Utilizing Machine Learning Models for Predicting Diamagnetic Susceptibility of Organic Compounds.

This research is centered on examining the magnetic characteristics of organic molecules, with a particular emphasis on magnetic susceptibility, an essential physical property that provides insights into molecular microstructures and reaction processes. Traditional approaches for determining and calculating magnetic susceptibility are generally inefficient and demanding. To overcome these challenges, we have introduced a novel approach using quantitative structure-property relationships, which efficiently elucidates the relationship between the structural properties of molecules and their molar magnetic susceptibility. In our study, we utilized a comprehensive database comprising molar magnetic susceptibility data for 382 organic molecules. We applied six distinct molecular fingerprinting methods-RDKit Fingerprint, Morgan Fingerprint, MACCS Keys, atom pair fingerprint, Avalon Fingerprint, and topology fingerprint-as feature inputs for training seven different machine learning models, namely random forest, AdaBoost, gradient boosting, extra trees, elastic net, support vector machine, and multilayer perceptron (MLP). Our findings revealed that the integration of the atom pair fingerprint with the MLP model yielded R2 values of 0.88 and 0.90 in the validation and test sets, respectively, showcasing exceptional predictive accuracy. This advancement significantly expedites research and development processes related to the magnetic properties of organic molecules. Moreover, by employing this effective predictive method, it is expected to considerably reduce both experimental and computational expenses while maintaining high accuracy. This development represents a breakthrough in the rapid screening and prediction of properties for various compounds, offering a new and efficient pathway in this field of study.

Surf4 (Surfeit Locus Protein 4) Deficiency Reduces Intestinal Lipid Absorption and Secretion and Decreases Metabolism in Mice.

BACKGROUND: Postprandial dyslipidemia is a causative risk factor for cardiovascular disease. The majority of absorbed dietary lipids are packaged into chylomicron and then delivered to circulation. Previous studies showed that Surf4 (surfeit locus protein 4) mediates very low-density lipoprotein secretion from hepatocytes. Silencing hepatic Surf4 markedly reduces the development of atherosclerosis in different mouse models of atherosclerosis without causing hepatic steatosis. However, the role of Surf4 in chylomicron secretion is unknown. METHODS: We developed inducible intestinal-specific Surf4 knockdown mice (Surf4IKO) using Vil1Cre-ERT2 and Surf4flox mice. Metabolic cages were used to monitor mouse metabolism. Enzymatic kits were employed to measure serum and tissue lipid levels. The expression of target genes was detected by qRT-PCR and Western Blot. Transmission electron microscopy and radiolabeled oleic acid were used to assess the structure of enterocytes and intestinal lipid absorption and secretion, respectively. Proteomics was performed to determine changes in protein expression in serum and jejunum. RESULTS: Surf4IKO mice, especially male Surf4IKO mice, displayed significant body weight loss, increased mortality, and reduced metabolism. Surf4IKO mice exhibited lipid accumulation in enterocytes and impaired fat absorption and secretion. Lipid droplets and small lipid vacuoles were accumulated in the cytosol and the endoplasmic reticulum lumen of the enterocytes of Surf4IKO mice, respectively. Surf4 colocalized with apoB and co-immunoprecipitated with apoB48 in differentiated Caco-2 cells. Intestinal Surf4 deficiency also significantly reduced serum triglyceride, cholesterol, and free fatty acid levels in mice. Proteomics data revealed that diverse pathways were altered in Surf4IKO mice. In addition, Surf4IKO mice had mild liver damage, decreased liver size and weight, and reduced hepatic triglyceride levels. CONCLUSIONS: Our findings demonstrate that intestinal Surf4 plays an essential role in lipid absorption and chylomicron secretion and suggest that the therapeutic use of Surf4 inhibition requires highly cell/tissue-specific targeting.

Molecular Hydrogen Inhibits Colorectal Cancer Growth via the AKT/SCD1 Signaling Pathway.

Objective: Molecular hydrogen (H2) has been considered a potential therapeutic target in many cancers. Therefore, we sought to assess the potential effect of H2 on colorectal cancer (CRC) in this study. Methods: The effect of H2 on the proliferation and apoptosis of RKO, SW480, and HCT116 CRC cell lines was assayed by CCK-8, colony formation, and flow cytometry assays. The effect of H2 on tumor growth was observed in xenograft implantation models (inhalation of 67% hydrogen two hours per day). Western blot and immunohistochemistry analyses were performed to examine the expression of p-PI3K, PI3K, AKT, pAKT, and SCD1 in CRC cell lines and xenograft mouse models. The expression of SCD1 in 491 formalin-fixed, paraffin-embedded CRC specimens was investigated with immunochemistry. The relationship between SCD1 status and clinicopathological characteristics and outcomes was determined. Results: Hydrogen treatment suppressed the proliferation of CRC cell lines independent of apoptosis, and the cell lines showed different responses to different doses of H2. Hydrogen also elicited a potent antitumor effect to reduce CRC tumor volume and weight in vivo. Western blot and IHC staining demonstrated that H2 inhibits CRC cell proliferation by decreasing pAKT/SCD1 levels, and the inhibition of cell proliferation induced by H2 was reversed by the AKT activator SC79. IHC showed that SCD1 expression was significantly higher in CRC tissues than in normal epithelial tissues (70.3% vs. 29.7%, p = 0.02) and was correlated with a more advanced TNM stage (III vs. I + II; 75.9% vs. 66.3%, p = 0.02), lymph node metastasis (with vs. without; 75.9% vs. 66.3%, p = 0.02), and patients without a family history of CRC (78.7% vs. 62.1%, p = 0.047). Conclusion: This study demonstrates that high concentrations of H2 exert an inhibitory effect on CRC by inhibiting the pAKT/SCD1 pathway. Further studies are warranted for clinical evaluation of H2 as SCD1 inhibitor to target CRC.

Atherosclerosis-associated hepatic secretion of VLDL but not PCSK9 is dependent on cargo receptor protein Surf4.

Plasma LDL is produced from catabolism of VLDL and cleared from circulation mainly via the hepatic LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes LDLR degradation, increasing plasma LDL-C levels. Circulating PCSK9 is mainly secreted by the liver, whereas VLDL is exclusively secreted by hepatocytes. However, the mechanism regulating their secretion is not completely understood. Surfeit 4 (Surf4) is a cargo receptor localized in the ER membrane. It recruits cargos into coat protein complex II vesicles to facilitate their secretion. Here, we investigated the role of Surf4 in VLDL and PCSK9 secretion. We generated Surf4 liver-specific knockout mice and found that knockout of Surf4 did not affect PCSK9 secretion, whereas it significantly reduced plasma levels of cholesterol, triglyceride, and lipid-binding protein apolipoprotein B (apoB). In cultured human hepatocytes, Surf4 coimmunoprecipitated and colocalized with apolipoprotein B100, and Surf4 silencing reduced secretion of apolipoprotein B100. Furthermore, knockdown of Surf4 in LDLR knockout (Ldlr-/-) mice significantly reduced triglyceride secretion, plasma levels of apoB and non-HDL-C, and the development of atherosclerosis. However, Surf4 liver-specific knockout mice and Surf4 knockdown in Ldlr-/- mice displayed similar levels of liver lipids and plasma alanine aminotransferase activity as control mice, indicating that inhibition of Surf4 does not cause notable liver damage. Expression of stearoyl-CoA desaturase-1 was also reduced in the liver of these mice, suggesting a reduction in de novo lipogenesis. In summary, hepatic deficiency of Surf4 reduced VLDL secretion and the development of atherosclerosis but did not cause significant hepatic lipid accumulation or liver damage.

A Perfused Microfluidic System to Study the Differentiation of Neural Stem Cells in vitro.

INTRODUCTION: Due to the ability to mimic in vivo cellular microenvironments, the development of multicell culture systems has received increasing interest for use as research models and serving as platforms for drug evaluation. METHODS: In this study, we developed a perfused microfluidic system to resemble the in vivo intercellular environment and applied it to study the differentiation from neural stem cells into neurons. RESULTS: As determined by immunofluorescence chemistry and quantitative real-time PCR, the neural stem cells grown in this microfluidic system showed an elevated differentiation rate toward the formation of neurons as determined by the increased level of ßIII-tubulin production, which is 4 times higher than that of culturing neural stem cells only. CONCLUSION: These results revealed that some factors secreted into the intercellular microenvironment by adult neuron cells can stimulate the differentiation of neural stem cells, pointing to the importance of developing multicellular culture systems such as the perfused microfluidic system we report here to better resemble the in vivo situation.