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Dipeptidyl peptidase-4 (DPP4) plays a crucial role in regulating the bioactivity of glucagon-like peptide-1 (GLP-1) that enhances insulin secretion and pancreatic β-cell proliferation, making it a therapeutic target for type 2 diabetes. Although the crystal structure of DPP4 has been determined, its structure-function mechanism is largely unknown. Here, we examined the biochemical properties of sporadic human DPP4 mutations distal from its catalytic site, among which V486M ablates DPP4 dimerization and causes loss of enzymatic activity. Unbiased molecular dynamics simulations revealed that the distal V486M mutation induces a local conformational collapse in a β-propeller loop (residues 234–260, defined as the flap) and disrupts the dimerization of DPP4. The “open/closed” conformational transitions of the flap whereby capping the active site, are involved in the enzymatic activity of DPP4. Further site-directed mutagenesis guided by theoretical predictions verified the importance of the conformational dynamics of the flap for the enzymatic activity of DPP4. Therefore, the current studies that combined theoretical modeling and experimental identification, provide important insights into the biological function of DPP4 and allow for the evaluation of directed DPP4 genetic mutations before initiating clinical applications and drug development.

The chemical constituents of the flower buds of Buddleja officinalis were investigated in this study. Eight compounds were isolated from the water extract of B. officinalis by column chromatography, and their structures were elucidated on the basis of physicochemical properties and spectral data. These compounds were identified as(Z)-hex-3-en-1-ol-1-O-β-D-glucopyranosyl-(1→2)-[β-D-xylcopyranosyl-(1→6)]-β-D-glucopyranoside(1), ebracteatoside B(2), jasmonic acid-11-O-β-D-glucopyranoside(3), 6-hydroxyluteolin-7-O-β-D-glucopyranoside(4), luteolin-7-O-galacturonide(5), vicenin-2(6), decaffeoylverbascoside(7), and 6-O-(E)-feruloyl-D-glucopyranoside(8). Compound 1 is a new 3-hexenol glycoside. Compounds 2, 3, and 6 were isolated from Buddleja genus for the first time, and compounds 4 and 5 were isolated from this plant for the first time.

Background: When liver metastasis in patients with breast cancer is diagnosed, treatment is generally palliative and usually consists of systemic therapies only. This study aimed to evaluate the efficacy and safety of hepatic arterial infusion (HAI) combined with systemic chemotherapy in patients with breast carcinoma liver metastases (BCLM). Methods: From January 2012 to December 2019, HAI catheter systems were implanted under the guide of digital subtract angiography (DSA) in 19 patients with BCLM. All patients received systemic chemotherapy and HAI gemcitabine plus floxuridine (FUDR). Methods: The overall response rate (ORR) of intrahepatic lesions was 73.7%, including 2 patients (10.5%) with complete remission (CR) and 12 patients (63.2%) with partial remission (PR). Additionally, we found that young patients (age

Cutaneous squamous cell carcinoma (CSCC) is one of the most common types of skin cancer in humans worldwide. The identification and characterization of cancer-associated transmembrane proteins are important for understanding the molecular biology of CSCC. The aim of the present study was to evaluate the expression pattern of transmembrane protein 40 (TMEM40) in CSCC and its clinical significance. The underlying mechanisms were also examined. Reverse transcription-quantitative PCR, western blot and immunohistochemistry analysis were used to determine the relative expression of TMEM40 in CSCC cell lines and clinical tissue samples. The effect of TMEM40 gene silencing on cell proliferation was also evaluated using Cell Counting Kit-8 assays. Wound healing assays, flow cytometry and Transwell assays were used to explore the migration, cell cycle distribution/apoptosis and invasion of CSCC cells following TMEM40 silencing, respectively. In the present study, increased TMEM40 expression was observed in CSCC tissue samples, compared with normal skin, and TMEM40 expression was associated with large tumor size in patients with CSCC. In vitro functional assays indicated that TMEM40 was involved in the regulation of A431 and SCL1 cell growth through its effects on the cell cycle and apoptosis. Silencing TMEM40 in A431 and SCL1 cells resulted in cell cycle arrest at the G0/G1 phase and promoted apoptosis. In addition, migration and invasion were significantly inhibited following silencing of TMEM40 expression in CSCC cells. Taken together, the results of the present study indicated that reduced TMEM40 expression could inhibit CSCC development and that TMEM40 may represent a therapeutic target in CSCC.

Fluorescent imaging of β-amyloid (Aβ) is one of the most promising methods for Alzheimer's disease diagnosis. Several fluorescent probes have been reported to detect Aβ both in vitro and in vivo. However, highly sensitive and highly selective probes with low background signals are still greatly needed. Herein, we rationally designed and synthesized a PIET quenched near-infrared probe QAD-1 to detect Aβ. This probe contains BODIPY as fluorophore and tetrahydroquinoxaline as the quenching group. QAD-1 exhibited significant fluorescent switch-on after binding to soluble and insoluble Aβ species, and the probe had the benefit of low background signal to stain Aβ plaques without the need of wash-out procedures in vitro, which was specially found by the fluorescence off-on probe. QAD-1 could identify the overproduced Aβ in transgenic (APPSWE/PSEN 1dE9) AD mice as early as 6 months old in vivo, which indicated that QAD-1 may be a potential probe for monitoring Aβ species at an early stage of AD.

Seven new acetophenone derivatives, three couples of enantiomers (±)-cynwilforones D − F (1 − 3) together with cynwilforone G (4), were isolated form the root bark of Cynanchum wilfordii (Maxim.) Hemsl. Their structures were deduced based on spectroscopic analysis and X-ray crystallography. Each racemate was separated into individual enantiomers, and electronic circular dichroism (ECD) calculations were used to assign their absolute configurations. All compounds exhibited inhibitory effect of Aβ oligomerization in different degrees. Among them, (+)-3 and (−)-3 showed neuroprotective effects on Aβ oligomers-treated SH-SY5Y cells.

Two novel nitrogenous diterpenoids, sarinfacetamides A (1) and B (2), featuring an uncommon tricyclo[6.3.1.0

(M)-Bicelaphanol A (1) and (P)-bicelaphanol A (2), two unprecedented dimeric trinorditerpenes existing as atropisomers, together with their monomer celaphanol A (3), were isolated from the root bark of Celastrus orbiculatus. The structures and absolute configurations of 1 and 2 were determined by spectroscopic and single-crystal X-ray diffraction analyses. Compound 1 exhibited a significant in vitro neuroprotective effect against a hydrogen peroxide-induced cell viability decrease in PC12 cells at 1 μM, while compounds 2 and 3 showed such effects at 10 μM.

The mutation of B-RafV600E 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-RafV600E is an ideal drug target. This study focused on developing novel B-RafV600E inhibitors as drug leads against various cancers with B-RafV600E 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-RafV600E 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-RafV600E inhibitors. A highly potent fragment binding to the hinge area of B-RafV600E 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-RafV600E inhibitors. Biological evaluation revealed that compound 1m is a potent B-RafV600E inhibitor with an IC50 value of 0.05 μmol/L, which was lower than that of vemurafenib (0.13 μmol/L). Moreover, the selectivity of 1m against B-RafWT 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-RafV600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.

Two new sulfated sesquiterpenoids, megastigman-7-ene-3, 5, 6, 9-tetrol-3-O-β-D-6'-sulfonated-glucopyranoside (1) and 3-O-β-D-6'-sulfonated-glucopyranosyl-6-(3-oxo-2-butenylidenyl)-1, 1, 5-trimethylcyclohexan-5-ol (2), along with one known sesquitepenoid compound icariside B1 (3) were isolated from the whole herb of Petasites tricholobus Franch. Their structures were identified by their chemical and spectroscopic characters. All obtained compounds were tested for their cytotoxicity against four cancer cell lines.

(2'R)-2',3'-Dihydro-2'-(1-hydroxy-1-methylethyl)-2,6'-bibenzofuran-6,4'-diol (DHMB) is a natural compound extracted from Morus notabilis. It was found that DHMB acts as a competitive inhibitor against mushroom tyrosinase with a Ki value of 14.77 μM. Docking results further indicated that it could form strong interactions with one copper ion with a distance of 2.7 Å, suggesting the mechanism of inhibition might be due to chelating copper ions in the active site. Furthermore, melanin production in B16-F10 murine melanoma cells was significantly inhibited by DHMB in a concentration-dependent manner without cytotoxicity. The results of western blotting also showed that DHMB decreased 3-isobuty-1-methxlzanthine-induced mature tyrosinase expression. Taken together, these findings indicated that DHMB may be a new promising pigmentation-altering agent for agriculture, cosmetic, and therapeutic applications.

The powerful anti-malarial drug, Qinghaosu (Artemisinin), has been studied using ab initio methods. The DFT B3LYP method with the 6-31G ∗ basis set gives an excellent geometry compared to experiments, especially for the OO bond length and the 1,2,4-Trioxane ring subsystem. The R (OO) bond length predicted at this level is 1.460 A, only 0.018 A shorter than the experimental measurement. The vibrational analysis shows that the OO stretching mode is combined with the OC vibration mode, having the character of an OOC entity. The OO vibrational band at 722 cm −1 suggested in the experimental studies has been assigned as 1,2,4-trioxane ring breathing.

To study the chemical constituents of Lysimachia patungensis Hand.-Mazz., silica gel column chromatography, reverse phase ODS column chromatography, MCI and Sephadex LH-20, were used to separate the 95% EtOH extract of the whole plant of Lysimachia patungensis Hand.-Mazz.. The structures of the isolated compounds have been established on the basis of chemical and NMR spectroscopic evidence as well as ESI-MS in some cases. Twelve phenolic compounds were obtained and identified as quercetin-3, 3'-di- O-alpha-L-rhamnoside (1), myricetrin (2), quercitrin (3), rutin (4), 2-hydroxynaringenin-4'-O-glucopyranoside (5), naringenin 7-O-glucopyranoside (6), liquiritin apioside (7), licochalcone B (8), tetrahydroxymethoxy chalcone (9), methyl-p-coumarate (10), 2, 4, 6-trihydroxy acetophenone-2-O-glucopyranoside (11) and vaccihein A (12). Among them, compound 1 is a new compound, and compounds 5, 11 and 12 are isolated from the genus Lysimachia L. for the first time, and the others are isolated from the plant for the first time.

BRAF is one of the most important pro-oncogenes, which is mutated in approximately 8% of human tumors. The most common BRAF mutation is a valine-to-glutamate transition (V600E) that is expressed primarily in melanoma, colorectal cancer and thyroid carcinoma. MEK/ERK is constitutively activated in the cells expressing BRAFV600E, leading to tumor development, invasion, and metastasis. Therefore, BRAFV600E is a therapeutic target for melanoma and some other BRAFV600E tumors. Vemurafenib, a BRAFV600E inhibitor, which was approved by FDA for the treatment of late-stage melanoma in 2011, produces improved rates of overall and progression-free survival in patients with the BRAFV600E mutation, making a dramatic breakthrough in melanoma treatment. Vemurafenib is also an individual target drug based on genetic diagnosis. However, its therapeutic success is limited by the emergence of drug resistance. Therefore, it is important to explore the mechanisms underlying the resistance for developing new inhibitor drugs and for preventing or delaying the resistance evolution to BRAF inhibitor drugs. In this review, we described the role of BRAFV600E as an anti-tumor drug target and the development of BRAF inhibitors. We also discussed the mechanisms leading to resistance of BRAFV600E inhibitors. Furthermore, therapeutic strategies that might be employed to overcome acquired resistance were proposed.

Flavonoids are a large class of compounds widely distributed in nature. Many pharmacological activities of flavonoids have been reported such as anti-cancer, antioxidant, anti-inflammatory, hepatoprotective, antithrombotic, vasodilator, antiviral, antibacterial, antiallergic, and so on. In recent years, domestic and foreign research groups choose natural flavonoids and optimize their chemical structures in order to develop a number of new derivatives with stronger pharmacological activities. As part of the mechanisms are not clear, we need to strengthen in-depth research in the SAR (structure-activity relationship) study for targeted and efficient structure optimization. This paper systematically summarize current researches in the SAR studies of flavonoids and their derivatives, which can serve as a reference for synthesizing new flavonoid derivatives.

To study the antiangiogenetic and tumor inhibitory effects of endostatin (Es) by intratumoral versus intravenous administration combined with adriamycin (Adm) for treatment of transplanted tumor in mice.Forty mice were subjected to subcutaneous implantation of H22 cells and randomly divided into 4 groups by the body weight when the tumor diameter reached 1 cm, namely the control group (with intratumoral and intravenous injection of normal saline), Es intratumoral group (with intratumoral injection Es and intraperitoneal Adm injection), Es vein group (with intravenous Es injection and intraperitoneal Adm injection), and Adm group (with intratumoral saline injection and intraperitoneal Adm injection). The tumor volumes and tumor inhibition rates were calculated, and the expression of vascular endothelial growth factor (VEGF) and the microvessel density (MVD) of the tumors were examined, with the survival time of the mice also observed.The tumor volume was smaller in Es intratumoral group than in the other groups (P0.05). The expression of VEGF and M VD in Es intratumoral group was significantly decreased as compared with that in the other groups (P0.05). The survival time was significantly longer in Es intratumoral group and Es vein group than in the other groups (P0.05), but showed no significant difference between Es intratumoral group and Es vein group (P0.05).In combination with Adm regimen, Es given intratumoral injection produces better effect than intravenous Es injection against angiogenesis and tumor growth, no significant difference can be found in the survival time between them.

To study the effect of of percutaneous para-toluenesulfonamide (PTS) injection on transplanted hepatocarcinoma in nude mice.Sixty nude mice with subcutaneous transplanted hepatocarcinoma were randomized into 6 groups, namely PTS, chemotherapy, radiotherapy, PTS+chemotherapy, PTS+radiotherapy and control groups. PTS were injected into the tumor in the nude mouse models as indicated, and the tumor growth rate and survival time of the mice were recorded.All the treatments resulted in effective arrest of the tumor growth, but the effects of PTS+chemotherapy and PTS+radiotherapy were more obvious. No significant difference in the survival time of the mice were noted between the groups.PTS+chemotherapy and PTS+radiotherapy are safe and reliable, and produces better effects than either radiotherapy or chemotherapy alone.

Berberine is a isoquinoline alkaloid extracted from Chinese herbs such as Coptidis rhizome. In the past decade, there are more than 2 000 published papers studying the clinical application, pharmacodynamic mechanism and structure-activity relationship (SAR) of berberine and its derivatives, for treating tumor, diabetes, cardiavascellum disease, hyperlipemia, inflammation, bacterium and virus infection, cerebral ischemia trauma, mental disease, Alzheimer disease, osteoporosis, and so on. These results demonstrate that berberine has wide physiologic function and has great potential for structural modification as new drug lead. However, there is no systematic review about the study of berberine and its derivatives up to now. This paper is a systematic review of the research advances of berberine and its derevatives in clinical application, pharmacodynamic mechanisms, molecular pharmacology, absorption and metabolism, and SAR studies. The current review would provide some useful information for further study on structural modification of berberine for discovering new drug leads based on its pharmacodynamic mechanisms.

To study the association of single nucleotide polymorphism at interleukin-10 gene 1082 locus with Helicobacter pylori (Hp) infection and the risk of gastric cancer in high prevalent region (Shaanxi Province)aand low prevalence region (Guangdong Province) in China.The genomic DNA was extracted from the peripheral blood of 104 healthy individuals, 104 gastric cancer patients from Guangdong Province, and from 102 healthy volunteers and 102 gastric cancer patients in Shaanxi Province, China. The single nucleotide polymorphism at IL-10 gene 1082 locus was analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The serum levels of anit-Hp IgG was measured by enzyme-linked immunosorbent assay.The frequencies of IL-10-1082 A/A, A/G and G/G genotypes in the 412 subjects were 86.7%, 10.7% and 2.4%, respectively. In the low prevalence region, the number of carriers of IL-10-1082 G* was much greater in the cancer patients than in the healthy controls (14.4% vs 7.7%, Chi2=4.02, P0.05, OR=1.01, 95% CI=1.08-3.10). The presence of IL-10-1082 G* was associated with significantly increased risk of gastric cancer following Hp infection (Chi(2)=5.36, P0.05, OR=6.0, 95% CI=1.23-17.52). In the high prevalence region, the frequency of IL-10-1082 G* was slightly higher among the cancer patients than in the healthy controls, but this difference was not statistically significant (12.7% vs 16.6%, P0.05).The G* genotype of IL-10 gene 1082 locus may be associated with increased risk of gastric cancer in China.

To investigate the dose-effect relationship of para-toluenesulfonamide (PTS) for treatment of hepatocellular carcinoma in rats.Forty-two SD rats bearing subcutaneous transplanted hepatocellular carcinoma were randomly divided into 6 groups (n=7), in which 0.02, 0.04, 0.06, 0.08, and 0.10 ml PTS and 0.10 ml normal saline were injected into the tumor, respectively. All of the rats were executed 24 h after the injection to observe the pathological changes in the tumor.In rats with saline injection, the tumor tissues exhibited no obvious changes and the tumor cells retained the active proliferation. PTS, in contrast, caused coagulation necrosis of the tumor tissue, and the necrotic area expanded with the increase of the injected doses. The necrotic volume of the tumor was in roughly linear correlation with the dose of PTS injected, with the linear regression equation of V (cm(3))=-0.018+2.595Y (where V represents tumor necrosis volume, and Y the injected dose of PTS).The dose-effect relationship of PTS is roughly linear, and the PTS dose for injection can be estimated according to the diameter of the tumor.

New cyclopentenones, bromomyrothenone B (1) and botrytinone (2), and the known cyclonerodiol (3) were isolated from the marine algicolous fungus of the genus Botrytis. The absolute stereostructures of compounds 1 and 2 were elucidated on the basis of chemical and physicochemical evidence including quantum chemistry calculation, X-ray analysis, and CD exciton chirality method.

To observe the effects of three commonly used local ablation methods in the treatment of transplanted hepatocellular carcinoma in mice to provide experimental evidence for treating hepatocellular carcinoma that defies surgical removal.Mouse models of hepatocellular carcinoma were established by means of subcutaneous transplantation, and treatment results of the three ablation methods, namely percutaneous ethanol injection therapy (PEIT), percutaneous acetic acid injection therapy (PAIT) and percutaneous local cryosurgery therapy (PLCT), were compared.The tumor inhibition rates of PLCT, PAIT and PEIT were 99.2%, 85.3%, and 72.8%, respectively. The rates for complete necrosis of the tumors were 100% (5/5), 60% (3/5), and 40% (2/5), with the survival time of 88.11+/-5.67, 86.67+/-7.26, and 72.89+/-12.86 days respectively.All of the three local ablation methods can inhibit the tumor growth to various degrees and prolong the survival time of the tumor-bearing mice. PLCT may yield relatively better result than the other two methods.