Bioinformatics and computational chemistry approaches to explore the mechanism of the anti-depressive effect of ligustilide.

Depression affects people with multiple adverse outcomes, and the side effects of antidepressants are troubling for depression sufferers. Aromatic drugs have been widely used to relieve symptoms of depression with fewer side effects. Ligustilide (LIG) is the main component of volatile oil in angelica sinensis, exhibiting an excellent anti-depressive effect. However, the mechanisms of the anti-depressive effect of LIG remain unclear. Therefore, this study aimed to explore the mechanisms of LIG exerting an anti-depressive effect. We obtained 12,969 depression-related genes and 204 LIG targets by a network pharmacology approach, which were intersected to get 150 LIG anti-depressive targets. Then, we identified core targets by MCODE, including MAPK3, EGF, MAPK14, CCND1, IL6, CASP3, IL2, MYC, TLR4, AKT1, ESR1, TP53, HIF1A, SRC, STAT3, AR, IL1B, and CREBBP. Functional enrichment analysis of core targets showed a significant association with PI3K/AKT and MAPK signaling pathways. Molecular docking showed strong affinities of LIG with AKT1, MAPK14, and ESR1. Finally, we validated the interactions between these proteins and LIG by molecular dynamics (MD) simulations. In conclusion, this study successfully predicted that LIG exerted an anti-depressive effect through multiple targets, including AKT1, MAPK14, and ESR1, and the pathways of PI3K/AKT and MAPK. The study provides a new strategy to explore the molecular mechanisms of LIG in treating depression.

Atomic-scale disproportionation in amorphous silicon monoxide.

Solid silicon monoxide is an amorphous material which has been commercialized for many functional applications. However, the amorphous structure of silicon monoxide is a long-standing question because of the uncommon valence state of silicon in the oxide. It has been deduced that amorphous silicon monoxide undergoes an unusual disproportionation by forming silicon- and silicon-dioxide-like regions. Nevertheless, the direct experimental observation is still missing. Here we report the amorphous structure characterized by angstrom-beam electron diffraction, supplemented by synchrotron X-ray scattering and computer simulations. In addition to the theoretically predicted amorphous silicon and silicon-dioxide clusters, suboxide-type tetrahedral coordinates are detected by angstrom-beam electron diffraction at silicon/silicon-dioxide interfaces, which provides compelling experimental evidence on the atomic-scale disproportionation of amorphous silicon monoxide. Eventually we develop a heterostructure model of the disproportionated silicon monoxide which well explains the distinctive structure and properties of the amorphous material.

Punicalagin Prevents Hypoxic Pulmonary Hypertension via Anti-Oxidant Effects in Rats.

Punicalagin (PG), a major bioactive ingredient in pomegranate juice, has been proven to have anti-oxidative stress properties and to exert protective effects on acute lung injuries induced by lipopolysaccharides. This study aimed to investigate the effects of PG treatment on hypoxic pulmonary hypertension (HPH) and the underlying mechanisms responsible for the effects. Rats were exposed to 10% oxygen for 2 wk (8 h/day) to induce the HPH model. PG (5, 15, 45[Formula: see text]mg/kg) was orally administered 10[Formula: see text]min before hypoxia each day. PG treatments at the doses of 15 and 45[Formula: see text]mg/kg/d decreased the mean pulmonary arterial pressure (mPAP) and alleviated right ventricular hypertrophy and vascular remodeling in HPH rats. Meanwhile, PG treatment attenuated the hypoxia-induced endothelial dysfunction of pulmonary artery rings. The beneficial effects of PG treatment were associated with improved nitric oxide (NO)-cGMP signaling and reduced oxidative stress, as evidenced by decreased superoxide generation, gp91[Formula: see text] expression and nitrotyrosine content in the pulmonary arteries. Furthermore, tempol's scavenging of oxidative stress also increased NO production and attenuated endothelial dysfunction and pulmonary hypertension in HPH rats. Combining tempol and PG did not exert additional beneficial effects compared to tempol alone. Our study indicated for the first time that PG treatment can protect against hypoxia-induced endothelial dysfunction and pulmonary hypertension in rats, which may be induced via its anti-oxidant actions.

NBM-T-BMX-OS01, an Osthole Derivative, Sensitizes Human Lung Cancer A549 Cells to Cisplatin through AMPK-Dependent Inhibition of ERK and Akt Pathway.

BACKGROUND: Drug combination therapies using cisplatin and natural products are common practice in the treatment of human lung cancer. Osthole is a natural compound extracted from a number of medicinal plants and has been shown to exert strong anticancer activities with low toxicity. METHODS: In the present study, NBM-T-BMX-OS01 (BMX), derived from the semi-synthesis of osthole, was evaluated in cisplatin treated A549 cells to investigate its effect on cisplatin resistance in human lung cancer. The anticancer effect of BMX were measured by cell viablity' colony formation' TUNEL staining' flow cytometry and cell cycle assay. The fluorescence staining was performed to detect intracellular and mitochondrial reactive oxygen species (ROS) generation. Western blot analysis, antagonists pretreatment and small interfering RNA (siRNA) transfection were used to determine the potential mechanism. RESULTS: It was found that, in comparison with single cisplatin treatment, the combination of BMX and cisplatin resulted in greater efficacy in inhibition of proliferation and colony formation, apoptosis induction and cell cycle arrest. The results of fluorescence staining showed that the combination effect of BMX and cisplatin was due to oxidative stress induced by mitochondrial ROS generation. In addition, BMX significantly attenuated the phosphorylation of ERK and Akt, two important pro-survival kinases. In contrast, BMX inhibited the activation of AMPK, and knockdown of AMPK using specific siRNA partially reversed BMX-induced inhibition of ERK and Akt, as well as its synthetic effects on cisplatin induced anticancer activity in A549 cells. CONCLUSION: Taken together, this study provides that BMX might modulate cisplatin resistance through AMPK-ERK and AMPK-Akt pathways. These results also support the role of BMX as a potential drug candidate for use in combination with cisplatin in the treatment of human lung cancer.

Stabilization of elusive silicon oxides.

Molecular SiO2 and other simple silicon oxides have remained elusive despite the indispensable use of silicon dioxide materials in advanced electronic devices. Owing to the great reactivity of silicon-oxygen double bonds, as well as the low oxidation state of silicon atoms, the chemistry of simple silicon oxides is essentially unknown. We now report that the soluble disilicon compound, L:Si=Si:L (where L: = :C{N(2,6-(i)Pr2C6H3)CH}2), can be directly oxidized by N2O and O2 to give the carbene-stabilized Si2O3 and Si2O4 moieties, respectively. The nature of the silicon oxide units in these compounds is probed by spectroscopic methods, complementary computations and single-crystal X-ray diffraction.

Broadly neutralizing DNA vaccine with specific mutation alters the antigenicity and sugar-binding activities of influenza hemagglutinin.

The rapid genetic drift of influenza virus hemagglutinin is an obstacle to vaccine efficacy. Previously, we found that the consensus hemagglutinin DNA vaccine (pCHA5) can only elicit moderate neutralization activities toward the H5N1 clade 2.1 and clade 2.3 viruses. Two approaches were thus taken to improve the protection broadness of CHA5. The first one was to include certain surface amino acids that are characteristic of clade 2.3 viruses to improve the protection profiles. When we immunized mice with CHA5 harboring individual mutations, the antibodies elicited by CHA5 containing P157S elicited higher neutralizing activity against the clade 2.3 viruses. Likewise, the viruses pseudotyped with hemagglutinin containing 157S became more susceptible to neutralization. The second approach was to update the consensus sequence with more recent H5N1 strains, generating a second-generation DNA vaccine pCHA5II. We showed that pCHA5II was able to elicit higher cross-neutralization activities against all H5N1 viruses. Comparison of the neutralization profiles of CHA5 and CHA5II, and the animal challenge studies, revealed that CHA5II induced the broadest protection profile. We concluded that CHA5II combined with electroporation delivery is a promising strategy to induce antibodies with broad cross-reactivities against divergent H5N1 influenza viruses.

[Application of amorphous silicon electronic portal imaging device (a-Si EPID) to dosimetry quality assurance of radiation therapy].

BACKGROUND & OBJECTIVE: Due to its good dosimetric properties, amorphous silicon electronic portal imaging device (a-Si EPID), as a rapid two-dimensional dosimetric measurement device, presents an attractive prospect in routine quality assurance (QA) test, dosimetric verification of intensity-modulated radiotherapy treatment (IMRT) and in vivo dose monitoring. This study was to explore the application of a-Si EPID as a detector for dosimetric QA of linear accelerator radiotherapy, and setup the calibration module. METHODS: The imaging calibration procedure of conventional a-Si EPID was modified for dosimetric measurement by acquiring the traditional "flush field" from integrated subfields to correct the dosimetric responding difference in pixel sensitivity. The energy dependence of the a-Si EPID detectors was analyzed through off-axis dose response curves. Calibrated dose profile obtained with a-Si EPID was compared with the measuring results of ion chamber in a 3-D water phantom. RESULTS: The calibrated dose profiles measured with a-Si EPID showed a deviation within 2% in high dose regions, but dropped much steeply in the penumbra region, as compared with that scanned using ion chamber in water. CONCLUSION: With the modeling management set up in this research, a-Si EPID can be applied for dosimetric QA of linear accelerator in radiotherapy.

[The inhibition of 20(R)-ginsenoside Rg3 on the expressions of angiogenesis factors proteins in human lung adenocarcinoma cell line A549 and HUVEC304 cell].

OBJECTIVE: To study the effect of 20( R)-ginsenoside Rg3 on the expressions of angiogenesis factors proteins (VEGF,bFGF, MMP-2) in human lung adenocarcinoma cell line A549 and HUVEC304 cell. METHOD: The cell lines of A549 and HUVEC304 were cultured with 20(R)- Rg3. The gray scale and positive rate of VEGF, bFGF, MMP-2 were detected by immunohistochemistry. The differential expressions of genes were studied by DNA microarray. RESULT: The positive rate of VEGF protein in A549 cell decreased significantly as compared with the control group ( P = 0.03). The gray scales of VEGF, Flt, KDT proteins in both A549 cell lines and HUVEC 304 cell lines decreased ( P = 0.05). Gray scale of MMP-2 also decreased in A549 cell lines. The result of differential expressions of genes of A549 cell lines showed that 14 genes were down-regulated and 10 genes were up-regulated. CONCLUSION: The Chinese materia medica of 20( R)-Rg3 can inhibit the expression of angiogenesis factors proteins via several target genes in both tumour cell and vascular endothelial cell.

[The effect of 20(R)-ginsenoside Rg3 on the differential expression of cell signaling genes and other related genes in human lung adenocarcinoma cell line A549].

OBJECTIVE: To study the effect of 20(R)-ginsenoside Rg3 [20(R)-Rg3] on the differential expression of cell signaling genes and other related genes in human lung adenocarcinoma cell line A549. METHODS: The cell line A549 was cultured with 20(R)-Rg3 (10(-6) mol/L) for 72 h, RNA was extracted, and the differential expression of cell signaling genes and other related genes were detected with DNA microarray. RESULTS: A total of 3 490 genes were detected, and the expression of 24 genes were changed after the addition of 20(R)-Rg3. Two cell signaling genes & transducin genes were up-regulated. Two cystoskeleton & locomotion genes were up-regulated. Three proto-oncogene & anti-oncogene genes were down-regulated. Two of the translation & synthetical genes were down-regulated, and 1 of them was up-regulated. One DNA recombination gene and one metabolism gene were down-regulated. CONCLUSION: 20(R)-Rg3 showed significant effect on the differential expression of cell signaling genes and other related genes in human lung cell line A549.