A pH-sensitive supramolecular nanosystem with chlorin e6 and triptolide co-delivery for chemo-photodynamic combination therapy

The combination of Ce6, an acknowledged photosensitizer, and TPL, a natural anticancer agent, has been demonstrated as a useful strategy to reinforce the tumor growth suppression, as well as decrease the systemic side effects compared with their monotherapy. However, in view of the optimal chemo-photodynamic combination efficiency, there is still short of the feasible nanovehicle to steadily co-deliver Ce6 and TPL, and stimuli-responsively burst release drugs in tumor site. Herein, we described ...     

Effects of Lactobacillus casei on Iron Metabolism and Intestinal Microflora in Rats Exposed to Alcohol and Iron

Background:Higher alcohol consumption was reported in those who consumed more red meat. Both excessive alcohol and iron intake can cause damage to the liver. The purpose of this study is to investigate the effect of Lactobacillus casei strain Shirota (L. casei) on iron metabolism and intestinal microflora in rats after alcohol and iron co-exposure.Methods:Sixty male rats were randomly divided into 3 groups for 12 weeks: the control group: treated with normal saline by gavage and normal diet; the model group: treated with alcohol (8-12 mL/kg/day) by gavage and iron (1500 mg/kg) in diet; the model group supplemented with L. casei (8 × 10⁸ CFU/kg/day) as the L. casei group.Results:Compared with the control group, the levels of serum ferritin, hepcidin, the protein expressions of ferroportin 1 and divalent metal transporter 1 in the model group were significantly increased, while it was significantly decreased after L. casei supplement (P < .05). Compared with the control group, the amount of Lactobacillus of the model group was significantly decreased, while the amount of Bacteroides and Escherichia coli was significantly increased (P < .05). After the supplementation of L. casei, the amount of Lactobacillus increased significantly, while the amount of Bacteroides and E. coli decreased significantly (P < .05).Conclusion:L. casei could effectively improve iron metabolism and intestinal flora disorder induced by excessive alcohol and iron. The effective treatment of iron metabolism may be related to the changes of intestinal flora.     

2019—2021年天津市人民医院贝伐珠单抗临床应用合理性分析

目的 对2019—2021年天津市人民医院贝伐珠单抗的临床应用情况进行评价,以期促进贝伐珠单抗超说明书用药的管理及其临床合理应用。方法 回顾性分析天津市人民医院2019年1月—2021年12月使用贝伐珠单抗患者的用药信息,根据说明书及指南评价其应用的合理性。结果 共收集1 313例患者（6 134次医嘱）,通过适应症、治疗方案、用法用量3个方面评价应用合理性。结果显示,存在适应症不适宜情况占比0.07%,用法用量不适宜情况占比4.77%,其中包括给药浓度不适宜（1.21%）、给药途径不适宜（0.23%）、与手术间隔时间不适宜（3.33%）。结论 天津市人民医院贝伐珠单抗的临床应用基本符合国内外说明书及指南要求,但也存在一定的超说明书用药情况。医院及临床药师应持续规范抗肿瘤药物超说明书使用的管理,促进抗肿瘤药物的合理应用。     

Dynamic Interactions of Post Cleaved NS2B Cofactor and NS3 Protease Identified by Integrative Structural Approaches

Diseases caused by flaviviruses such as dengue virus (DENV) and West Nile Virus (WNV), are a serious threat to public health. The flavivirus single-stranded RNA genome is translated into a polyprotein which is cleaved into three structural proteins and seven non-structural proteins by the viral and cellular proteases. Non-structural (NS) protein 3 is a multifunctional protein that has N-terminal protease and C-terminal helicase domains. The NS3 protease requires co-factor NS2B for enzymatic activity and folding. Due to its essential role in viral replication, NS2B-NS3 protease is an attractive target for antiviral drugs. Despite the availability of crystal structures, dynamic interactions of the N- and C-termini of NS2B co-factor have been elusive due to their flexible fold. In this study, we employ integrative structural approaches combined with biochemical assays to elucidate the dynamic interactions of the flexible DENV4 NS2B and NS3 N- and C-termini. We captured the crystal structure of self-cleaved DENV4 NS2B₄₇NS3 protease in post cleavage state. The intermediate conformation adopted in the reported structure can be targeted by allosteric inhibitors. Comparison of our new findings from DENV4 against previously studied ZIKV NS2B-NS3 proteins reveals differences in NS2B-NS3 function between the two viruses. No inhibition of protease activity was observed for unlinked DENV NS2B-NS3 in presence of the cleavage site while ZIKV NS2B-NS3 cleavage inhibits protease activity. Another difference is that binding of the NS2B C-terminus to DENV4 eNS2B₄₇NS3Pro active site is mediated via interactions with P4-P6 residues while for ZIKV, the binding of NS2B C-terminus to active site is mediated by P1-P3 residues. The mapping of NS2B N- and C-termini with NS3 indicates that these intermolecular interactions occur mainly on the beta-barrel 2 of the NS3 protease domain. Our integrative approach enables a comprehensive understanding of the folding and dynamic interactions of DENV NS3 protease and its cofactor NS2B.     

Construction of sulfur-containing N-vinylimides: N-addition of imides to propargyl sulfonium salts

An N-addition reaction between imides and propargyl sulfonium salts was developed to afford sulfur-containing N-vinylimides with moderate to excellent yields. Under the activation of NaOAc·3H₂O, imides could undergo deprotonation and propargyl sulfonium salts could isomerize to allenic sulfonium salts. The N-nucleophilic attack initiates the reaction and gives the desired products. Various imides, including arylimides, aliphatic imides and N-(arylsulfonyl) alkyl acylamides, and even bioactive saccharin, thalidomide and pomalidomide could provide organosulfur N-vinylimides compounds. The simple, mild and metal-free reaction conditions, the broad scope of substrates, gram-scale synthesis and convenient transformation embody the synthetic superiority of this process.

An N-addition reaction between imides and propargyl sulfonium salts was developed to afford sulfur-containing N-vinylimides with moderate to excellent yields.

N-vinylimides represent crucial structural motifs due to the importance of these frameworks (Fig. 1), which are the core structure found in biologically active structures,¹ functional materials² and natural products such as the parazoanthines A–E.³ They can also serve as versatile synthetic intermediates in the synthesis of β-2-amino acid derivatives⁴ and other complex structures.⁵Open in a separate windowFig. 1Representative functional N-vinylimides scaffolds.Due to the importance of these N-vinylimides frameworks, the growing interest in this featured moiety has catalyzed a recent spurt of attention for methodology appropriate for its construction. Conventionally, protocols for the synthesis of this important substrate class included transition-metal-catalyzed en-imidic C(sp²)–N bond formation reactions of imides with vinyl halides, pseudohalides or alkynes. The main strategies involved Cu-catalyzed Chan–Lam–Evans reactions,⁶ Ru-catalyzed hydroimidation reaction of imide with alkyne⁷ and Pd-catalyzed oxidative amination of alkenes.⁸ In 2021, Sandtorv''s group reported Cu-catalyzed Chan–Lam–Evans reaction for coupling cyclic imides and alkenylboronic acids by forming C(sp²)–N-bonds, enables the practical and mild preparation of (E)-enimides (Scheme 1a).^6a In 2020, Schaub''s group reported Ru-phosphine catalyzed hydroimidation reaction of cyclic amides with acetylene under low pressure, affording new method for synthesis of N-vinylimides (Scheme 1b).^7a Hull''s group reported Pd-catalyzed anti-Markovnikov oxidative amination reaction, alkenes are shown to react with imides in the presence of a palladate catalyst to generate the terminal imide, providing mild and robust complementary routes (Scheme 1c).^8a Besides, rarely examples of organo-catalytic conjugate additions of imides to acetylene can also provide methods for the synthesis of N-vinylimides.⁹Open in a separate windowScheme 1Approaches for vinylation of imides.The previously reported synthesis strategies mainly involved the use of expensive Ru and Pd-catalysts, otherwise toxic copper catalyst, and the structural limitations imposed to phthalimide and therefore specialized. Considering the limitation in generality, the harsh reaction condition, and the use of metal-catalysis decreased the attractiveness for synthetic applications, the development of new kind of vinylation reagents and their application of building N-vinylimides in a simple, mild, metal-free and efficient manner are highly desirable.Our earlier work inspired our interest in synthesis of N-vinylimides by employing propargyl sulfonium salts as vinylation reagent. We have been exploring new reaction patterns of sulfonium salts and developed propargyl sulfonium salts involved [3 + 2] annulation/substitution reaction and N-addition/[2,3]-sigmatropic rearrangement reaction in an acyclic model.¹⁰ Based on our processive interests on constructing N-functionalized vinylation reaction and exploring the diverse reactive pathway of propargyl sulfonium salts, we herein report the realization of inorganic base promoted N-addition reaction of imides and propargyl sulfonium salts, delivering potential bioactive sulfur-containing N-vinylimides in moderate to excellent yields (Scheme 1).We began our investigation by selecting phthalimide 1a and propargyl sulfonium salt 2a as model substrates (†).Optimization of the reaction conditions^a

Chemosensitizing effect and mechanism of imperatorin on the anti-tumor activity of doxorubicin in tumor cells and transplantation tumor model

Multidrug resistance of tumors has been a severe obstacle to the success of cancer chemotherapy. The study wants to investigate the reversal effects of imperatorin (IMP) on doxorubicin (DOX) resistance in K562/DOX leukemia cells, A2780/Taxol cells and in NOD/SCID mice, to explore the possible molecular mechanisms. K562/DOX and A2780/Taxol cells were treated with various concentrations of DOX and Taol with or without different concentrations of IMP, respectively. K562/DOX xenograft model was used to assess anti-tumor effect of IMP combined with DOX. MTT assay, Rhodamine 123 efflux assay, RT-PCR, and Western blot analysis were determined in vivo and in vitro. Results showed that IMP significantly enhanced the cytotoxicity of DOX and Taxol toward corresponding resistance cells. In vivo results illustrated both the tumor volume and tumor weight were significantly decreased after 2-week treatment with IMP combined with DOX compared to the DOX alone group. Western blotting and RT-PCR analyses indicated that IMP downregulated the expression of P-gp in K562/DOX xenograft tumors in NOD/SCID mice. We also evaluated glycolysis and glutamine metabolism in K562/DOX cells by measuring glucose consumption and lactate production. The results revealed that IMP could significantly reduce the glucose consumption and lactate production of K562/DOX cells. Furthermore, IMP could also remarkably repress the glutamine consumption, α-KG and ATP production of K562/DOX cells. Thus, IMP may sensitize K562/DOX cells to DOX and enhance the anti-tumor effect of DOX in K562/DOX xenograft tumors in NOD/SCID mice. IMP may be an adjuvant therapy to mitigate the multidrug resistance in leukemia chemotherapy.     

针刺通过调节DKK1通路调控骨代谢改善去卵巢模型大鼠骨质疏松的机制研究

目的 探讨针刺通过调节DKK1通路调控骨代谢对于去卵巢模型大鼠(ovariectomized rats,OVX)骨质疏松的影响及其机制.方法 采用经典的双侧卵巢切除进行雌性SD大鼠的原发性骨质疏松造模,阿伦磷酸盐阳性药物对照组服用阿伦磷酸盐治疗,各期针灸组采取针刺双侧"肾腧"穴.观察针刺治疗对OVX大鼠全身骨量、生物力...     

富氧水对高原移居青年心肺功能的影响

目的：探讨在高原服用富氧水对移居青年心肺功能的影响。方法：对进驻海拔3700m1年的10名青年在服用富氧水前和服用富氧水（每次500mL,一日2次）15天后分别用EGM-II型踏车功量计做坐位踏车运动,初始负荷功率为50W,每3min递增50W,以60r/min连续踏车至200W,3min后终止。用直线回归法计算每位受试者功率200W时的心率（HR）及血氧饱和度（SaO2）,记录运动终止5min后恢复HR,按公式计算心功能指数。结果：服用富氧水15天后,心功能指数增高,功率200W时SaO2增高;功率200W时的HR和运动终止5min恢复HR降低,差别有非常显著性意义（P〈0.01）。结论：服用富氧水能提高高原移居青年的心肺功能。     

肝癌肝移植17例

目的探讨肝癌肝移植方法,并评价其疗效,以提高肝癌救治成功率。方法回顾2003年9月以来本院17例肝癌肝移植诊治过程,总结治疗过程中的成功经验和教训。结果17例肝移植病人围手术期均顺利恢复,全部获得随访,随访时间:3～19个月;14例存活,3例死亡,此3例分别于术后4个月、7个月、9个月因肺和(或)肝转移死亡外,14例均存活中带癌生存3例,1年以上6例,6～12个月5例,3～6个月3例。结论肝癌是肝移植相对适应证,是一种疗效肯定的治疗方法,规范围手术期处理方法,并进行术后合理治疗,部分病人可获长期生存。