Compound 6 isolated from the leaves of Gynura nepalensis potently protects H9c2 cardiomyoblasts against HO-induced apoptosis, possibly by inhibiting intrinsic apoptosis and the ERK/JNK pathway.

Drug repositioning has been attracting increasingly attention for its advantages of reducing costs and risks. Statistics showed that around one quarter of the marketed drugs are organohalogens. However, no study has been reported, to the best of our knowledge, to aim at efficiently repositioning organohalogen drugs, which may be attributed to the lack of accurate halogen bonding scoring function. Here, we present a study to show that two organohalogen drugs were successfully repositioned as potent B-Raf V600E inhibitors via molecular docking with halogen bonding scoring function, namely D3DOCKxb developed in our lab, and bioassay. After virtual screening by D3DOCKxb against the database CMC (Comprehensive Medicinal Chemistry), 3 organohalogen drugs that were predicted to form strong halogen bonding with B-Raf V600E were purchased and tested with ELISA-based assay. In the end, 2 of them, rafoxanide and closantel, were identified as potent inhibitors with IC50 values of 0.07 μM and 1.90 μM, respectively, which are comparable to that of vemurafenib (IC50: 0.17 μM), a marketed drug targeting B-Raf V600E. Single point mutagenesis experiments confirmed the conformations predicted by D3DOCKxb. And comparison experiment revealed that halogen bonding scoring function is essential for repositioning those drugs with heavy halogen atoms in their molecular structures.

The mean circulation pattern and its mechanism over Caiwei Guyot (1,308-5,600 m) in the Northwest Pacific were studied utilizing 3 years of in situ data. A deep anticyclonic cap was found to enclose the entire guyot from its bottom up to a depth of 728 m, which is composed of a stable but highly asymmetric anticyclonic circulation at the foot and a bottom-trapped anticyclonic circulation over the summit. On the slope, the circulation is complex with a dominant anticyclonic circulation near the bottom and a weak cyclonic circulation at ∼2,200 m. The anticyclonic cap intensity over the summit is significantly modulated by the time-varying impinging flow. An intensified cold ring above the summit edge was observed at Caiwei Guyot, which differs from the cold domes observed over traditional conic seamounts. Further analysis suggests that the impinging flow is primarily responsible for the cap formation, and the M 2 tide-seamount interaction plays a secondary role. The anticyclonic cap may play a role in the local geological distribution. Plain Language Summary Seamounts are ubiquitous topographic features found in the global ocean, and understanding the effect of seamounts on local circulation has garnered significant attention from oceanographers. This study examines a topographically induced deep anticyclonic circulation system over Caiwei Guyot (CG, 1,308-5,600 m), which is a deep flat-topped seamount located in the Northwest Pacific Ocean, utilizing 3 years of in situ data. It was found to have a time-varying anticyclonic circulation at the summit and spatially variable anticyclonic circulation at the foot; however, along the slopes, the circulation is complex with a dominant anticyclonic circulation near the bottom and weak cyclonic circulation at ∼2,200 m. A ring of cold water above the summit edge was observed, which differs from the classical anticyclonic circulation system observed above a conical seamount. The mean impinging flow and the interaction between the semidiurnal tide and topography are responsible for generating the anticyclonic circulation system. Moreover, the anticyclonic circulation system could potentially influence the local geological distribution. To the authors' knowledge, this study provides the first comprehensive evaluation of an observed anticyclonic circulation system covering an entire deep flat-topped seamount.

Conventional Mohr-Coulomb strength criterion only describing the relationship between normal stress and shear stress on the failure surface at the peak strength is used as a criterion to determine whether the beginning of rock's failure. This study extends the concept of the Mohr-Coulomb strength criterion by suggesting that the Mohr-Coulomb yield criterion can express the stress relationship of strain and stress of failure surface under various stress states after plastic deformation occurs. Based on experimental studies, an experiment approach which employs triaxial compression testing data to determine plastic parameters c and ϕ which vary with the internal variable κ was established, and parameter expression used to assess the accuracy of isotropic modeling and some testing results were given. The Mohr-Coulomb yield criterion of isotropic hardening or softening, in which stress-strain curves of whole process is simplified into a four-line model using initial, peak and remnant parameters of rock, is more applicable than the trilinear model by Toshikazu. The results of this study provides theoretical and experimental basis for engineering and geological numerical simulation, thus being of instructive importance.

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Previous studies demonstrated that prolonged exposure to elevated levels of free fatty acids (FFA), especially saturated fatty acids, could lead to pancreatic β-cell apoptosis, which plays an important role in the progression of type 2 diabetes (T2D). Diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the final step of triglyceride (TG) synthesis, has been reported as a novel target for the treatment of multiple metabolic diseases. In this study we evaluated the potential beneficial effects of DGAT1 inhibitors on pancreatic β-cells, and further verified their antidiabetic effects in db/db mice. We showed that DGAT1 inhibitors (4a and LCQ908) at the concentration of 1 μM significantly ameliorated palmitic acid (PA)-induced apoptosis in MIN6 pancreatic β-cells and primary cultured mouse islets; oral administration of a DGAT1 inhibitor (4a) (100 mg/kg) for 4 weeks significantly reduced the apoptosis of pancreatic islets in db/db mice. Meanwhile, 4a administration significantly decreased fasting blood glucose and TG levels, and improved glucose tolerance and insulin tolerance in db/db mice. Furthermore, we revealed that pretreatment with 4a (1 μM) significantly alleviated PA-induced intracellular lipid accumulation, endoplasmic reticulum (ER) stress, and proinflammatory responses in MIN6 cells, which might contribute to the protective effects of DGAT1 inhibitors on pancreatic β-cells. These findings provided a better understanding of the antidiabetic effects of DGAT1 inhibitors.

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The mutation of B-Raf is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-Raf is an ideal drug target. This study focused on developing novel B-Raf inhibitors as drug leads against various cancers with B-Raf mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-Raf were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-Raf inhibitors. A highly potent fragment binding to the hinge area of B-Raf was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-Raf inhibitors. Biological evaluation revealed that compound 1m is a potent B-Raf inhibitor with an IC value of 0.05 μmol/L, which was lower than that of vemurafenib (0.13 μmol/L). Moreover, the selectivity of 1m against B-Raf was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-Raf inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.