A neutrophil-biomimic platform for eradicating metastatic breast cancer stem-like cells by redox microenvironment modulation and hypoxia-triggered differentiation therapy

Metastasis accounts for 90% of breast cancer deaths, where the lethality could be attributed to the poor drug accumulation at the metastatic loci. The tolerance to chemotherapy induced by breast cancer stem cells (BCSCs) and their particular redox microenvironment further aggravate the therapeutic dilemma. To be specific, therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly, and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy. Herein, we develop a specifically-designed biomimic platform employing neutrophil membrane as shell to inherit a neutrophil-like tumor-targeting capability, and anchored chemotherapeutic and BCSCs-differentiating reagents with nitroimidazole (NI) to yield two hypoxia-responsive prodrugs, which could be encapsulated into a polymeric nitroimidazole core. The platform can actively target the lung metastasis sites of triple negative breast cancer (TNBC), and release the escorted drugs upon being triggered by the hypoxia microenvironment. During the responsiveness, the differentiating agent could promote transferring BCSCs into non-BCSCs, and simultaneously the nitroimidazole moieties conjugated on the polymer and prodrugs could modulate the tumor microenvironment by depleting nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and amplifying intracellular oxidative stress to prevent tumor cells retro-differentiation into BCSCs. In combination, the BCSCs differentiation and tumor microenvironment modulation synergistically could enhance the chemotherapeutic cytotoxicity, and remarkably suppress tumor growth and lung metastasis. Hopefully, this work can provide a new insight in to comprehensively treat TNBC and lung metastasis using a versatile platform.

Efficacy of robot-assisted single-port laparoscopic transvaginal surgery in the treatment of vesicovaginal fistula / 现代泌尿外科杂志

【Objective】 To investigate the efficacy of robot-assisted single-port laparoscopic transvaginal vesicovaginal fistula repair. 【Methods】 The clinical data of 3 patients with high vesicovaginal fistula treated during Jun.2020 and Jun.2021 were retrospectively analyzed. 【Results】 All operations were completed successfully, with no conversion to other surgical methods. Operation time: 98 min, 104 min and 115 min; Intraoperative bleeding volume: 15 mL, 20 mL and 22 mL; Postoperative hospital stay was 2 days. The catheter was removed after 1-month follow-up, and the patients had no bleeding, urine leakage, infection or other complications. There was no recurrence of urine leakage at the end of 12-month follow-up. 【Conclusion】 Robot-assisted single-port laparoscopic transvaginal vesicovaginal fistula repair has the advantages of fine suture and minor damage, which can be an effective treatment of vesicovaginal fistula.

ROS-removing nano-medicine for navigating inflammatory microenvironment to enhance anti-epileptic therapy

As a neurological disorder in the brain, epilepsy is not only associated with abnormal synchronized discharging of neurons, but also inseparable from non-neuronal elements in the altered microenvironment. Anti-epileptic drugs (AEDs) merely focusing on neuronal circuits frequently turn out deficient, which is necessitating comprehensive strategies of medications to cover over-exciting neurons, activated glial cells, oxidative stress and chronic inflammation synchronously. Therefore, we would report the design of a polymeric micelle drug delivery system that was functioned with brain targeting and cerebral microenvironment modulation. In brief, reactive oxygen species (ROS)-sensitive phenylboronic ester was conjugated with poly-ethylene glycol (PEG) to form amphiphilic copolymers. Additionally, dehydroascorbic acid (DHAA), an analogue of glucose, was applied to target glucose transporter 1 (GLUT1) and facilitate micelle penetration across the blood‒brain barrier (BBB). A classic hydrophobic AED, lamotrigine (LTG), was encapsulated in the micelles via self-assembly. When administrated and transferred across the BBB, ROS-scavenging polymers were expected to integrate anti-oxidation, anti-inflammation and neuro-electric modulation into one strategy. Moreover, micelles would alter LTG distribution in vivo with improved efficacy. Overall, the combined anti-epileptic therapy might provide effective opinions on how to maximize neuroprotection during early epileptogenesis.

Mechanism of total flavonoids of Rhododendra simsii in alleviating ischemic brain injury / 中国中药杂志

This study explores the effect of total flavonoids of Rhododendra simsii(TFR) on middle cerebral artery occlusion(MCAO)-induced cerebral injury in rats and oxygen-glucose deprivation/reoxygenation(OGD/R) injury in PC12 cells and the underlying mechanism. The MCAO method was used to induce focal ischemic cerebral injury in rats. Male SD rats were randomized into sham group, model group, and TFR group. After MCAO, TFR(60 mg·kg~(-1)) was administered for 3 days. The content of tumor necrosis factor-α(TNF-α), interleukin-1(IL-1), and interleukin-6(IL-6) in serum was detected by enzyme-linked immunosorbent assay(ELISA). The pathological changes of brain tissue and cerebral infarction were observed based on hematoxylin and eosin(HE) staining and 2,3,5-triphenyltetrazolium chloride(TTC) staining. RT-qPCR and Western blot were used to detect the mRNA and protein levels of calcium release-activated calcium channel modulator 1(ORAI1), stromal interaction molecule 1(STIM1), stromal intera-ction molecule 2(STIM2), protein kinase B(PKB), and cysteinyl aspartate specific proteinase 3(caspase-3) in brain tissues. The OGD/R method was employed to induce injury in PC12 cells. Cells were randomized into the normal group, model group, gene silencing group, TFR(30 μg·mL~(-1)) group, and TFR(30 μg·mL~(-1))+gene overexpression plasmid group. Intracellular Ca~(2+) concentration and apoptosis rate of PC12 cells were measured by laser scanning confocal microscopy and flow cytometry. The effect of STIM-ORAI-regulated store-operated calcium entry(SOCE) pathway on TFR was explored based on gene silencing and gene overexpression techniques. The results showed that TFR significantly alleviated the histopathological damage of brains in MCAO rats after 3 days of admini-stration, reduced the contents of TNF-α, IL-1, and IL-6 in the serum, down-regulated the expression of ORAI1, STIM1, STIM2, and caspase-3 genes, and up-regulated the expression of PKB gene in brain tissues of MCAO rats. TFR significantly decreased OGD/R induced Ca~(2+) overload and apoptosis in PC12 cells. However, it induced TFR-like effect by ORAI1, STIM1 and STIM2 genes silencing. However, overexpression of these genes significantly blocked the effect of TFR in reducing Ca~(2+) overload and apoptosis in PC12 cells. In summary, in the early stage of focal cerebral ischemia-reperfusion injury and OGD/R-induced injury in PC12 cells TFR attenuates ischemic brain injury by inhibiting the STIM-ORAI-regulated SOCE pathway and reducing Ca~(2+) overload and inflammatory factor expression, and apoptosis.

Molecular mechanism of ligustilide attenuating OGD/R injury in PC12 cells by inhibiting ferroptosis / 中国中药杂志

The aim of this study is to explore the mechanism of ligustilide, the main active constituent of essential oils of traditional Chinese medicine Angelicae Sinensis Radix, on alleviating oxygen-glucose deprivation/reperfusion(OGD/R) injury in PC12 cells from the perspective of ferroptosis. OGD/R was induced in vitro, and 12 h after ligustilide addition during reperfusion, cell viability was detected by cell counting kit-8(CCK-8) assay. DCFH-DA staining was used to detect the level of intracellular reactive oxygen species(ROS). Western blot was employed to detect the expression of ferroptosis-related proteins, glutathione peroxidase 4(GPX4), transferrin receptor 1(TFR1), and solute carrier family 7 member 11(SLC7A11), and ferritinophagy-related proteins, nuclear receptor coactivator 4(NCOA4), ferritin heavy chain 1(FTH1), and microtubule-associated protein 1 light chain 3(LC3). The fluorescence intensity of LC3 protein was analyzed by immunofluorescence staining. The content of glutathione(GSH), malondialdehyde(MDA), and Fe was detected by chemiluminescent immunoassay. The effect of ligustilide on ferroptosis was observed by overexpression of NCOA4 gene. The results showed that ligustilide increased the viability of PC12 cells damaged by OGD/R, inhibited the release of ROS, reduced the content of Fe and MDA and the expression of TFR1, NCOA4, and LC3, and improved the content of GSH and the expression of GPX4, SLC7A11, and FTH1 compared with OGD/R group. After overexpression of the key protein NCOA4 in ferritinophagy, the inhibitory effect of ligustilide on ferroptosis was partially reversed, indicating that ligustilide may alleviate OGD/R injury of PC12 cells by blocking ferritinophagy and then inhibiting ferroptosis. The mechanism by which ligustilide reduced OGD/R injury in PC12 cells is that it suppressed the ferroptosis involved in ferritinophagy.

Betulin Targets Lipin1/2-Meidated P2X7 Receptor as a Therapeutic Approach to Attenuate Lipid Accumulation and Metaflammation

The present study focused on the potential mechanism of betulin (BT), a pentacyclic triterpenoid isolated from the bark of white birch (Betula pubescens), against chronic alcohol-induced lipid accumulation and metaflammation. AML-12 and RAW 264.7 cells were administered ethanol (EtOH), lipopolysaccharide (LPS) or BT. Male C57BL/6 mice were fed Lieber-DeCarli liquid diets containing 5% EtOH for 4 weeks, followed by single EtOH gavage on the last day and simultaneous treatment with BT (20 or 50 mg/ kg) by oral gavage once per day. In vitro, MTT showed that 0-25 mM EtOH and 0-25 μM BT had no toxic effect on AML-12 cells. BT could regulate sterolregulatory-element-binding protein 1 (SREBP1), lipin1/2, P2X7 receptor (P2X7r) and NOD-like receptor family, pyrin domains-containing protein 3 (NLRP3) expressions again EtOH-stimulation. Oil Red O staining also indicated that BT significantly reduced lipid accumulation in EtOH-stimulated AML-12 cells. Lipin1/2 deficiency indicated that BT might mediate lipin1/2 to regulate SREBP1 and P2X7r expression and further alleviate lipid accumulation and inflammation. In vivo, BT significantly alleviated histopathological changes, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and triglyceride (TG) levels, and regulated lipin1/2, SREBP1, peroxisome proliferator activated receptor α/γ (PPARα/γ) and PGC-1α expression compared with the EtOH group. BT reduced the secretion of inflammatory factors and blocked the P2X7rNLRP3 signaling pathway. Collectively, BT attenuated lipid accumulation and metaflammation by regulating the lipin1/2-mediated P2X7r signaling pathway.

Preparation and targeting evaluation of reductant-sensitive oxaliplatin-loaded Fe3O4 nanoparticles / 药学学报

The non-specific accumulation and release of drugs are the main factors affecting the therapeutic effect as well as causing toxic side effects of chemotherapeutic drugs. Nowadays, the application of nanotechnology and responsive drug release is an important strategy to improve the tumor-specific accumulation of drugs and reduce their side effects. In this study, an α-enolase targeted peptide (ETP)-modified polyethylene glycol poly-lysine block copolymer loaded with oxaliplatin prodrug was synthesized first, and then, polymer-coating Fe3O4 nanoparticles were prepared by phase transfer dialysis method to improve the blood circulation stability and tumor targeting of oxaliplatin. At the same time, the physicochemical properties, reductant-responsive drug release, cellular uptake, tumor targeting and other biological functions of ETP modified oxaliplatin-loaded Fe3O4 nanoparticles were studied in vitro and in vivo. First, the results of reductant-triggered drug release study showed that the drug-loaded nanoparticles could achieve rapid release of more than 80% of the prototype oxaliplatin within 3 h under the reduction conditions simulating the tumor cytoplasmic microenvironment. Secondly, the results of flow cytometry showed that the modification of ETP could increase the ratio of cellular uptake of drug-loaded nanoparticles in tumor cells, and the way that drug-loaded nanoparticles endocytosed by tumor cells were mainly through the energy-dependent and receptor protein and fossin-mediated endocytosis pathway. The animal procedures were approved by the Institutional Animal Care and Use Committee of School of Pharmacy of Fudan University. Moreover, the results of pharmacokinetic experiment showed that the area under the curve (AUC0-∞) of oxaliplatin could be significantly increased by nano-formulation which was about 5 times than that of free oxaliplatin. Besides, the pharmacokinetic results also showed that the drug-loaded Fe3O4 nanoparticles constructed by covalent linkage and chelation had good overall stability in vivo. Finally, the in vivo imaging results showed that ETP modification could increase tumor accumulation of drug-loaded nanoparticles, which would be conducive to the efficacy of oxaliplatin in tumor lesions. In summary, the oxaliplatin-loaded Fe3O4 nanoparticles with the capability of reductant-responsive drug release have good drug release characteristics, blood circulation stability and tumor targeting ability, and have the potential to improve the anti-tumor therapeutic effect of oxaliplatin.

Intravenous route to choroidal neovascularization by macrophage-disguised nanocarriers for mTOR modulation

Retinal pigment epithelial (RPE) is primarily impaired in age-related macular degeneration (AMD), leading to progressive loss of photoreceptors and sometimes choroidal neovascularization (CNV). mTOR has been proposed as a promising therapeutic target, while the usage of its specific inhibitor, rapamycin, was greatly limited. To mediate the mTOR pathway in the retina by a noninvasive approach, we developed novel biomimetic nanocomplexes where rapamycin-loaded nanoparticles were coated with cell membrane derived from macrophages (termed as MRaNPs). Taking advantage of the macrophage-inherited property, intravenous injection of MRaNPs exhibited significantly enhanced accumulation in the CNV lesions, thereby increasing the local concentration of rapamycin. Consequently, MRaNPs effectively downregulated the mTOR pathway and attenuate angiogenesis in the eye. Particularly, MRaNPs also efficiently activated autophagy in the RPE, which was acknowledged to rescue RPE in response to deleterious stimuli. Overall, we design and prepare macrophage-disguised rapamycin nanocarriers and demonstrate the therapeutic advantages of employing biomimetic cell membrane materials for treatment of AMD.

Macular vessel defects for Coats' disease associated with subfoveal fibrotic nodule / 中华眼底病杂志

Objective:To investigate macular microvascular abnormalities in eyes with subfoveal fibrotic nodules secondary to Coats' disease.Methods:A cross-sectional study. From January 1, 2018 to July 30, 2021, 45 eyes of 45 patients diagnosed with Coats' disease with or without subfoveal fibrotic nodules in Eye and ENT Hospital, Shanghai Medical College of Fudan University were included in this study. There were 40 eyes in 40 males and 5 eyes in 5 females. All were under 21 years old. According to the presence or absence of subfoveal fiber nodules, the patients were divided into fibrotic group (26 cases, 26 eyes) and non-fibrotic group (19 cases, 19 eyes). Optical coherence tomography angiography was used to scan 3 mm×3 mm or 6 mm×6 mm macular area of both eyes. The software of the device automatically processed the images. The presence of FAZ edge anastomotic vascular arch ring breakage and abnormal microvascular branch (AMB) in the foveal avascular zone (FAZ) were observed.Results:In 26 eyes of fibrosis group, AMB originating from the parafoveal retinal capillary network was observed, which grew into and destroyed the integrity of the vascular arch ring at the edge of FAZ. AMB was crisscrossing and winding, and its curvature expands. B-scan images showed the blood flow signal in the subfoveal fiber nodule, and the blood flow signal traversed between the inner retina and the fiber nodule in 23 eyes (88.46%, 23/26). In the non-fibrosis group, all the vascular abnormalities were characterized by capillary dilation and defect, and no breakage of FAZ anastomotic vascular arch ring or AMB was observed.Conclusions:In Coats' disease with subfoveal fiber nodules, staggered and dilated AMBs emerge from the parafoveal vascular network, grow into and destroy the integrity of the vascular arch ring at the edge of FAZ, and grow down longitudinally into the fiber nodules.

A prospective case-control study of intravitreal injection of anti-vascular endothelial factor drugs in the treatment of Coats disease / 中华眼底病杂志

Objective:To investigate the efficacy and safety of traditional laser photocoagulation, laser combined with intravitreal injection of anti-vascular endothelial factor (anti-VEGF) drugs and intravitreal injection of anti-VEGF drugs alone in Coats disease.Methods:The patients diagnosed as Coats disease stage 2B-3A2 in Department of Ophthalmology, Eye and ENT Hospital of Shanghai Medical College of Fudan University from December 2016 to November 2019 were included in this study. Patients were divided into three groups, including laser group, combined group and drug group, according to the different treatment. In the laser group, the initial treatment was traditional laser photocoagulation alone. In the drug group, the anti-VEGF drug was injected into vitreous once a month for three months. The initial treatment of the eyes in the combined group was laser combined with intravitreal injection of anti-VEGF drugs, or laser treatment within 1 week after anti-VEGF drug treatment. The follow-up time was more than 6 months, and best-corrected visual acuity (BCVA), ultra-wide-angle fundus photography, and fluorescein fundus angiography were performed during follow-up. The treatment efficiency, subretinal fluid (SRF), macular edema, BCVA and complications were compared among the three groups.Results:Among 60 patients (60 eyes), there were 55 males (55 eyes) and 5 females (5 eyes), with the mean age of 17.1±2.0 years. Among 60 eyes, there were 26 eyes in 2B stage, 23 eyes in 3A1 stage, and 11 eyes in 3A2 stage. Twenty patients (20 eyes) was in the laser group, combined group and drug group, respectively. After the initial treatment of all eyes in the drug group, the abnormal blood vessels did not regress significantly; the absorption and increase of SRF were 4 (20.0%, 4/20) and 5 (25.0%, 5/20) eyes, respectively. Supplementary laser therapy was given to 16 eyes, and vitrectomy (PPV) was given to 4 eyes. Among the 16 eyes treated by laser, 10 eyes were effective (50.0%, 10/20); vitreous hemorrhage, fibrous membrane hyperplasia, and complicated cataract occurred in 1, 1, and 2 eyes during the treatment, respectively, and PPV was given again in all eyes. Recurrent and persistent macular edema occurred in 4 and 1 eyes, respectively. Among the eyes in the combined group, treatment were effective in 11 eyes (55.0%, 11/20); 5, 2, and 2 eyes had SRF, fibrous membrane hyperplasia, and complicated cataract during the treatment, and PPV was given again; the edema was repeated and persisted in 1 eye, respectively. Among the affected eyes in the laser group, 15 eyes (75.0%, 15/20) were treated effectively; 2, 2, and 1 eyes developed a large number of vitreous hemorrhage, fibrous membrane hyperplasia, and complicated cataract during the treatment, and PPV was given again.Conclusions:Anti-VEGF drugs alone are ineffective in the treatment of Coats disease, and ablation of other abnormal blood vessels is needed. In the treatment of Coats disease, anti-VEGF drugs can not only promote the absorption of SRF, but also may lead to its increase, and the application should be cautious.

Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

Blood-brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (

Recent advances in nanomedicines for the treatment of ischemic stroke

Ischemic stroke is a cerebrovascular disease normally caused by interrupted blood supply to the brain. Ischemia would initiate the cascade reaction consisted of multiple biochemical events in the damaged areas of the brain, where the ischemic cascade eventually leads to cell death and brain infarction. Extensive researches focusing on different stages of the cascade reaction have been conducted with the aim of curing ischemic stroke. However, traditional treatment methods based on antithrombotic therapy and neuroprotective therapy are greatly limited for their poor safety and treatment efficacy. Nanomedicine provides new possibilities for treating stroke as they could improve the pharmacokinetic behavior of drugs

Study on potential mechanism of hyperoside on improving ischemia/reperfusion injury based on network pharmacology / 中国药理学与毒理学杂志

OBJECTIVE To predict the potential targets of hyperoside (Hyp) on improving ischemia/reperfusion injury by network pharmacology, and explore its possible mechanism combined with related literature. METHODS The action targets of Hyp and ischemia/reperfusion injury were obtained by TCMSP, Swiss Target Prediction, Pharm Mapper, Simi?larity ensemble approach, Online Mendelian Inheritance in Man, DisGENT and database. The common targets of drugs and diseases were screened by Omishare and STRING database respectively, and the protein-protein interaction (PPI) network map was constructed. Then the interaction network between Hyp and disease targets was constructed by Cyto?scape software and topological cross-linking analysis was carried out. Then the interaction network between Hyp and disease targets was constructed and cross-linked analysis was carried out by using Cytoscape software. The gene ontol?ogy (GO) of the core target was analyzed by David database, and then the related pathways of the core target were enriched by KEGG database. RESULTS A total of 54 GO enrichment processes were obtained by GO enrichment anal?ysis of 44 common genes, including 38 biological processes (BP), 15 cell composition (CC) processes, and 1 molecular functional (MF) process. 43 items were obtained by signal pathway enrichment analysis in KEGG database. CONCLU?SION It is suggested that the mechanism of Hyp may be related to PI3K-Akt, RAP1, RAS, VEGF and other signal trans?duction pathways. The above results laid a theoretical foundation for the study of the mechanism and clinical application of the treatment of ischemia/reperfusion injury.

Effects of total flavonoids of Rhododendra simsii on ameliorating brain injury via G protein-coupled SOCE pathway mediated by STIM and Orai in subacute phase of ischemia/reperfusion / 中国药理学与毒理学杂志

OBJECTIVE To explore the effect of total flavonoids of Rhododendra simsii (TFR) on improving cerebral ischemia/reperfusion injury (CIRI) and its relationship with STIM/Orai-regulated operational Ca2+influx (SOCE) pathway. METHODS Oxygen-glucose deprivation/reoxygenation (OGD/R) PC12 cells were used to simulate CIRI in vitro, and the intracellular Ca2+ concentration and apoptosis rate of PC12 cells were detected by laser confocal microscope and flow cytometry, respectively. The regulation of STIM/Orai on SOCE was analyzed by STIM/Orai gene silencing and STIM/Orai gene overexpression. The CIRI model was established by MCAO in SD rats. The activities of inflammatory cyto?kines IL-1, IL-6 and TNF-αin serum were detected by ELISA. The pathological changes of ischemic brain tissue and the infarction of rat brain tissue were detected by HE staining and TTC staining. The protein and mRNA expression levels of STIM1, STIM2, Orai1, caspase-3 and PKB in brain tissue were detected by Western blotting and RT-qPCR, respectively. RESULTS The results of in vitro experiment showed that the fluorescence intensity of Ca2+ and apoptosis rate in PC12 cells treated with TFR were significantly lower than those in OGD/R group, and this trend was enhanced by SOCE antagonist 2-APB. STIM1/STIM2/Orai1 gene silencing significantly reduced apoptosis and Ca2+overload in OGD/R model, while TFR combined with overexpression of STIM1/STIM2/Orai1 aggravated apoptosis and Ca2+overload. In the in vivo experiment, TFR significantly reduced the brain histopathological damage, infarction of brain tissue, the contents of IL-1, IL-6 and TNF-α in the serum in MCAO rats and down-regulated the expression of STIM1, STIM2, Orai1 and caspase-3 protein and mRNA in the brain tissue, and up-regulated the expression of PKB. The above effects were enhanced by the addition of 2-APB. CONCLUSION The above results indicate that TFR may reduce the contents of inflammatory factors and apoptosis, decrease Ca2+ overload and ameliorate brain injury by inhibiting SOCE pathway mediated by STIM and Orai, suggesting that it has a protective effect against subacute CIRI.

Baicalin protects against 17α-ethinylestradiol-induced cholestasis via Sirt1/HNF-1α/FXR pathway / 中国药理学与毒理学杂志

OBJECTIVE Baicalin is a major flavonoid component of Scutellaria baicalensis, and has been used in the treatment of liver diseases for many years. However, the role of baicalin in estrogen-induced cholestasis (EIC) remains to be elucidated. This present study explored the protective effect of baicalin against estrogen-induced liver injury and further elucidated the mechanisms involved both in vivo and in vitro. METHODS We conducted a series of experiments using 17α-ethinylestradiol (EE) induced cholestatic rats and cultured HepG2 cells. Serum, bile, and liver samples were collected for biochemical and histological analyses. Bile acid composition in liver was analyzed by LC-MS/MS. The mechanisms underlying the hepatoprotective of baicalin were investigated by RT-PCR, Western blotting analyses and immunohistochemistry. RESULTS Baicalin showed obvious hepatoprotective effects in EIC rats by reducing serum bio?markers and increasing the bile flow rate, as well as by alleviating liver histology and restoring the abnormal composition of hepatic bile acids (BAs). In addition, baicalin protected against EE induced liver injury by up-regulation of the expres?sion of hepatic efflux transporters and down-regulation of hepatic uptake transporters. Furthermore, baicalin increased the expression of hepatic BA synthase (CYP27A1) and metabolic enzymes (Bal, Baat and Sult2a1) in EIC rats. We showed that baicalin significantly inhibited hepatic inflammatory responses in EIC rats through reducing elevated levels of TNF-α, IL-1β, IL-6 and NF-κB. Finally, we confirmed that baicalin maintains BA homeostasis and alleviates inflamma?tion through Sirt1/HNF-1α/FXR signaling pathway. CONCLUSION Baicalin protects against estrogen-induced cholestatic liver injury, and the underlying mechanism involved is related to activation of the Sirt1/HNF-1α/FXR signaling pathway.

Interferon-regulatory factors regulate macrophage polarization and its role in diseases / 药学学报

Macrophages are highly plastic and heterogeneous. In different types of inflammatory diseases, or at different stages of the same disease, macrophages can undergo phenotypic transformation to elicit different functions. Hence, exploring new regulatory mechanism of macrophage polarization and seeking for new key mediators will lay the foundation for the diagnosis and treatment of macrophage-related diseases, such as inflammatory diseases, autoimmune diseases, and cancer. Interferon regulatory factors (IRFs) have been reported to play an important role in the maturation and differentiation of macrophages. In this review, we will describe the structure and modulation pattern of IRFs, and then further summarize the molecular mechanism and signal regulation network of IRFs in pathological processes of related diseases through controlling macrophage polarization. Our review will explore the new therapeutic strategy and potential drug targets for related diseases.

The research of relationship between medical students' time engagement outside classes and general self-efficacy / 中华医学教育探索杂志

Objective:To analyze the relationship between the clinical medical college students' time investment (including study, activities, entertainment and exercise) and general self-efficacy (GSE) in a medical university in Liaoning province, China.Methods:The first-year medical students were asked to participate the survey. Their GSE was measured by using general self-efficacy scale (GSES) in 2018. One year later, the independent variable table was used to investigate the extracurricular activity time, and 683 valid questionnaires were collected. Ordered logistic regression method was used to analyze the correlation between students' extracurricular activities and GSE.Results:Medical students' GSE was positively associated with their time in extracurricular study ( OR = 1.94, 95%CI = 1.49-2.54), volunteer activities ( OR=1.36, 95%CI = 1.01-1.83), and physical activities ( OR = 1.37, 95%CI = 1.01-1.85). However, there was no significant correlation with the time in activities organized by students ( OR = 1.09, 95%CI = 0.79-1.50) or activities organized by school ( OR = 1.15, 95%CI = 0.84-1.59). Furthermore, compared with clinical students of "5+3" year program, the 5-year program clinical students had a stronger correlation between medical students' GSE and the input of extracurricular study time. Conclusion:There is a positive correlation between medical students' GSE and their extracurricular time investment, which indicates that increasing medical students' GSE could be an effective method to improve their extracurricular time investment and eventually improve their comprehensive quality.

Network Meta-analysis of 14 oral Chinese patent medicines combined with Azithromycin in treatment of mycoplasma pneumonia in children / 中国中药杂志

To systematically evaluate the clinical efficacy of 14 oral Chinese patent medicines combined with Azithromycin in the treatment of mycoplasma pneumonia in children with network Meta-analysis. Computer retrieval was performed for such databases as CNKI, VIP, Wanfang, CBM, PubMed, EMbase and Cochrane Library to screen out randomized controlled trials of oral Chinese patent medicines combined with Azithromycin in the treatment of mycoplasma pneumonia in children from the time of database establishment to September 2020. The included studies were evaluated by the Cochrane Risk Assessment tool. Stata 14.0 and Review Manager 5.3 software were used for data statistical analysis. A total of 60 RCTs were included in this study, involving 14 oral Chinese patent medicines. The efficacy ranking based on network Meta-analysis was as follows:(1)in terms of total effective rate, top five Chinese patent medicines in surface under the cumulative ranking curve(SUCRA) were Xiao'er Xiaoji Zhike Oral Liquid, Xiao'er Chiqiao Qingre Granules, Xiao'er Feike Granules, Pudilan Xiaoyan Oral Liquid and Lanqin Oral Liquid;(2)in terms of antifebrile time, top five Chinese patent medicines in SUCRA were Huaiqihuang Granules, Xiao'er Magan Granules, Xiao'er Kechuanling Granules/Oral Liquid, Shuanghuang-lian Oral Liquid for children and Xiao'er Xiaoji Zhike Oral Liquid;(3)in terms of cough disappearance time, top five Chinese patent medicines in SUCRA were Xiao'er Magan Granules, Huaiqihuang Granules, Xiao'er Chiqiao Qingre Granules, Xiao'er Feire Kechuan Oral Liquid and Xiao'er Kechuanling Granules/Oral Liquid;(4)in terms of rale disappearance time, top five Chinese patent medicines in SUCRA were Xiao'er Magan Granules, Huaiqihuang Granules, Xiao'er Feire Kechuan Oral Liquid, Shuanghuanglian Oral Liquid for children and Yupingfeng Granules. The results showed that on the basis of the use of Azithromycin, combined administration with oral Chinese patent medicines could improve the overall clinical efficacy in the treatment of mycoplasma pneumonia in children. However, due to the large differences in the quality and the number of included studies among various therapeutic measures, the ranking results of SUCRA of Chinese patent medicines need to be verified by high-quality multi-center, large-sample, randomized double-blind trials in the future.

A method to create a new rat model of combination of disease and syndrome with cervical vertigo hyperactivity of liver yang syndrome / 中国骨伤

OBJECTIVE@#To establish a simple and reliable model of cervical vertigo in rats with hyperactivity of liver-yang syndrome, and to establish a simple and feasible method for evaluating the degree of vertigo in animals.@*METHODS@#SPF male SD rats (aged 8 weeks, weighing 280 to 320 g) were randomly divided into 4 groups (6 rats in each group). The model of cervical vertigo of hyperactivity of liver yang syndrome (joint modeling group) was established by combining local injection of lauromacrogol (hardener) and receiving decoction by gavage. The joint modeling group was compared with the hardener group, the decoction group and the blank control group. The vertigo degree of rats was measured by the time of passing through a glass tube (running time) before modeling, 2 weeks and 3 weeks after the established model.@*RESULTS@#There was no statistical difference in the running time between control group and decoction group, between joint modeling group and hardener group. The running time in the hardener group and the joint modeling group was longer than that in the control group (0.05).@*CONCLUSION@#This method can effectively establish a rat model of cervical vertigo with hyperactivity of liver-yang syndrome, and the running time can reflect the degree of vertigo in rats to a certain extent. This experiment provides a simple and feasible animal model and detection method for research of cervical vertigo in the future.

Analysis of surveillance results of human brucellosis monitoring sites in Jiangsu Province from 2013 to 2017 / 中华地方病学杂志

Objective:To explore the epidemic situation and brucellosis in key occupational populations of brucellosis monitoring sites in Jiangsu Province, and provide a basis for development of prevention and control strategies against brucellosis.Methods:From 2013 to 2017, according to the requirements of the "National Brucella Surveillance Programme", two brucellosis monitoring sites in Yixing City of Wuxi and Huaiyin District of Huai'an, Jiangsu Province were established to monitor brucellosis. Brucellosis epidemic data were collected and analyzed of the two monitoring sites in Yixing City and Huaiyin District from 2013 to 2017 (data were from Jiangsu Provincial Legal Infectious Disease Reporting System). Blood samples were collected from the general occupational populations (health check-up population) and the key occupational populations (people engaged in livestock trading, livestock slaughtering, and the fur, milk and meat processing) in the monitoring sites. Tiger red plate agglutination test (RBPT) and serum tube agglutination test (SAT) were used for serological examination. Results:From 2013 to 2017, a total of 18 cases of brucellosis were reported at the two monitoring sites in Yixing City and Huaiyin District, Jiangsu Province, including 13 males and 5 females, with a male to female sex ratio of 2.6∶1.0; the age of onset was mainly 35 - 64 years, accounting for 72.22% (13/18); the time of onset was mainly from January to June, accounting for 94.44% (17/18); and the occupational distribution was mainly farmers, accounting for 77.78% (14/18); there was no epidemic and outbreaks of brucellosis. A general occupational populations survey was conducted in 17 743 cases, serological tests were negative, no infection and no signs and symptoms were found in the two monitoring sites. In 2013 - 2017, a total of 113 cases of serological tests were positive in the key occupational populations of brucellosis in Jiangsu Province, with a positive rate of 7.83% (113/1 444), and the overall trend was downward year by year ( t = 6.463, P < 0.05). Among them, the positive rates in Yixing City and Huaiyin District were 11.79% (106/899) and 1.28% (7/545), respectively. The difference between different regions was statistically significant (χ 2 = 51.926, P < 0.01). The positive rates of occupational groups engaged in livestock trading, livestock slaughtering, and the fur, milk and meat processing were 5.10% (20/392), 9.74% (49/503), and 8.01% (44/549), respectively. The differences were statistically significant between different occupations (χ 2 = 6.618, P < 0.05); and the positive rates of livestock slaughtering occupations and the fur, milk and meat processing occupations were higher than that of livestock trading occupations ( P < 0.05). Conclusions:The positive rate of brucellosis in key occupational populations has showed a general downward trend, the livestock slaughtering occupations and the fur, milk and meat processing occupations are more susceptible to Brucella infection. It is still necessary to strengthen the health education for the key occupational populations of brucellosis and inspection and quarantine work for prevention of the epidemic of brucellosis in humans.