Design, synthesis, and biological evaluation of naphthoylamide derivatives as inhibitors of STAT3 phosphorylation.

The phosphorylation of STAT3 plays a critical physiological role in the proliferation of rectal cancer. Hence, inhibiting STAT3 phosphorylation is an effective anticancer approach. In this work, we designed a novel 5-R'-1-naphthylmethylamide scaffold as a small molecule inhibitor of STAT3 phosphorylation. The results showed that 3D and 4D have exceptional inhibitory ability against three different colorectal cancer (CRC) cell lines, and can induce apoptosis of CRC cells by inhibiting STAT3 phosphorylation, while having no killing effect on normal human cells. 3D and 4D can inhibit STAT3 phosphorylation in a time- and concentration-dependent manner, and also inhibit the nuclear translocation of interleukin (IL)-6-induced STAT3. In the in vivo tumor model research, 4D significantly reduced the tumor volume of mice and had no drug toxicity on other organ tissues. Furthermore, molecular docking studies revealed that 3D and 4D had greater binding free energy when interacting with the STAT3 SH2 structural domain, and could establish H-π interaction modes. Dynamic simulation studies indicated that both compounds were able to bind tightly to STAT3.

Synthesis, spectroscopic analysis, DFT, docking, MD and antioxidant activity of tetrahydrocurcumin.

In recent years, numerous researchers have made local chemical modifications to the structure of curcumin while its basic structure remains unchanged, thus, producing curcumin derivatives. In this article, tetrahydrocurcumin was obtained by hydrogenation of curcumin, DFT calculation and characterization at the theoretical level of B3LYP/6 -311++G(d,p) were carried out. The observed IR and Raman spectra are in good agreement with the theoretical spectra. The FMO and ESP of tetrahydrocurcumin are predicted. The interaction in the system is shown graphically and analyzed by IGMH. Compared with curcumin, tetrahydrocurcumin lacks the unsaturated C = C bond, which makes it more stable and more bioavailable. Molecular docking with antioxidant targets elucidated the ligand-protein interaction and molecular dynamics simulation showed the antioxidant activity of tetrahydrocurcumin. The antioxidant activity of tetrahydrocurcumin was proved by DPPH• and •OH radical scavenging experiments. In essence, these derivatives exhibit enhanced physiological activity in certain aspects compared to the original curcumin. Moreover, the computational pharmacology techniques lay a theoretical groundwork for the development and modification of high-efficiency, low-toxicity drugs that interface with various targets of curcumin in the future.Communicated by Ramaswamy H. Sarma.

An electrochemical immunosensor for the detection of Glypican-3 based on enzymatic ferrocene-tyramine deposition reaction.

An ultrasensitive electrochemical immunosensor based on signal amplification of the deposition of the electroactive ferrocene-tyramine (Fc-Tyr) molecule, catalyzed by horseradish peroxidase (HRP), was constructed for the detection of the liver cancer marker Glypican-3 (GPC3). Functional electroactive molecule Fc-Tyr is reported to exhibit both the enzymatic cascade catalytic activity of tyramine signal amplification (TSA) and the excellent redox properties of ferrocene. In terms of design, the low matrix effects inherent in using the magnetic bead platforms, a quasi-homogeneous system, allowed capturing the target protein GPC3 without sample pretreatment, and loading HRP to trigger the TSA, which induced a large amount of Fc-Tyr deposited on the electrode surface layer by layer as a signal probe for the detection of GPC3. The concept of Fc-Tyr as an electroactive label was validated, GPC3 biosensor exhibited high selectivity and sensitivity to GPC3 in the range of 0.1 ng mL-1-1 µg mL-1. Finally, the sensor was used simultaneously with ELISA to assess GPC3 levels in the serum of clinical liver cancer patients, and the results showed consistency, with a recovery of 98.33-105.35% and a relative standard deviation (RSD) of 4.38-8.18%, providing a theoretical basis for achieving portable, rapid and point of care testing (POCT) of tumor markers.

Design, Synthesis, and Molecular Docking Study of Novel 3-Cyanopyridine Derivatives for the Anti-Cancer Drug Target Survivin Protein.

Survivin is an important member of the antiapoptotic protein family and controls the cell's life cycle. Overexpression of survivin in tumor cells leads to inhibition of apoptosis, thus contributing to cancer cell proliferation. The largest binding pocket in the survivin dimer was located in the BIR domain. The key to the efficacy of 3-cyanopyridines was their surface interaction with the survivin amino acid Ile74. METHODS: Through the optimization of the 3-cyanopyridine, 29 new compounds with a 3- Cyanopyridine structure were designed, synthesized, and characterized by NMR, IR, and mass spectrometry. The antitumor activity of the compounds in vitro was detected by the MTT method. RESULTS: In vitro anti-tumor experiments showed that some compounds exhibited good anti-cancer effects. The IC50 values of the compound 2-amino-6-(2,4-difluorophenyl)-4-(4-hydroxyphenyl) nicotinonitrile (10n) against human liver cancer (Huh7), human glioma (U251), and human melanoma (A375) cells were 5.9, 6.0 and 7.2 µM, respectively. The IC50 values of the compound 6-(2,4-difluorophenyl)- 4-(4-hydroxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (9o) against Huh7, U251 and A375 cells were 2.4, 17.5 and 7.2 µM, respectively, which were better than those of 10- hydroxycamptothecin and 5-fluorouracil. Analysis of the results of molecular dynamics simulation established that the BIR domain is the optimal binding site on the survivin protein, and the fingerprints of the eight most active compounds and the molecular docking to the survivin protein are analyzed. CONCLUSION: 3-Cyanopyridine is an excellent backbone for antitumor lead compounds, 10n and 9o, as derivatives of 3-Cyanopyridine are excellent survivin protein-targeting inhibitors worthy of further study. The key factor in inhibiting survivin protein through the action of amino acid Ile74.

UHPLC-QTOF-MS based metabolite profiling analysis and the correlation with biological properties of wild and artificial agarwood.

To date, the agarwood has been over exploited worldwide in the wild due to high demand. As an alternative, the agarwood obtained through artificial methods has greatly resolved the shortage of agarwood supply in the global market. However, little information about the difference in chemical constituents and bioactivities of the wild agarwood and the artificial agarwood is available. This study aims to systematically compare the chemical composition and the bioactivities between wild and artificial agarwood on the basis of the integrated method of ultra-high-performance liquid chromatography coupled with time-of-flight mass spectrometry (UHPLC-TOF-MS) and multivariate statistical analysis. The invitro antioxidant activity was determined using the 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH) radical scavenging activity assays. The cytotoxic activity of agarwood from different origin against three human cancer cell lines (i.e., A375, U251, and Skov3) were compared using the MTT assay. Fifty metabolites from UPLC-QTOF-MS spectra were identified and included in the multivariate analysis. Among these metabolites, 2-(2-phenylethyl) chromone derivatives (PECs), bi-2-(2-phenylethyl) chromone derivatives (BPECs) and sesquiterpene-2-(2-phenylethyl) chromone conjugates (SPECs) were found to be the major metabolites and acted as discriminant compounds in agarwood from different origin. The antioxidant activity study showed that the wild agarwood displayed significant antioxidant capacity compared with the artificial agarwood. Particularly, the content of secondary metabolites of SPEC analogs shown a positive effect on the radical scavenging activities, whereas the PECs were negatively correlated. Interestingly, no significant difference was observed between wild and artificial agarwood in terms of cytotoxic activity against three human cancer cell lines (i.e., A375, U251, and Skov3). To the best of our knowledge, this research is the first to study the metabolite profiles and bioactivities of the wild and the artificial agarwood in a holistic approach, and is expected to provide a rational basis for the quality assessment of artificial agarwood as a substitute for wild agarwood.

Label-free electrochemical lead (II) aptasensor using thionine as the signaling molecule and graphene as signal-enhancing platform.

A label-free and highly sensitive electrochemical aptasensor for Pb(2+) was constructed using thionine (TH) as the signaling molecule and graphene (GR) as the signal-enhancing platform. The electrochemical sensing interface was fabricated by stepwise assembly of GR and TH on the lead (II) specific aptamer (LSA) modified electrode. Upon interaction with Pb(2+), the aptamer probe on the sensor underwent conformational switch from a single-stranded DNA form to the G-quadruplex structure, causing the GR with assembled TH released from the electrode surface into solution. As a result, the electrochemical signal of TH on the aptasensor was substantially reduced. Under the optimal experimental conditions, the attenuation of peak currents presented a good linear relationship with the logarithm of Pb(2+) concentrations over the range from 1.6×10(-13) to 1.6×10(-10)M. The detection limit was estimated to be 3.2×10(-14)M. The aptasensor also exhibited good regenerability, excellent selectivity, and acceptable reproducibility, indicating promising application in environment monitoring of lead.

Effective and mild method for converting 3ß-hydroxysteroids to 3-keto steroids via DDQ/TEMPO.

A mild and efficient oxidation of 3ß-hydroxysteroids to the corresponding 3-keto steroids can be carried out at room temperature, using DDQ in the presence of catalytic TEMPO. Oxidation of saturated 3ß-hydroxysteroids gave the corresponding ketones in excellent yield. The 5-unsaturated 3ß-hydroxysteroids are oxidized selectively to 4-en-3-one or 4,6-diene-3-one derivatives according to the amount of DDQ in reaction. This is a good method for the synthesis of 4,6-diene-3-one from the corresponding 3ß-hydroxy-5-ene steroids. Meanwhile, configurations of the oxidation compounds 2a, 2b, 3b, 2c, 2f and 2g were identified by X-ray diffraction. A possible mechanism is presented and discussed.

Observation and measurements of long thoracic nerve: a cadaver study and clinical consideration.

Long thoracic nerve (LTN) is an important nerve originating from cervical nerve roots. It varies a lot in origins and branches, which lead to several clinical problems, such as diagnosis, prophylaxis and treatment of LTN injury. LTN was dissected in 38 cadavers in the present study. Origin, level of union, branches, sites where nerve entered the muscle, length of nerve trunk and branches as well as transverse diameter were documented. Different derivations of LTN were observed, and C4-7, C5-7, C5 and C7, C5-7, C5-8, C6 and C7, and branch from C6 was the most important components of LTN. After evolution, LTN trunk was composed by superior and inferior trunks at scalenus muscle or the three superior slips level. Branches of LTN traveled on the surface of the six superior slips of anterior serratus muscle and then penetrated through the inferior slips without correlation between different branches. Mean length of trunk of LTN is 111.73 (30.08) mm, axis of cross section was 2.27x0.96 mm at the union level and 1.91 x 0.68 mm at the end branch. Each slip was innervated by 1-4 branches of LTN. The observation and measurement data described in our study presented some variations and could provide clinicians with important information on diagnosis, prophylaxis and treatment of LTN injury and pursuing more suitable muscle flaps for reconstruction operation.

[Effect of Salvia miltiorrhiza on neuropeptide Y1-36 and calcitonin gene-related peptide in neonatal rats with hypoxia-ischemic brain injury].

OBJECTIVE: To observe the effects of Salvia miltiorrhiza (SM) on levels of neuropeptide Y1-36 and calcitonin gene-related peptide immune reactive substances (ir-NPY, ir-CGRP) in blood plasma and pons-oblongata after hypoxia-ischemic brain injury (HIBI) in neonatal rats. METHODS: Seven-day old rats were randomized into HIBI group (A), HIBI + SM group (B) and sham operation group(C). And each group was subdivided into 4 subgroups according to the different time after operation. 0.5 ml SM was injected intraperitoneally immediately and every 12 hrs afterwards. Changes of ir-NPY and ir-CGRP levels in plasma and pons-oblongata were observed immediately and 12, 24 and 48 hrs after HIBI by radioimmunoassay. RESULTS: Plasma levels of ir-NPY and ir-CGRP in different times after HIBI were all significantly raised but those in pons-oblongata were either raised or lowered to a certain degree. Part of the elevated ir-NPY could be reversed by SM injection. CONCLUSION: Central and peripheral neuropeptide Y1-36 and calcitonin gene-related peptide take part in the pathophysiological process of HIBI, SM could partially reverse the abnormal post-HIBI elevation of ir-NPY, which may be one of the pathways of SM in promoting recovery of damaged brain function.