Identifying resistance molecules in TiO2 nanoparticle-tolerant strains to facilitate the development of strategies for combating TiO2 nanoparticle pollution.

The severity of environmental pollution caused by TiO2 nanoparticles (nTiO2) is increasing, highlighting the urgent need for the development of strategies to combat nTiO2 pollution. Insights into resistance molecules from nTiO2-tolerant strains may facilitate such development. In this study, we utilized multi-omics, genetic manipulation, physiological and biochemical experiments to identify relevant resistance molecules in two strains (Physarum polycephalum Z259 and T83) tolerated to mixed-phase nTiO2 (MPnTiO2). We discovered that a competing endogenous RNA (ceRNA) network, comprising one long non-coding RNA (lncRNA), four microRNAs, and nine mRNAs, influenced metabolic rearrangement and was associated with significant resistance in these strains. Additionally, we found that the lncRNA in the ceRNAs network and certain small-weight metabolites associated with the ceRNA exhibited notable mitigation effects not only against MPnTiO2 but also against other types of nTiO2 with broad species applicability (they significantly improved the resistance of several non-nTiO2-tolerant cells/organisms in the laboratory and reduced cell damage of non-nTiO2-tolerant cells/organisms in highly suspected nTiO2-polluted areas of the real world). In summary, this study deepens our understanding of nTiO2-tolerant strains, provides valuable insights into resistance molecules in these strains, and facilitates the development of strategies to combat nTiO2 pollution.

Veno-arterial extracorporeal membrane oxygenation for the treatment of obstructive shock caused by venous air embolism: A case report.

BACKGROUND: Venous air embolism (VAE) is a potentially lethal condition, with a reported incidence rate of about 0.13%, and the true incidence may be higher since many VAE are asymptomatic. The current treatments for VAE include Durant's maneuver, aspiration and removal of air through venous catheters, and hyperbaric oxygen therapy. For critically ill patients, use of cardiotonic drugs and chest compressions remain useful strategies. The wider availability of extracorporeal membrane oxygenation (ECMO) has brought a new option for VAE patients. CASE SUMMARY: A 53-year-old female patient with VAE presented to the emergency clinic due to abdominal pain with fever for 1 d and unconsciousness for 2 h. One day ago, the patient suffered from abdominal pain, fever, and diarrhea. She suddenly became unconscious after going to the toilet during the intravenous infusion of ciprofloxacin 2 h ago, accompanied by nausea and vomiting, during which a small amount of gastric contents were discharged. She was immediately sent to a local hospital, where cranial and chest computed tomography showed bilateral pneumonia as well as accumulated air visible in the right ventricle and pulmonary artery. The condition deteriorated despite endotracheal intubation, rehydration, and other treatments, and the patient was then transferred to our hospital. Veno-arterial ECMO was applied in our hospital, and the patient's condition gradually improved. The patient was successfully weaned from ECMO and extubated after two days. CONCLUSION: ECMO may be an important treatment for patients with VAE in critical condition.

Physarum polycephalum macroplasmodium exhibits countermeasures against TiO2 nanoparticle toxicity: A physiological, biochemical, transcriptional, and metabolic perspective.

Concerns about the environmental and human health implications of TiO2 nanoparticles (nTiO2) are growing with their increased use in consumer and industrial products. Investigations of the underlying molecular mechanisms of nTiO2 tolerance in organisms will assist in countering nTiO2 toxicity. In this study, the countermeasures exhibited by the slime mold Physarum polycephalum macroplasmodium against nTiO2 toxicity were investigated from a physiological, transcriptional, and metabolic perspective. The results suggested that the countermeasures against nTiO2 exposure include gene-associated metabolic rearrangements in cellular pathways involved in amino acid, carbohydrate, and nucleic acid metabolism. Gene-associated nonmetabolic rearrangements involve processes such as DNA repair, DNA replication, and the cell cycle, and occur mainly when macroplasmodia are exposed to inhibitory doses of nTiO2. Interestingly, the growth of macroplasmodia and mammal cells was significantly restored by supplementation with a combination of responsive metabolites identified by metabolome analysis. Taken together, we report a novel model organism for the study of nTiO2 tolerance and provide insights into countermeasures taken by macroplasmodia in response to nTiO2 toxicity. Furthermore, we also present an approach to mitigate the effects of nTiO2 toxicity in cells by metabolic intervention.

MicroRNA-24 aggravates atherosclerosis by inhibiting selective lipid uptake from HDL cholesterol via the post-transcriptional repression of scavenger receptor class B type I.

BACKGROUND AND AIMS: Liver scavenger receptor class B type I (SR-BI) exerts atheroprotective effects through selective lipid uptake (SLU) from high-density lipoprotein cholesterol (HDL-C). Low hepatic SR-BI expression leads to high HDL-C levels in the circulation and an increased risk of atherosclerosis. Furthermore, macrophage SR-BI mediates bidirectional cholesterol flux and may protect against atherogenesis. Previous studies have revealed that miR-24 is closely related to cardiovascular disease (CVD) progression. We aimed to investigate the molecular mechanisms by which miR-24 participates in SR-BI-mediated selective HDL cholesteryl ester (HDL-CE) uptake and further atherogenesis in apoE-/- mice. METHODS: Bioinformatic predictions and luciferase reporter assays were utilized to detect the association between miR-24 and the SR-BI 3' untranslated region (3' UTR), and RT-PCR and western blotting were used to evaluate SR-BI mRNA and protein expression, respectively. The effects of miR-24 on Dil-HDL uptake were determined by flow cytometry assay. Double-radiolabeled HDL (125I-TC-/[3H] CEt-HDL) was utilized to measure the effects of miR-24 on HDL and CE binding and SLU in HepG2 and PMA-treated THP-1 cells. In addition, total cholesterol (TC) levels in HepG2 cells were analyzed using enzymatic methods, and macrophage lipid content was evaluated by high-performance liquid chromatography (HPLC) assay. Small interfering RNA (siRNA) and pcDNA3.1(-)-hSR-BI plasmid transfection procedures were utilized to confirm the role of SR-BI in the effects of miR-24 on Dil-HDL uptake, SLU and cholesterol levels in both cell types. Hepatic SR-BI level in apoE-/- mice was measured by western blotting. Liver TC, FC and CE levels and plasma triglycerides (TG), TC and HDL-C levels were evaluated enzymatically using commercial test kits. Atherosclerotic lesion sizes were measured using Oil Red O and hematoxylin-eosin staining. RESULTS: miR-24 directly repressed SR-BI expression by targeting its 3'UTR. In addition, miR-24 decreased Dil-HDL uptake and SLU in HepG2 and THP-1 macrophages. In the presence of HDL, miR-24 decreased TC levels in HepG2 cells and TC, free cholesterol (FC) and CE levels in macrophages. Overexpression and down-regulation assays showed that SR-BI mediated the effects of miR-24 on Dil-HDL uptake, SLU and cholesterol levels. Lastly, miR-24 administration decreased hepatic SR-BI expression and promoted atheromatous plaque formation in apoE-/- mice, findings in line with those of our in vitro studies. CONCLUSIONS: These findings indicate that miR-24 accelerates atherogenesis by repressing SR-BI-mediated SLU from HDL-C.

PRMT2ß, a C-terminal splice variant of PRMT2, inhibits the growth of breast cancer cells.

Our previous study reported several alternative splicing variants of arginine N-methyltransferase 2 (PRMT2), which lose different exons in the C-terminals of the wild-type PRMT2 gene. Particularly, due to frame-shifting, PRMT2ß encodes a novel amino acid sequence at the C-terminus of the protein, the function of which is not understood. In the present study, we determined the role of PRMT2ß in breast cancer cell proliferation, apoptosis and its effect on the Akt signaling pathway. Stable breast cancer MCF7 cell line with lentivirus-mediated PRMT2ß overexpression was obtained after selection by puromycin for 2 weeks. The effect of lentivirus-mediated PRMT2ß overexpression on breast cancer cellular oncogenic properties was evaluated by MTT, colony formation, cell cycle analysis and apoptosis assays in MCF7 cells. Luciferase activity assay and western blot analysis were performed to characterize the effects of PRMT2ß on cyclin D1 promoter activities and the Akt signaling pathway. Tissue microarray was performed to investigate the association of PRMT2ß with breast cancer progression. Lentivirus-mediated PRMT2ß overexpression suppressed the cell proliferation and colony formation of breast cancer MCF7 cells. PRMT2ß overexpression induced cell cycle arrest and apoptosis of MCF7 cells. Furthermore, PRMT2ß was revealed to suppress the transcription activity of the cyclin D1 promoter, and PRMT2ß was also found to inhibit cyclin D1 expression via the suppression of Akt/GSK-3ß signaling in breast cancer cells. Clinically, it was revealed that PRMT2ß expression was negatively correlated with human epidermal growth factor receptor 2 (HER2) (p=0.033) in breast tumors. Our results revealed that PRMT2ß, a novel splice variant of PRMT2, plays potential antitumor effect by suppressing cyclin D1 expression and inhibiting Akt signaling activity. This also opens a new avenue for treating breast cancer.

ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs

Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Scavenger receptor class B member I (SR-BI), a high-affinity receptor for apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL), inhibits nuclear factor-κB (NF-κB) translocation and decreases the plasma levels of inflammatory mediators via the PI3K/Akt pathway. We hypothesized that the inflammatory effects of S1P/S1PR2 on ECs may be regulated by apoA-I/SR-BI. The results showed that ox-LDL, a pro-inflammatory factor, augmented the S1PR2 level in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. In addition, S1P/S1PR2 signaling influenced the levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-10, aggravating inflammation in HUVECs. Moreover, the pro-inflammatory effects induced by S1P/S1PR2 were attenuated by SR-BI overexpression and enhanced by an SR-BI inhibitor, BLT-1. Further experiments showed that the PI3K/Akt signaling pathway was involved in this process. Taken together, these results demonstrate that apoA-I/SR-BI negatively regulates S1P/S1PR2-mediated inflammation in HUVECs by activating the PI3K/Akt signaling pathway (AU)

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TGF-ß1 induces HMGA1 expression: The role of HMGA1 in thyroid cancer proliferation and invasion.

The role of transforming growth factor-ß1 (TGF-ß1) is complicated and plays a different role in the development of cancer. High mobility group A (HMGA1) participates in multiple cellular biology processes, and exerts important roles in the epithelial-mesenchymal transition (EMT). However, the correlation of TGF-ß1 and HMGA1 in cancer cells is not yet fully understood. In this study, we determined the effects of TGF-ß1 on HMGA1 expression in thyroid cancer cells and examined the role of HMGA1 in thyroid cancer progression. With real-time PCR and immunofluorescence staining, our study demonstrated that TGF-ß1 induced the expression of HMGA1 through phosphoinositide 3-kinase (PI3K) and the extracellular signal-related kinase (ERK) signaling in thyroid cancer cells. With luciferase reported assay, the HMGA1 promoter activity was activated by TGF-ß1 in the SW579 cells. Furthermore, lentivirus-mediated HMGA1 knockdown inhibits cellular oncogenic properties of thyroid cancer cells. Clinically, tissue microarray revealed that HMGA1 was expressed in thyroid carcinoma more than that in normal thyroid tissues (P<0.001); expression of HMGA1 and MMP-2 was identified to be positively correlated (P=0.017). The present study established the first link between HMGA1 and TGF-ß1 in the regulation of thyroid cancer proliferation and invasion, and provided evidence for the pivotal role of HMGA1 in the progression of thyroid cancer, indicating HMGA1 to be potential biological marker for the diagnosis of thyroid cancer.

ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs.

Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Scavenger receptor class B member I (SR-BI), a high-affinity receptor for apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL), inhibits nuclear factor-κB (NF-κB) translocation and decreases the plasma levels of inflammatory mediators via the PI3K/Akt pathway. We hypothesized that the inflammatory effects of S1P/S1PR2 on ECs may be regulated by apoA-I/SR-BI. The results showed that ox-LDL, a pro-inflammatory factor, augmented the S1PR2 level in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. In addition, S1P/S1PR2 signaling influenced the levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-10, aggravating inflammation in HUVECs. Moreover, the pro-inflammatory effects induced by S1P/S1PR2 were attenuated by SR-BI overexpression and enhanced by an SR-BI inhibitor, BLT-1. Further experiments showed that the PI3K/Akt signaling pathway was involved in this process. Taken together, these results demonstrate that apoA-I/SR-BI negatively regulates S1P/S1PR2-mediated inflammation in HUVECs by activating the PI3K/Akt signaling pathway.

TGF-ß Down-regulates Apolipoprotein M Expression through the TAK-1-JNK-c-Jun Pathway in HepG2 Cells.

Apolipoprotein M (apoM) is a relatively novel apolipoprotein that plays pivotal roles in many dyslipidemia-associated diseases; however, its regulatory mechanisms are poorly understood. Many cytokines have been identified that down-regulate apoM expression in HepG2 cells, among which transforming growth factor-ß (TGF-ß) exerts the most potent effects. In addition, c-Jun, a member of the activated protein 1 (AP-1) family whose activity is modulated by c-Jun N-terminal kinase (JNK), decreases apoM expression at the transcriptional level by binding to the regulatory element in the proximal apoM promoter. In this study, we investigated the molecular mechanisms through which TGF-ß decreases the apoM level in HepG2 cells. The results revealed that TGF-ß inhibited apoM expression at both the mRNA and protein levels in a dose- and time-dependent manner and that it suppressed apoM secretion. These effects were attenuated by treatment of cells with either SP600125 (JNK inhibitor) or c-Jun siRNA. 5Z-7-oxozeaenol [(a TGF-ß-activated kinase 1 (TAK-1) inhibitor)] also attenuated the TGF-ß-mediated inhibition of apoM expression and suppressed the activation of JNK and c-Jun. These results have demonstrated that TGF-ß suppresses apoM expression through the TAK-1-JNK-c-Jun pathway in HepG2 cells.

ApoA-I induces S1P release from endothelial cells through ABCA1 and SR-BI in a positive feedback manner

Sphingosine-1-phosphate (S1P), which has emerged as a pivotal signaling mediator that participates in the regulation of multiple cellular processes, is derived from various cells, including vascular endothelial cells. S1P accumulates in lipoproteins, especially HDL, and the majority of free plasma S1P is bound to HDL. We hypothesized that HDL-associated S1P is released through mechanisms associated with the HDL maturation process. ApoA-I, a major HDL apolipoprotein, is a critical factor for nascent HDL formation and lipid trafficking via ABCA1. Moreover, apoA-I is capable of promoting bidirectional lipid movement through SR-BI. In the present study, we confirmed that apoA-I can facilitate the production and release of S1P by HUVECs. Furthermore, we demonstrated that ERK1/2 and SphK activation induced by apoA-I is involved in the release of S1P from HUVECs. Inhibitor and siRNA experiments showed that ABCA1 and SR-BI are required for S1P release and ERK1/2 phosphorylation induced by apoA-I. However, the effects triggered by apoA-I were not suppressed by inhibiting ABCA1/JAK2 or the SR-BI/Src pathway. S1P released due to apoA-I activation can stimulate the (ERK1/2)/SphK1 pathway through S1PR (S1P receptor) 1/3. These results indicated that apoA-I not only promotes S1P release through ABCA1 and SR-BI but also indirectly activates the (ERK1/2)/SphK1 pathway by releasing S1P to trigger their receptors. In conclusion, we suggest that release of S1P induced by apoA-I from endothelial cells through ABCA1 and SR-BI is a self-positive-feedback process: apoA-I-(ABCA1 and SR-BI)-(S1P release)-S1PR-ERK1/2-SphK1-(S1P production)-(more S1P release induced by apoA-I) (AU)

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