Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

Background::Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma.Methods::The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro. A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8 + T cells in TME were analyzed by flow cytometry. Results::Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro. AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1 +/CD8 + T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ) + or Ki67 + CD8 T cells and decreasing the levels of CD8 + Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8 + T cells proliferation, and weakening CD8 + T cells depletion. Conclusions::This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8 + T cells in TME.

Objective:To investigate the chemical constituents of Vitex negundo var.heterophylla.Methods:The chemical constituents were separated and purified by silica gel,opening ODS column chromatography,Sephadex LH-20,and semi-preparative HPLC.Their structures were elucidated on the basis of physico-chemical properties and spectroscopic data.Results:Five compounds were isolated from the 95%ethanol extract of the leaves and seeds of Vitex negundo var.heterophylla.They were identified as 5,4'-dihydroxy-3,6,7-trimethoxyflavone,5,4'-dihydroxy-3,6,7,8-tetramethoxyflavone,p-hydroxybenzaldehyde,p-hydroxybenzoic acid,and p-hydroxybenzoic acid methyl ester.Conclusion:The study of the chemical constituents of Vitex negundo var.heterophylla enriches the chemical composition of Vitex negundo var.heterophylla and the material basis for its potential pharmacological effects.

Objective To systematically review the effects of Baduanjin in knee osteoarthritis patients. Methods Randomized controlled trial(RCT)on effects of Baduanjin in knee osteoarthritis patients was retrieved in the Web of Science,CINAHL,PubMed,EMbase,The Cochrane Library,Chinese National Knowledge Infrastructure(CNKI),WanFang Data and VIP by computer from building database to 23rd January 2019. Two researchers independently screened literatures,extracted data and assessed the risk of bias of included literatures. The RevMan 5.3 was used to the meta-analysis and GRADE pro was applied to grade the quality of evidence. Results Finally,a total of 6 RCTs were included and involved 328 subjects. Meta-analysis showed that Baduanjin compared with control group could improve the pain of patients[SMD=-1.50, 95％CI(-2.43,-0.58),P=0.001],stiff[SMD=-0.85,95％CI(-1.46,-0.23),P=0.007],physiologic function [SMD=-1.28,95％CI(-2.45,-0.10),P=0.03]and mobility[SMD=1.04,95％CI(0.07,2.02),P=0.03] with statistical differences. Evidence levels of five evidences were all the extremely low degree of quality. Conclusions The existing evidences show that Baduanjin has significant clinical effects on improving the pain of knee osteoarthritis patients,stiff and mobility. The evidences still need to be confirmed by many high quality of researches restricted by research quality of included literatures.

Cognitive dysfunction,as a common symptom among patients with chronic fatigue syndrome (CFS) and patients with fibromyalgia(FM),impacts on life quality,occupation and study of these patients.However,the neural correlates to the cognitive impairment are unknown.Event related potentials,which reflect the information processing objectively and constantly,provide possibility for taking a insight into and estimating the dysfunction.By summarizing and analyzing studies in event related potentials about chronic fatigue syndrome,fibromyalgia,we found that CFS patients were characterized with prolonged latency of N200 and P300 accompanied by decreased P300 amplitude when they performed on Oddball paradigm,fibromyalgia patients were characterized with lower P300 amplitude when they concentrated on Oddball task,meanwhile,fibromyalgia patients also showed decreased P100/N100,P200,P300,LPC in emotional word decision task and somatic pictures decision task.It's suggests that the cognitive dysfunction in CFS is mainly caused by slowed speed of information identification and classification,whereas in FM it's dysregulation in attention control system results in the cognitive dysfunction.Limitations in current studies and prospects on researches about cognitive dysfunction in CFS for future were also discussed.

Objective To develop a mouse model for acute otitis media (AOM) via transbullar injection method and evaluate its feasibility and practicability.Methods The middle ears (ME) of C57BL/6 mice were inoculated via transbullar injection method with 5 μl streptococcus pneumoniae (S.pn)19F suspension (1 × 107 CFU/ml),and the control group was inoculated equivalent phosphate buffered solution(PBS).Behavior changes were observed daily following inoculation.The ME tissues for histological examination and the middle ear lavage fluid (MELF) for total cells quantification,S.pn load determination and cytokines measurement were collected at 12 h,day 1,2,3,5,7 after inoculation,respectively.Results Within 24 hours after instillation,the density of S.pn and the level of acute inflammatory cytokines in ME cavity increased rapidly,some mucosal hyperplasia was evident and leukocytic infiltration (primarily neutrophils) began.The level of ME inflammatory response reached maximal at 2-3 days after inoculation,with extensive effusion,leukocytic infiltration and mucosal thickening.Meanwhile,the density of S.pn decreased gradually.Bacterial clearance was completed by day 5 with extensive resolution of ME inflammation,although mucosal hyperplasia did not resolute until day 7.Conclusion A mouse model for AOM is successfully established via transbullar injection method,laying foundation for future study of AOM.

Objective To study the clinical characteristics of the patients of GH-secreting pituitary adenoma with hyperprolactinaemia. Methods The clinical data of 124 cases of GH-secreting pituitary adenoma with hyperprolactinaemia treated in Peking Union Medical College Hospital from 1984 to 2004, including 87 cases followed up for over one year , were analyzed retrospectively. Results Of 124 patients, there are 88 females and 36 males and the course of disease in males (8.0?7.3) years was longer than that in females (5.5?4.3)years (P

This article reports the development of hyperosmolar hypernatremic hyperchloremic coma and acute renal failure in a male diabetic patient after recovery from hyperosmolar hypergly-cemic nonketonic coma, of which the cause is fluid retention in excess of urinary output due to the obstruction of lower urethra by diabetic neurogenic urinary bladder and hyper-plasia of prostate gland.By our experience each old diabetic man should be examined to confirm if he has neuro-genic urinary bladder and/or hyperplasia of prostate gland. Care should be taken to keep the balance of fluid intake and output provided that both of these conditions are present. The acute obstructive nephropathy can quickly ameliorate with release of the obstruction.