Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation.

As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.

Ferritinophagy induced ferroptosis in the management of cancer.

BACKGROUND: Ferroptosis, a newly form of regulated cell death (RCD), is characterized by iron dyshomeostasis and unrestricted lipid peroxidation. Emerging evidence depicts a pivotal role for ferroptosis in driving some pathological processes, especially in cancer. Triggering ferroptosis can suppress tumor growth and induce an anti-tumor immune response, denoting the therapeutic promises for targeting ferroptosis in the management of cancer. As an autophagic phenomenon, ferritinophagy is critical to induce ferroptosis by degradation of ferritin to release intracellular free iron. Recently, a great deal of effort has gone into designing and developing anti-cancer strategies based on targeting ferritinophagy to induce ferroptosis. CONCLUSION: This review delineates the regulatory mechanism of ferritinophagy firstly and summarizes the role of ferritinophagy-induced ferroptosis in cancer. Moreover, the strategies targeting ferritinophagy to induce ferroptosis are highlighted to unveil the therapeutic value of ferritinophagy as a target to manage cancer. Finally, the future research directions on how to cope with the challenges in developing ferritinophagy promoters into clinical therapeutics are discussed.

Inhibitory effect of 4,4'-dihydroxy-α-truxillic acid derivatives on NO production in lipopolysaccharide-induced RAW 264.7 macrophages and exploration of structure-activity relationships.

The inhibitory activity of 4,4'-dihydroxy-α-truxillic acid and its derivatives (5-1a-5-35a) on nitric oxide (NO) release was evaluated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Compounds 5-3a, 5-4a, 5-5a, 5-10a, 5-24a, 5-26a and 5-30a exhibited significant inhibitory effects on NO production, with IC50 values of 19.8, 21.1, 16.4, 17.5, 20.8, 22.6 and 17.6 µM, respectively. Their cytotoxicities were also estimated using a CCK-8 assay. Among them, compound 5-10a showed no cytotoxic effect on cells up to a concentration of 50 µM. The structure-activity relationships of the compounds are also discussed.

Clinical value of multiband mucosectomy for the treatment of squamous intraepithelial neoplasia of the esophagus.

BACKGROUND AND AIM: To evaluate the clinical value of multiband mucosectomy (MBM) for the treatment of squamous intraepithelial neoplasia of the esophagus. METHODS: A total of 51 lesions located at esophagus from 43 patients were treated with MBM, among which 11 were diagnosed as middle-grade intraepithelial neoplasia, 25 as high-grade intraepithelial neoplasia, and 15 as early esophageal cancer pathologically. Primary end-points were the rate of complete endoscopic resection and the mean operation time; the second end-points were the postoperative local recurrence rate and acute plus early complications. The histopathological results were compared between pre-MBM biopsy and MBM specimens. All patients were followed up endoscopically. RESULTS: A total of 52 MBM procedures with 180 resections were performed in 43 patients. The complete endoscopic resection was achieved in 92.3% (95% confidence interval [CI] 81.8-96.9%). The sizes of the lesions ranged from 10 × 8 mm to 25 × 23 mm. The mean operation time is 37 ± 5 min. The operative acute bleeding complication was 7.6% (95% CI 3-18.1%); no perforations occurred. Early complications consisted of delayed bleeding (one patient 1.9%; 95% CI 0.3-10.1%) and slight esophageal stenosis (one patient). The histopathological diagnosis of 26 cases (51%) was consistent between biopsy and MBM samples, while 20 lesions exhibited higher grade dysplasia. The local recurrence rate was 6.9% (3/43) at 1 year, 9.3% (4/43) at 2 years, and 9.3% at 2.5 years. No death occurred during follow-up. CONCLUSIONS: MBM is a safe and effective technique for the treatment of early esophageal cancer and precancerous lesions.

Efficient total synthesis and biological activities of 6-deoxyisojacareubin.

6-Deoxyisojacareubin was directly synthesized in a six-step route with an overall yield of about 20%. In this route, the excellent site selectivity of this Claisen rearrangement-cyclization reaction cascade was achieved by inserting a bulky p-tosyl group into the free 1-OH, and in the last step, some efficient demethylation methods were explored. Furthermore, all synthesized intermediates including 6-deoxyisojacareubin were evaluated for their inhibitory activity against the QGY-7703 cell line. Of these, compound 1 and 6-deoxyisojacareubin showed moderate activities with IC50 values of 39.61 and 9.65 µM, respectively, when compared to the positive control 5-fluorouracil with an IC50 value of 11.24 µM. Further investigation using non-radioactive detection of protein kinase C (PKC) suggested that these two compounds possessed potency in the inhibition of PKC.

Meta-analysis for evaluating the accuracy of endoscopy with narrow band imaging in detecting colorectal adenomas.

BACKGROUND AND AIM: The aim of this study was to determine whether the use of the narrow band imaging (NBI) system could enhance the accuracy of adenoma detection during an endoscopic examination of the colon and rectum. METHODS: MEDLINE, EMBASE, and the Cochrane Library databases were searched along with a hand search of abstracts from relevant conferences up to June 2011. The rates of adenoma and flat adenoma detection, and withdrawal time were analyzed using Review Manager 4.2. RESULTS: A total of 3049 subjects in eight trials were included. Meta-analysis revealed that there was no statistically significant difference in the rates of adenoma detection between the NBI group and the white light colonoscopy group (pooled relative risk [RR]: 1.09, 95% confidence interval [CI]: 1.00-1.19, P = 0.05). However, after exclusion of high-definition television modalities, the rate of adenoma detection by NBI was significantly higher than that by white light, particularly for patients with one adenoma (pooled RR 1.36, 95%CI 1.07-1.71, P = 0.02). Endoscopy with the NBI system significantly increased the rate of flat adenoma detection (pooled RR 1.96, 95%CI 1.09-3.52, P = 0.02). However, endoscopy with NBI had longer withdrawal time than that with white light (pooled weighted mean difference: 0.90, 95%CI: 0.38-1.42, P = 0.0006). CONCLUSIONS: Endoscopy with NBI seems to improve the detection of flat adenomas, particularly with high-definition technology, but prolongs the withdrawal time. These results indicate that endoscopy routinely using the NBI system for the surveillance of adenomas may be recommended after the technique is further modified.

[The protective effect of tea polyphenols on chronic alcoholic liver injury in rats].

OBJECTIVE: To investigate the protective effects and potential mechanisms of tea polyphenols intervention on excess alcohol intake induced liver injury in rats. This study established the animal model of chronic liver injury rats induced by alcohol. Our results will provide experimental evidence for the effects of tea polyphenol on chronic alcoholic liver injury. METHODS: Alcohol-induced liver injury rat models were established, and the tea polyphenols intervention was performed in the meantime. After 8 weeks, rats were anesthetized, and visceral fat and liver samples were separated, weighted and stored. Visceral fat content was evaluated in fat/body weight ratio. Liver lipid accumulation was assessed by liver index and the result of Oil Red O staining. Hepatic superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, total antioxidant capacity assay (T-AOC) and glutathione peroxidase (GSH-Px) activity were detected. And fatty acid translocase (FAT/CD36) protein level in liver was detected. RESULTS: Compared with the control group rats, the fat/body weight ratio, SOD/MDA, T-AOC and GSH-Px activity of chronic liver injury rats were decreased significantly (P<0.05,P<0.01). Meanwhile the liver index, FAT/CD36 protein level and lipid deposition in liver of chronic liver injury rats were increased (P<0.01). Compared with chronic liver injury rats, the tea polyphenols intervention increased fat/body weight ratio (P<0.05), and significantly increased SOD/MDA, T-AOC and GSH-Px activity (P<0.01). Meanwhile the tea polyphenols intervention reduced liver index (P<0.01), FAT/CD36 protein level (P<0.01) and lipid deposition in liver. CONCLUSIONS: Tea polyphenols intervention can improve lipid deposition and oxidative stress in chronic alcoholic liver, which is concurrent with decreased FAT/CD36 protein expression on the hepatocyte membrane.

Synthesis of novel triazole derivatives as inhibitors of cytochrome P450 14alpha-demethylase (CYP51).

A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols have been designed and synthesized on the basis of the structure-activity relationships and antimycotic mechanism of azole antifungal agents. Their structures were confirmed by elemental analysis, IR, MS and (1)H NMR. Results of preliminary antifungal tests against eight human pathogenic fungi (Candida albicans, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, Fonsecaea compacta, and Microsporum gypseum) in vitro showed that all title compounds exhibited activity against fungi tested to some extent. Among the compounds tested, all compounds showed higher activity against C. albicans than fluconazole in vitro. Compounds 3, 6-8, 28, 29, and 32 exhibited the same activities against C. albicans as voriconazole (with the MIC value of 0.0152microg/mL). Compounds 3, 6, and 7 showed higher activity against C. parapsilosis than all five positive controls.

Synthesis and evaluation of novel 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols as antifungal agents.

A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols have been designed and synthesized on the basis of the structure-activity relationships and antimycotic mechanism of azole antifungal agents. Their structures were confirmed by elemental analysis, IR, MS, (1)H NMR and (13)C NMR. Results of preliminary antifungal tests against six human pathogenic fungi (Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida tropicalis, inherently fluconazole-resistant Candida krusei, Candida glabrata) in vitro showed that all title compounds exhibited activity against fungi tested to some extent except against C. tropicalis. Compound 5b showed higher activity against C. albicans, C. parapsilosis and C. krusei than fluconazole, and its MIC values were determined to be 0.5microg/mL, 1microg/mL and 4microg/mL, respectively. Compound 5k showed higher activities against Torulopsis glabrata than fluconazole (with the MIC value of 2microg/mL). Compounds 5a, 5c, 5f, 5g, 5i exhibited higher activities against C. parapsilosis than fluconazole (with the MIC values of 2microg/mL, 2microg/mL, 2microg/mL, 1microg/mL and 2microg/mL, respectively).

Novel triazolyl berberine derivatives prepared via CuAAC click chemistry: synthesis, anticancer activity and structure-activity relationships.

To search for novel anticancer agents, we designed and synthesized a series of new triazolyl berberine derivatives. The evaluation of all the synthesized compounds and their anticancer activities against a panel of four human cancer cell lines including MCF-7 (breast), MCF-7/ADR (breast), SW-1990 (pancreatic), SMMC-7721 (liver) and the noncancer cell line HUVEC (human umbilical vein endothelial cell). The results showed that most of the compounds displayed better anticancer activities against MCF-7 and SMMC-7721 compared with berberine. Among these derivatives, compounds 5p and 5a exhibited the most potent inhibitory activities against the SMMC-7721 and SW-1990 cell lines with IC50 values of 14.861 ± 2.4 µM and 16.798 ± 3.4 µM. Furthermore, compounds 5p, 5a and 5n exhibited much better selectivity toward the normal cell line HUVEC than berberine.

Color-tunable and white-light emission of one-dimensional L-di-2-thenoyltartaric acid mixed-lanthanide coordination polymers.

A series of L-di-2-thenoyltartaric acid lanthanide coordination polymers, namely, {[La2L3(CH3OH)6(H2O)]·CH3OH·H2O}n (1), {[Ln2L3(CH3OH)x(H2O)6−x]·aCH3OH·bH2O}n, [Ln = Eu (2), x = 2, a = 0.5, b = 0.25; Ln = Gd (3), x = 3, a = 1, b = 0; Ln = Tb (4), x = 2, a = 1, b = 0], {[(Eu0.037Tb0.963)2L3(CH3OH)2(H2O)4]·CH3OH·2.75H2O}n (5), {[(Eu0.051Tb0.406La0.543)2L3(CH3OH)2(H2O)4]·0.5CH3OH·2H2O}n (6), and {[(Eu0.068Tb0.363Gd0.569)2L3(CH3OH)3(H2O)3]·CH3OH·H2O}n (7), have been synthesized using facile reactions of H2L (H2L = L-di-2-thenoyltartaric acid) with LnCl3·6H2O under ambient temperature. X-ray crystallographic analysis reveals that complexes 1­4 are isostructural, featuring one-dimensional (1D) ladder-like chain structures, in which the Ln(3+) ions are bridged by the carboxylate groups of the ligands. The luminescent spectra in the solid state at room temperature reveal that complexes 2 and 4 exhibit the characteristic red and green luminescence of Eu(3+) and Tb(3+) ions, respectively, whereas complexes 1 and 3 display the blue emission of the ligand with a broad band centered at 422 nm. Notably, the mixed-lanthanide coordination polymers 5­7 exhibit color-tunable luminescence from yellow and white to blue upon variation of the excitation wavelength. It realizes color-tunable and white-light emission in 1D carboxylic acid mixed-lanthanide coordination polymers.

Synthesis and evaluation of new α-methylene-γ-lactone carbamates with NO production inhibitory effects in lipopolysaccharide-induced RAW 264.7 macrophages.

A series of new α-methylene-γ-lactone carbamates were synthesized by an asymmetric synthetic route. The activities on inhibiting nitric oxide (NO) release of these compounds were evaluated in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. The results indicated that most of the compounds except one exhibited potent NO inhibitory effect with IC50 value more than 2 µΜ. The cytotoxicities of these compounds were estimated via MTT assays. The results suggested that six compounds were accompanied by low cytotoxicity. The structure-activity relationships were also discussed. The S configuration of C3 on lactones ring would be more helpful to NO inhibitory effect.

[Effects of exercise and low-fat diet on the TNF-alpha expression of insulin resistance in rats].

OBJECTIVE: To investigate the effects of exercise (EX), low-fat diet (LFD) and their combination intervention on the tumor necrosis factor-alpha (TNF-alpha) expression of insulin resistance in rats. METHODS: One hundred and thirty male rats randomly assigned to 2 groups: Control (CON)-10 rats consuming a low-fat diet; HFD-120 rats consuming a high-fat diet (HFD). The dietary regimen was sustained for 8 wk, at which point the 40 HFD group rats gaining the most weight were referred to as the obese rats. Glucose tolerance was assessed by an oral glucose tolerance test (OGTT). During the procedure of OGTT, the blood was drawn for insulin assay (insulin release test). The whole body insulin resistance was assessed by glucose-insulin index. The obese HFD group rats were randomized into one of four intervention groups: HFD-sedentary (HFD-SED), HFD-exercise(HFD-EX), low fat diet-SED (LFD-SED), LFD-EX. Ex rats performed 8-wk exercise training on a motorized treadmill. The CON group had access to low-fat diet for another 8 wk. After 8 wk of exercise and low-fat diet intervention, the OGTT and insulin release test were performed again. To use ELISA technique for detecting TNF-alpha in soleus muscle and adipose tissue. RESULTS: After being fed high-fat diet for 8 wk, glucose-insulin index in the HFD group were significantly greater than that in CON group (P < 0.01). After 8-week exercise and low-fat diet intervention, glucose-insulin index in HFD-SED group was significantly greater than that in CON group (P < 0.01). The index in three intervention groups was significantly less than that in HFD-SED group (P < 0.01) . TNF-alpha content in adipose tissue and the soleus muscle for HFD-SED group was significantly greater than that in CON group (P < 0.01). Three intervention groups were significantly less than HFD-SED group (P < 0.01). CONCLUSION: Exercise and low-fat diet interventions can decrease the TNF-alpha expression in insulin resistance rat.

Design, synthesis, and anticancer activity of novel berberine derivatives prepared via CuAAC "click" chemistry as potential anticancer agents.

A series of novel derivatives of phenyl-substituted berberine triazolyls has been designed and synthesized via copper-catalyzed azide-alkyne cycloaddition click chemistry in an attempt to develop antitumor agents. All of the compounds were evaluated for anticancer activity against a panel of three human cancer cell lines, including MCF-7 (breast), SW-1990 (pancreatic), and SMMC-7721 (liver) and the noncancerous human umbilical vein endothelial cell (HUVEC) cell lines. The results indicated that most of the compounds displayed notable anticancer activities against the MCF-7 cells compared with berberine. Among these derivatives, compound 16 showed the most potent inhibitory activity against the SW-1990 and SMMC-7721 cell lines, with half-maximal inhibitory concentration (IC50) values of 8.54±1.97 µM and 11.87±1.83 µM, respectively. Compound 36 exhibited the most potent inhibitory activity against the MCF-7 cell line, with an IC50 value of 12.57±1.96 µM. Compound 16 and compound 36 exhibited low cytotoxicity in the HUVEC cell line, with IC50 values of 25.49±3.24 µM and 30.47±3.47 µM. Furthermore, compounds 14, 15, 16, 17, 18, 32, and 36 exhibited much better selectivity than berberine toward the normal cell line HUVEC.

Novel Triazolyl berberine derivatives prepared via CuAAC click chemistry: Synthesis, Anticancer Activity and Structure-Activity Relationships.

To search for novel anticancer agents, we designed and synthesized a series of new triazolyl berberine derivatives. The evaluation of all the synthesized compounds and their anticancer activities against a panel of four human cancer cell lines including MCF-7 (breast), MCF-7/ADR (breast), SW-1990 (pancreatic), SMMC-7721 (liver) and the non-cancer cell line HUVEC (human umbilical vein endothelial cell). The results showed that most of the compounds displayed better anticancer activities against MCF-7 and SMMC-7721 compared with berberine. Among these derivatives, compounds 5p and 5a exhibited the most potent inhibitory activities against the SMMC-7721 and SW-1990 cell lines with IC50 values of 14.861 ± 2.4 µM and 16.798 ± 3.4 µM. Furthermore, compounds 5p, 5a and 5n exhibited much better selectivity toward the normal cell line HUVEC than berberine.

Synthesis and structure-activity relationships of guaiane-type sesquiterpene lactone derivatives with respect to inhibiting NO production in lipopolysaccharide-induced RAW 264.7 macrophages.

A guaiane framework was scaffolded by photochemical rearrangement reactions using α-santonin 1 as a starting material. Then, using a series of reactions, we synthesized the guaiane-type sesquiterpene lactone 5 in high yield. The inhibitory activities of compound 5 and of a series of derivatives on nitric oxide (NO) release were evaluated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Compounds 6g, 7h, 7i, 7k and 8g, exhibited significant inhibitory effects on NO production, with IC50 values of 14.8, 22.3, 18.3, 17.4 and 7.0 µM, respectively. Their cytotoxicities were also estimated using an MTT assay. The structure-activity relationships of these compounds were also discussed.

Two novel innovanoside dimers from Daphne aurantiaca and a concise total synthesis of diinnovanoside A.

Chemical examination of the methanolic extract from the stem bark of Daphne aurantiaca led to the isolation of two innovanoside dimers (1 and 2) with an unusual four-membered cyclobutane ring, together with the isoinnovanoside 3. Their chemical structures and configurations were elucidated by extensive spectral analysis and synthesis.

Construction of 2-substituted-3-functionalized benzofurans via intramolecular Heck coupling: application to enantioselective total synthesis of daphnodorin B.

A novel approach was developed for the synthesis of 2-substituted-3-functionalized benzofurans, using an intramolecular Heck reaction which was further applied in the first enantioselective total synthesis of Daphnodorin B.

Synthesis and biological evaluation of phenyl substituted polyoxygenated xanthone derivatives as anti-hepatoma agents.

A series of novel derivatives of phenyl substituted tetramethoxy xanthone were synthesized and evaluated for their in vitro cytotoxicity against human hepatocellular carcinoma (HCC) and non-tumor hepatic cells. Among these derivatives, compound 6 was more potent than positive control 5-fluorouracil (5-Fu) on QGY-7703 and SMMC-7721 cells with IC50 values of 6.27 µM, 7.50 µM and 15.56 µM, 14.55 µM, respectively. Furthermore, compounds 6, 14, 16, and 29 exhibited much better selectivity toward the normal hepatic cell line QSG-7701 than 5-Fu. Additionally, compound 6 significantly induced cell apoptosis in QGY-7703 cells. Our findings suggested that these phenylxanthone derivatives may hold promise as chemotherapeutic agents for the treatment of human HCC.