ideas for developing effective anti-AML targets., (Copyright © 2021. Published by Elsevier B.V.)

AIM: To investigate the therapeutic effect of mitochondrial fission inhibitor-1 (Mdivi-1) on experimental autoimmune encephalomyelitis (EAE) in mice, and to explore its mechanism. METHODS: The mice immunized with myelin oligodendrocyte glycoprotein peptide fragment 35-55 (MOG35-55) were randomly divided into DMSO model group and Mdivi-1 intervention group. All mice were sacrificed on the 28th day after the first immunization. The demyelination was analyzed by Luxol fast blue staining. The protective mechanism of Mdivi-1 in the spinal cord tissue was investigated by immunofluorescence staining, TUNEL staining and the in vitro experiment with MO3. 13 oligodendrocytes treated with staurosporine. The mitochondrial depolarization was detected by JC-1 staining, the cell injury was checked by LDH leakage, and the viability of MO3. 13 oligodendrocytes was determined by MTT assay. RESULTS: Compared with DMSO model group, the demyelinating injury was alleviated and the proportion of apoptotic CC1+ oligodendrocytes in Mdivi-1 group was decreased. The cleaved caspase-3, caspase-9, cytochrome C and Bax protein expression levels in the spinal cord of Mdivi-1-treated mice was also attenuated. The in vitro MO3. 13 cell experiments suggested that Mdivi-1 inhibited MO3. 13 cell mitochondrial depolarization, attenuated the cell damage and increased the cell viability. CONCLUSION: Mdivi-1 protects against the myelin injury in EAE mice, which may be related to the suppression of oligodendrocyte apoptosis. [ABSTRACT FROM AUTHOR]

Clostridium perfringens beta-1 toxin (CPB1) is responsible for necrotizing enteritis and enterotoxemia. However, whether the release of host inflammatory factors caused by CPB1 is related to pyroptosis, an inflammatory form of programmed cell death, has not been reported. A construct expressing recombinant Clostridium perfringens beta-1 toxin (rCPB1) was created, and the cytotoxic activity of the purified rCPB1 toxin was assessed via CCK-8 assay. The rCPB1-induced macrophage pyroptosis by assessing changes to the expression of pyroptosis-related signal molecules and the pyroptosis pathway of macrophages using quantitative real-time PCR, immunoblotting, ELISA, immunofluorescence, and electron microscopic assays. The results showed that the intact rCPB1 protein was purified from an E. coli expression system, which exhibited moderate cytotoxicity on mouse mononuclear macrophage leukemia cells (RAW264.7), normal colon mucosal epithelial cells (NCM460), and human umbilical vein endothelial cells (HUVEC). rCPB1 could induce pyroptosis in macrophages and HUVEC cells, in part through the Caspase-1-dependent pathway. The rCPB1-induced pyroptosis of RAW264.7 cells could be blocked by inflammasome inhibitor MCC950. These results demonstrated that rCPB1 treatment of macrophages promoted the assembly of NLRP3 inflammasomes and activated Caspase 1; the activated Caspase 1 caused gasdermin D to form plasma membrane pores, leading to the release of inflammatory factors IL-18 and IL-1β, resulting in macrophage pyroptosis. NLRP3 may be a potential therapeutic target for Clostridium perfringes disease. This study provided a novel insight into the pathogenesis of CPB1. [ABSTRACT FROM AUTHOR]

The widespread application of black phosphorus nanosheets (BPNSs) raises concerns about their potential impact on human health. Although that the autophagy-inducing properties of BPNSs in cancer cells are documented, their effects on macrophages—key components of the immune system and the mechanisms involved remain obscure, especially in terms of the influences of BPNS the size and surface modifications on the autophagic process. This study investigated the effects of bare BPNSs and PEGylated BPNSs (BP-PEG) on macrophage autophagy and its underlying mechanisms by comprehensive biochemical analyses. The results indicated that both BPNSs and BP-PEG are internalized by RAW264.7 cells through phagocytosis and caveolin-dependent endocytosis, leading to lysosomal accumulation. The internalized BPNSs induced mitochondrial dysfunction, which subsequently elevated the NAD+/NADH ratio and activated the SIRT-1 pathway, initiating autophagy. However, BPNSs disrupted the autophagic flux by impairing autolysosome formation, leading to apoptosis in a size-dependent manner. In contrast, BP-PEG preserved lysosomal integrity, maintaining autophagic activity and cell viability. These findings deepen our understanding of the influence of nanosheet size and surface modifications on macrophage autophagy, contributing to the formulation of regulatory guidelines to minimize the potential adverse effects and health risks associated with BPNS utilization in various applications. • Internalization of BPNSs and BP-PEG by RAW264.7 cells led to lysosomal accumulation and mitochondrial dysfunction. • Both BPNSs and BP-PEG initiated autophagy through activating SIRT-1 pathway. • BPNSs blocked autophagic flux through disrupting autolysosome formation, inducing size-dependent apoptosis. • BP-PEG preserved autophagic function, allowing for maintaining the cell viability. [ABSTRACT FROM AUTHOR]

Aim. To investigate the mechanism of progesterone inhibiting the scorch death of SH-SY5Y cells induced by exogenous adenosine triphosphate (ATP). Methods. SH-SY5Y cells with good logarithmic growth were used in the experiment. The cells were randomly divided into 5 groups: normal control group, DMSO group, BBG group, ATP group, and ATP+progesterone group. The cell survival rate of each group was measured by CCK-8 method. The expressions of P2X7 receptor, caspase-1, caspase-11, and IL-1β were detected by western blotting. Results. (1) After SH-SY5Y cells were treated with ATP at different concentrations (1, 3, 6, and 9 mmol/L) for 2 hours, the cell survival rate decreased in a concentration-dependent manner compared with the normal blank group. The results showed that the optimal lethal concentration of ATP was 6 mmol/L. SH-SY5Y cells were preincubated with progesterone at different concentrations (3, 10, 30, and 100 nmol/L) for 30 minutes and then incubated with 6 mmol/L ATP. The cell survival rate of this group was significantly improved (P < 0.01). The optimal concentration of progesterone to improve cell survival and inhibit cell death was 30 nmol/L. (2) Compared to the control group, there was no significant difference (P > 0.05) in P2X7 receptor, caspase-1, caspase-11, and IL-1β with the DMSO group (0.001% DMSO, 24 h) and BBG group (bbg1 mmol/L, 24 h). (3) In the ATP group, the expression of P2X7 receptor and caspase-1 (the key protein of classical cell death pathway) increased significantly (P < 0.01), which was related to inflammatory factor IL-1β with consistent performance (P < 0.01). There was no significant change in caspase-11 (the key protein of nonclassical focal death pathway) (P > 0.05). (4) The expression of P2X7 receptor, caspase-1, and inflammatory factor IL-1β in the progesterone+ATP group was significantly downregulated (P < 0.01). There was no significant change in caspase-11 (P > 0.05). Conclusion. Certain dose of progesterone can inhibit the focal death of SH-SY5Y cells induced by extracellular high concentration ATP. It can reduce the expression of P2X7 receptor, inhibit the conduction pathway of cell death, reduce the release of inflammatory factor IL-1β, and improve cell survival. [ABSTRACT FROM AUTHOR]

The immune cell inflammation response is closely related to the occurrence of disease, and much evidence has shown that circular RNAs (circRNAs) play vital roles in the occurrence of disease. However, the biological function and regulatory mechanisms of circRNAs in the immune cell inflammation response remain poorly understood. In this study, we constructed an inflammatory model using lipopolysaccharide (LPS)-stimulated chicken macrophage lines (also known as HD11) to verify the function and mechanism of the novel circDCLRE1C (ID: gga_circ_0001674), which was significantly upregulated in spleen tissues infected by coccidia and the macrophage cells exposed to LPS. The results showed that circDCLRE1C aggravated LPS-induced inflammation and apoptosis in HD11 cells. Systemically, circDCLRE1C acted as a sponge for miR-214b-3p binding sites thereby regulating the expression of STAT3. The overexpression of miR-214b-3p rescued the pro-inflammatory effect of circDCLRE1C in HD11 cells stimulated with LPS, and rescued the high expression of STAT3. In conclusion, our study showed that circDCLRE1C could aggravate LPS-induced inflammation and apoptosis through competitive adsorption of miR-214b-3p, thereby increasing the expression of STAT3. [ABSTRACT FROM AUTHOR]

Background: Bisbenzimides, or Hoechst 33258 (H258), and its derivative Hoechst 33342 (H342) are archetypal molecules for designing minor groove binders, and widely used as tools for staining DNA and analyzing side population cells. They are supravital DNA minor groove binders with AT selectivity. H342 and H258 share similar biological effects based on the similarity of their chemical structures, but also have their unique biological effects. For example, H342, but not H258, is a potent apoptotic inducer and both H342 and H258 can induce transgene overexpression in in vitro studies. However, the molecular mechanisms by which Hoechst dyes induce apoptosis and enhance transgene overexpression are unclear. Methodology/Principal Findings: To determine the molecular mechanisms underlying different biological effects between H342 and H258, microarray technique coupled with bioinformatics analyses and multiple other techniques has been utilized to detect differential global gene expression profiles, Hoechst dye-specific gene expression signatures, and changes in cell morphology and levels of apoptosis-associated proteins in malignant mesothelioma cells. H342-induced apoptosis occurs in a dose-dependent fashion and is associated with morphological changes, caspase-3 activation, cytochrome c mitochondrial translocation, and cleavage of apoptosis-associated proteins. The antagonistic effect of H258 on H342-induced apoptosis indicates a pharmacokinetic basis for the two dyes' different biological effects. Differential global gene expression profiles induced by H258 and H342 are accompanied by unique gene expression signatures determined by DNA microarray and bioinformatics software, indicating a genetic basis for their different biological effects. Conclusions/Significance: A unique gene expression signature associated with H342-induced apoptosis provides a new avenue to predict and classify the therapeutic class of minor groove binders in the drug development process. Further analysis of H258-upregulated genes of transcription regulation may identify the genes that enhance transgene overexpression in gene therapy and promote recombinant protein products in biopharmaceutical companies. Data Deposition: The microarray data reported in this article have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no.GSE28616). [ABSTRACT FROM AUTHOR]

Highlight: [•] MSCs promote the production of IL-4 from splenocytes in stressed mice. [ABSTRACT FROM AUTHOR]