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Objective To design and synthesize the conjugate (compound 1) of chlorin e6 (compound 3) with fluorouracil (5-Fu) as novel pH-responsive dual-mode antitumor photosensitizer by acyl hydrazone bond coupling, based on literature reports that combination of 5-Fu and photosensitizer possess synergistic anti-tumor effect, and investigate its photodynamic antitumor activity and mechanism. Methods Lead compound 3 was obtained by alkali degradation with 25% KOH-CH3OH on pheophorbide a (compound 4) which was prepared through acid hydrolysis of chlorophyll a in crude chlorophyll extracts from silkworm excrement. Reflux reaction of 5-Fu with P2S5 in pyridine formed crude 4-thio-5-fluorouracil which was followed to react with hydrazine hydrate (N2H4·H2O) in CH3OH to give 5-fluorouracil-4-hydrazone (compound 2). Then, treatment of compound 3 i.e. acid alkali degradation product of chlorophyll a in silkworm excrement with EDC·HCl generated its 171- and 152 cyclic anhydride which was followed to directly react with intermediate compound 2 to successfully get title compound 1. In addition, its pH-responsive 5-Fu release and photodynamic antitumor activity and their mechanisms in vitro were investigated. Results Compound 1 could responsively release 5-Fu at pH 5.0, with a cumulative release rate of 60.3% within 24 h. It exhibited much higher phototoxicity against melanoma B16-F10 and liver cancer HepG2 cells than talaporfin and its precursor compound 3, with IC50 value being 0.73 μmol/L for B16-F10 cells and 0.90 μmol/L for HepG2 cells, respectively. Upon light irradiation, it also could significantly induce cell apoptosis and intracellular ROS level and block cell cycle in S phase. Its structure was confirmed by UV, 1H-NMR, ESI-MS and elemental analysis data. Conclusion The conjugate compound 1 of compound 3 and 5-Fu has the advantages of strong PDT anticancer activity, high therapeutic index (i.e. dark toxicity/phototoxicity ratio) and responsively release 5-Fu at pH 5.0 etc. which shows “unimolecular” dual antitumor effects of PDT and chemotherapy and is worthy of further research and development.
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Objective@#To investigate the social support of medical students during the outbreak of COVID-19 and its mediating effect on the correlation between epidemic exposure and depression with anxiety.@*Methods@#A total of 5 593 medical students were enrolled, and Social Support Rating Scale(SSRS), Patient Health Questionnaire-9 and 7-tiem Generalize Anxiety Disorder Scale were used to measure.@*Results@#The social support score of SSRS of male students was lower than that of female students (t=-4.36, P<0.05) and juniors and seniors scored lower than other grades(F=4.84, P<0.05). Epidemic exposure proportion was positively correlated with both depressive proportionand anxiety proportion(r=0.05, 0.06, P<0.01), while epidemic exposure and depressive proportion and anxiety proportion were negatively correlated with social support score(r=-0.05, -0.25, -0.19, P<0.01). After controlling for gender and grade, the mediating effect of social support in the correlation between epidemic exposure and depression accounted for 26.6% of the total effect, and the mediating effect of subjective support and supportive utilization was 32.3% and 25.7% respectively. After controlling for gender and grade, the mediating effect of social support in the correlation between epidemic exposure and depression accounted for 20.0% of the total effect, and the mediating effect of subjective support and supportive utilization was 15.9% and 12.2% respectively.@*Conclusion@#Social support has partially mediating effect in the correlation between epidemic exposure with depression and anxiety.
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Objective To designe, synthesize a series of chlorin p6 ether photosensitizers and preliminarily investigate their photodynamic antitumor activity based on previous research results that alkoxyl ether derivatives of 3-vinyl on chlorin f exhibited stronger photosensitive antitumor activity than parent compound. Methods Purpurin-18 (4) was obtained by oxidative degradation with air and alkali on pheophorbide a (5) which was prepared through acid hydrolysis of chlorophyll a from crude chlorophyll extracts in Chinese traditional herb named Silkworm excrement. Then, chlorin p6 trimethylester (2) were formed via basic hydrolysis of internal anhydride ring for lead compound 3 and following immediately methylation with CH2N2. The intermediate 2 reacted with 33% HBr, following nucleophilic substitution with various alkoxyl alcohol to get six title compounds (1). All title compounds were subjected to photodynamic antitumor activity screening for melanoma B16-F10 cell in vitro. Results All title compounds showed much higher phototoxicity against melanoma B16-F10 cells than talaporfin and verteporfin. Their structures were confirmed by 1H-NMR, 13C-NMR, ESI-MS and ESI-HRMS spectra. Conclusion Chlorin p6 ether compounds were promising candidate photosensitizers for PDT applications due to theirs high dark toxicity/phototoxicity ratio and excellent phototoxicity, which were worthy of further research and development.
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Objective To design and prepare 13 ,15-cycloimides chlorin p6 (1) ,a class of chlorin related antitumor photo-sensitizers ,which contain a more stable six-membered cyclic imide comparing to the exocyclic anhydride ring of purpurin-18 (2) .Compounds (1) exhibit strong absorption at long wavelengths near λmax 700 nm to take full advantage of greater tissue penetration .Methods Pheophorbide a (3) was obtained by acid hydrolysis of chlorophyll a ,which was from crude chlorophyll extracts of Chinese traditional herb named Silkworm excrement .Purpurin-18 (2) was prepared by air oxidation and alkali open loop simultaneously on five-membered beta-keto carboxylic ester ring of pheophorbide a (3) .Finally ,the target compounds 1a~1j were synthesized via condensation of its anhydride ring with various amines including carboxyl-protected amino acids . Results Target compounds 1a~1j were successfully synthesized in yields ranged from 32 .6% to 65 .2% .Their structures were confirmed by elemental analysis ,ESI-MS and 1 H NMR spectra .Conclusion Treatment of purpurin-18 (2) with amines can produce target compounds 1a~1j .The starting raw material was inexpensive and readily available .The reaction conditions were mild and workup was convinient .
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Objective To investigate the therapeutic effect of stereotactic surgical treatment and postoperative cognitive functions in patients with treat-resistant obsessive compulsive disorder(TRO). Methods Twelve patients with TRO receiving MRI stereotactic bilateral anterior capsulotomy was retrospectively studied. The evaluation was conducted using the Yale-Brown obsessive compulsive rating scale (Y-BOCS),Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC),Wechsler Memory Scale-Revised in China(WMS-R), Modified Version of Wisconsin Card Sorting Tests (M-WCST) before and 6 months after the operation. Results The scores of Y-BOCS was 5.00(1.00,12.25) and 25.00 (20.25,32.00) after and before surgery, respectively. The scores of Y-BOCS were significantly lower after surgery than before (P0.05).There were significant improvements in several cognitive tests after surgery including im-mediately logical memory 20.00(12.50,24.00),delayed logical memory16.50(11.50,21.75),immediately visual reproduc- tion 12.00(11.00,14.00),delayed visual reproduction11.00(8.50,14.00) and block design test scores 36.50(29.75,46.75), immediately logical memory14.00(13.00,18.75),delayed logical memory 14.50 (8.75,17.00),immediately visual reproduc-tion 11.00(6.50,11.75),delayed visual reproduction 8.50(6.25,10.00) and block design test scores 30.50(21.00,41.50) (P<0.05). Conclusions MRI-guided bilateral anterior internal capsulotomy is effective and safe treatment for patients with TRO and can improve their cognitive function.