As competitive HMG-CoA reductase (HMGCR) inhibitors, statins not only reduce cholesterol and improve cardiovascular risk, but also exhibit pleiotropic effects that are independent of their lipid-lowering effects. Among them, the anti-cancer properties of statins have attracted much attention and indicated the potential of statins as repurposed drugs for the treatment of cancer. A large number of clinical and epidemiological studies have described the anticancer properties of statins, but the evidence for anticancer effectiveness of statins is inconsistent. It may be that certain molecular subtypes of cancer are more vulnerable to statin therapy than others. Whether statins have clinical anticancer effects is still an active area of research. Statins appear to enhance the efficacy and address the shortcomings associated with conventional cancer treatments, suggesting that statins should be considered in the context of combined therapies for cancer. Here, we present a comprehensive review of the potential of statins in anti-cancer treatments. We discuss the current understanding of the mechanisms underlying the anti-cancer properties of statins and their effects on different malignancies. We also provide recommendations for the design of future well-designed clinical trials of the anti-cancer efficacy of statins.

/pdf/statins-a-repurposed-drug-to-fight-cancer-jca6ssq5mz.pdf

Statins: a repurposed drug to fight cancer

There is a lack of early specific diagnosis and effective evaluation of sepsis, and the clinical treatment is not timely. As a result, the mortality is high, which seriously threatens the health of the people. Data were collected from the human blood samples of the hospital by gas chromatography mass spectrometry. Thirty-five healthy controls and 42 sepsis patients were enrolled. Machine-learning techniques were used to diagnose the sepsis. Using the metabolic data from the sepsis patients, the proposed method has got 81.6% recognition rate, 89.57% sensitivity, and 65.77% specificity. A new learning strategy was proposed to boost the performance of the kernel extreme learning machine, known as, chaotic fruit fly optimization, and two new mechanisms were introduced into the original a fruit fly optimization, including the chaotic population initialization and the chaotic local search strategy. To further enhance the diagnosis accuracy and identify the most important biomarkers, we performed the feature selection using the random forest before the construction of the classification model. The final established model, random forest-improved fruit fly optimization algorithm-kernel extreme learning machine, was used to effectively diagnose the sepsis. Experimental results demonstrate that the proposed method obtains better results than other methods across four performance metrics. We screened out five biomarkers and performed statistical analysis on these five substances. The level of acetic acid increased (p < 0.05) in the sepsis group, while the level of linoleic acid and cholesterol decreased (p < 0.05). The promising results suggest that the developed methodology can be a useful diagnostic tool for clinical decision support.

A New Effective Machine Learning Framework for Sepsis Diagnosis

Casearin D inhibits ERK phosphorylation and induces downregulation of cyclin D1 in HepG2 cells.

Breast cancer is the most common cancer in women and a leading cause of cancer-associated mortalities in the world. Epithelial-to-mesenchymal transition (EMT) serves an important role in the process of metastasis and invasive ability in cancer cells, and transforming growth factor β1 (TGF-β1) have been investigated for promoting EMT. However, in the present study, the role of the sphingomyelin synthase 1 (SMS1) in TGF-β1-induced EMT development was investigated. Firstly, bioinformatics analysis demonstrated that the overexpression of SMS1 negatively regulated the TGFβ receptor I (TβRI) level of expression. Subsequently, the expression of SMS1 was decreased, whereas, SMS2 had no significant difference when MDA-MB-231 cells were treated by TGF-β1 for 72 h. Furthermore, the present study constructed an overexpression cells model of SMS1 and these cells were treated by TGF-β1. These results demonstrated that overexpression of SMS1 inhibited TGF-β1-induced EMT and the migration and invasion of MDA-MB-231 cells, increasing the expression of E-cadherin while decreasing the expression of vimentin. Furthermore, the present study further confirmed that SMS1 overexpression could decrease TβRI expression levels and blocked smad family member 2 phosphorylation. Overall, the present results suggested that SMS1 could inhibit EMT and the migration and invasion of MDA-MB-231 cells via TGF-β/Smad signaling pathway.

/pdf/sphingomyelin-synthase-1-regulates-the-epithelial-to-433a8zwysq.pdf

Sphingomyelin synthase 1 regulates the epithelial‑to‑mesenchymal transition mediated by the TGF‑β/Smad pathway in MDA‑MB‑231 cells.

Sphingomylin participates in sperm function in animals, and also regulates the Akt and ERK signaling pathways, both of which are associated with the asthenospermia. Sphingomyelin synthase 2 (SMS2) is involved in the biosynthesis of sphingomylin. To determine the relationship between SMS2 and human sperm function, we analyzed the distribution of SMS2 in human sperm and testes, and SMS2 expression in patients with asthenospermia and normozoospermia; human sperm were treated with anti-SMS2, and the sperm motility, penetration ability into methylcellulose, capacitation and acrosome reaction, and sperm [Ca2+]i imaging were evaluated, while the Akt and ERK pathway and cleaved caspase 3 were also analyzed. Results showed that SMS2 was localized in the testis and human sperm, and the protein levels of normozoospermia were higher than asthenospermia. Inhibition of SMS2 activity significantly decreased sperm motility and penetration ability into methylcellulose, but had no influence on capacitation and acrosome reaction, or on intracellular [Ca2+]i compared to IgG-treated control groups. Moreover, the phosphorylation level of Akt was decreased, whereas the phosphorylation of ERK and cleaved-caspase 3 levels were significantly increased. Taken together, SMS2 can affect sperm motility and penetration ability into methylcellulose, and participate in apoptosis associated with the Akt and ERK signaling pathways.

https://www.mdpi.com/1420-3049/25/18/4231/pdf

Sphingomyelin Synthase 2 Participate in the Regulation of Sperm Motility and Apoptosis.

Sepsis is characterized by a severe inflammatory response to infection. With the spread of sepsis, various tissues, including the lungs, liver and kidney, may be damaged. This may finally develop into multiple organ dysfunction syndrome. Sphingomyelin and cholesterol are two main lipids involved in sepsis. The metabolism of sphingomyelin and cholesterol in the livers of mice with sepsis needs to be clarified. To achieve this, the present study intraperitoneally injected mice with PBS, lipopolysaccharide (LPS; 10 mg/kg) and LPS + pyrrolidine dithiocarbamate (PDTC; 30 mg/kg). Subsequently, sphingomyelin and cholesterol content were measured using kits, the sphingomyelin synthase (SMS) activity was measured using thin layer chromatography, and the expression levels of SMS1 and 2, hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), ATP binding cassette subfamily A member 1 (ABCA1), scavenger receptor class B member 1 (SR-B1) and apolipoprotein A1 (Apo A1) were determined by western blotting in the livers of mice. Results demonstrated that, in the LPS group, sphingomyelin and cholesterol content was significantly increased (P 0.05; n=6), compared to the levels in the control group. However, PDTC was able to attenuate these alterations. These results indicated that sphingomyelin and cholesterol content may increase in the liver dysfunction of sepsis by increasing the expression of SMS2, HMGCR, SR-B1 and ABCA1, and downregulating Apo A1.

/pdf/effects-of-sepsis-on-the-metabolism-of-sphingomyelin-and-15zbp088jf.pdf

Effects of sepsis on the metabolism of sphingomyelin and cholesterol in mice with liver dysfunction.

Hepatocellular carcinoma is the sixth most prevalent malignant tumor and the third most common cause of cancer-associated mortality. Statins have been investigated for carcinoma prevention and treatment. In addition, receptor-interacting protein 140 (RIP140) has been observed to inhibit the Wnt/β-catenin signaling pathway and cell growth. The present study aimed to investigate whether simvastatin (SV) is able to induce SMCC-7721 cell apoptosis through the Wnt/β-catenin signaling pathway. Initially, a cell model of RIP140 overexpression was established, and then cells were treated with SV. The cell growth, viability and apoptosis were measured by cell counting kit-8 and flow cytometry. Furthermore, the expression levels of RIP140, β-catenin, c-myc and cyclin D1 were detected by reverse transcription-quantitative polymerase chain, western blot analysis and immunofluorescence. The results demonstrated that SV significantly increased the expression of RIP140 in SMCC-7721 cells; however, β-catenin, c-myc and cyclin D1 levels were significantly decreased. Furthermore, the immunofluorescence assay of β-catenin confirmed that SV decreased the content of this protein in SMCC-7721 cells. Notably, RIP140 exerted a synergistic effect on the apoptosis rate induced by SV (RIP140 + SV group), while the alteration in RIP140, β-catenin, c-myc and cyclin D1 levels was more evident in the combination group as compared with the RIP140 or SV alone groups. In conclusion, these results suggested that SV is able to induce the apoptosis of SMCC-7721 cells through the Wnt/β-catenin signaling pathway, as well as that RIP140 and SV exert a synergistic effect on the inhibition of cell proliferation and survival.

/pdf/synergistic-effect-of-receptor-interacting-protein-140-and-1xpiz32fiv.pdf

Synergistic effect of receptor-interacting protein 140 and simvastatin on the inhibition of proliferation and survival of hepatocellular carcinoma cells.

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Effects of sepsis on the metabolism of sphingomyelin and cholesterol in mice with liver dysfunction.

Synergistic effect of receptor-interacting protein 140 and simvastatin on the inhibition of proliferation and survival of hepatocellular carcinoma cells.