Identification and expression analysis of the YABBY gene family in strawberry / 生物工程学报

YABBY proteins are important transcription factors that regulate morphogenesis and organ development in plants. In order to study the YABBY of strawberry, bioinformatic technique were used to identify the YABBY gene families in Fragaria vesca (diploid) and Fragaria×ananassa (octoploid), and then analyze the sequence characters, phylogeny and collinearity of the family members. The RNA-seq data and the quantitative reverse transcription-polymerase chain reaction (qRT-PCR) technique were used to assay the expression patterns of the family members. A green fluorescent protein (GFP) was fused with FvYABBYs and transiently expressed in tobacco leaf cells for the subcellular localization. As the results, six FvYABBY genes and 26 FxaYABBY genes were identified from F. vesca and F.×ananassa, respectively. The FvYABBY genes were grouped into five clades, and five family members were orthologous with AtYABBY genes of Arabidopsis. In F. vesca, all of the FvYABBYs were basically not expressed not expressed in root and receptacle, while FvYABBY1, FvYABBY2, FvYABBY5 and FvYABBY6 were highly expressed in leaf, shoot, flower and achene. In F.×ananassa, FxaYABBY1, FxaYABBY2, FxaYABBY5 and FxaYABBY6 were expressed in achene, and all FxaYABBY were poorly or not expressed in receptacle. Additionally, under the abiotic stresses of low temperature, high salt and drought, the expression of FvYABBY1, FvYABBY3, FvYABBY4 and FvYABBY6 were down-regulated, FvYABBY5 was up-regulated, and FvYABBY2 was up-regulated and then down-regulated. In tobacco leaf cells, the subcellular localization of FvYABBY proteins were in the nucleus. These results provides a foundation for the functional researches of YABBY gene in strawberry.

Analysis on Components Absorbed into Blood and Cerebrospinal Fluid of Schisandrae Chinensis Fructus Based on Sequential Metabolism / 中国实验方剂学杂志

ObjectiveTo identify the prototypical components and metabolites absorbed into blood and cerebrospinal fluid of Schisandrae Chinensis Fructus（SCF） based on sequential metabolism combined with liquid chromatography-mass spectrometry. MethodBlood and cerebrospinal fluid samples of integrated metabolism， intestinal metabolism and hepatic metabolism were collected from male SD rats after gavage and in situ intestinal perfusion administration， and ultra-performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry（UPLC Q-Exactive Orbitrap MS） was used to analyze and compare the differences in the spectra of SCF extract， blank plasma， administered plasma， blank cerebrospinal fluid and administered cerebrospinal fluid with ACQUITY UPLC BEH Shield RP18 column（2.1 mm×100 mm， 1.7 µm）， the mobile phase was acetonitrile（A）-0.1% formic acid aqueous solution（B） for gradient elution（0-7 min， 95%B； 7-12 min， 95%-35%B； 12-17 min， 35%-15%B； 17-20 min， 15%-12%B； 20-22 min， 12%-5%B； 22-23 min， 5%B； 23-25 min， 5%-95%B； 25-28 min， 95%B）. And heated electrospray ionization（HESI） was used with positive and negative ion modes， the scanning range was m/z 100-1 500. The prototypical constituents and their metabolites absorbed into blood and cerebrospinal fluid of SCF were identified according to the retention time， characteristic fragments， molecular formulae and the information of reference substances. ResultA total of 42 chemical components were identified in the extract of SCF， including lignans， flavonoids， amino acids， tannins， and others， of which lignans were the main ones. A total of 27 prototypical components and 14 metabolites were identified in plasma samples from different sites. A total of 15 prototypical components and 9 metabolites were identified in cerebrospinal fluid. The main metabolic reactions involved in the formation of metabolites were mainly demethylation， methylation， demethoxylation and hydroxylation. ConclusionThrough the systematic identification of the prototypical components and metabolites of SCF in rats， it provides data support for further better exploring the material basis of SCF in the treatment of central nervous system diseases.

Analysis of Inhibitory Effect of Berberine Compounds on Acetylcholinesterase and Blood-brain Barrier Permeability / 中国实验方剂学杂志

ObjectiveTo examine the inhibitory effects of berberine compounds， including columbamine， on acetylcholinesterase from the perspectives of drug-target binding affinity and kinetics and explore the blood-brain barrier （BBB） permeability of these compounds in different multi-component backgrounds. MethodThe median inhibitory concentration （IC50） of acetylcholinesterase by berberine compounds including columbamine was measured using the Ellman-modified spectrophotometric method. The binding kinetic parameters （Koff） of these compounds with acetylcholinesterase were determined using the enzyme activity recovery method. A qualitative analysis of the ability of these components to penetrate the BBB and arrive at the brain tissue in diverse multi-component backgrounds （including medicinal herbs and compound formulas） was conducted using ultra performance liquid chromatography-high resolution mass spectrometry （UPLC-HRMS）. ResultBerberine compounds， including columbamine， exhibited strong inhibition of acetylcholinesterase， with IC50 values in the nanomolar range. Moreover， they displayed better drug-target binding kinetics characteristics （with smaller Koff values） than the positive control of donepezil hydrochloride （P<0.01）， indicating a longer inhibition duration of acetylcholinesterase. Berberine components such as columbamine could penetrate the BBB to arrive at brain tissue in the form of a monomer， as well as in the multi-component backgrounds of Coptis and Phellodendri Chinensis Cortex medicinal extracts and the compound formula Huanglian Jiedutang. ConclusionThese berberine compounds such as columbamine exhibit a strong inhibitory effect on acetylcholinesterase and can arrive at brain tissue in multi-component backgrounds. In the level of pharmacological substance， this supports the clinical efficacy of compound Huanglian Jiedutang in improving Alzheimer's disease， providing data support for elucidating the pharmacological basis of compound Huanglian Jiedutang.

Polarity protein AF6 functions as a modulator of necroptosis by regulating ubiquitination of RIPK1 in liver diseases.

AF6, a known polarity protein, contributes to the maintenance of homeostasis while ensuring tissue architecture, repair, and integrity. Mice that lack AF6 display embryonic lethality owing to cell-cell junction disruption. However, we show AF6 promotes necroptosis via regulating the ubiquitination of RIPK1 by directly interact with the intermediate domain of RIPK1, which was mediated by the deubiquitylase enzyme USP21. Consistently, while injection of mice with an adenovirus providing AF6 overexpression resulted in accelerated TNFα-induced necroptosis-mediated mortality in vivo, we observed that mice with hepatocyte-specific deletion of AF6 prevented hepatocytes from necroptosis and the subsequent inflammatory response in various liver diseases model, including non-alcoholic steatohepatitis (NASH) and the systemic inflammatory response syndrome (SIRS).Together, these data suggest that AF6 represents a novel regulator of RIPK1-RIPK3 dependent necroptotic pathway. Thus, the AF6-RIPK1-USP21 axis are potential therapeutic targets for treatment of various liver injuries and metabolic diseases.

Advances in anti-invasive fungal drug delivery systems / 浙江大学学报·医学版

Currently, the first-line drugs for invasive fungal infections (IFI), such as amphotericin B, fluconazole and itraconazole, have drawbacks including poor water solubility, low bioavailability, and severe side effects. Using drug delivery systems is a promising strategy to improve the efficacy and safety of traditional antifungal therapy. Synthetic and biomimetic carriers have greatly facilitated the development of targeted delivery systems for antifungal drugs. Synthetic carrier drug delivery systems, such as liposomes, nanoparticles, polymer micelles, and microspheres, can improve the physicochemical properties of antifungal drugs, prolong their circulation time, enhance targeting capabilities, and reduce toxic side effects. Cell membrane biomimetic drug delivery systems, such as macrophage or red blood cell membrane-coated drug delivery systems, retain the membrane structure of somatic cells and confer various biological functions and specific targeting abilities to the loaded antifungal drugs, exhibiting better biocompatibility and lower toxicity. This article reviews the development of antifungal drug delivery systems and their application in the treatment of IFI, and also discusses the prospects of novel biomimetic carriers in antifungal drug delivery.

Intervention of Traditional Chinese and Western Medicine in NLRP3 Inflammasome-mediated Digestive System Diseases： A Review / 中国实验方剂学杂志

The aberrant activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 （NLRP3） inflammasome as an essential component of the innate system is implicated in the pathogenesis of several human inflammatory diseases. Studies have confirmed its association with digestive system diseases such as ulcerative colitis， Crohn's disease， and acute pancreatitis， suggesting that the NLRP3 inflammasome plays a role in the initiation and progression of these diseases. Based on the mechanism of NLRP3 inflammasome activation and the pathways that mediate the inflammatory response， this article introduced the relationship between the NLRP3 inflammasome and the pathogenesis of multiple digestive system diseases and the Chinese and western medical therapies. Traditional Chinese medicine （TCM） has demonstrated definite effects on the NLRP3 inflammasome-mediated digestive system diseases. Some single Chinese medicines or TCM prescriptions can treat digestive system diseases by activating or inhibiting NLRP3 inflammasome activation. NLRP3 inflammasome can receive a variety of endogenous and exogenous stimulatory signals， which can initiate， activate， and mediate inflammatory responses. The inflammasome formation and downstream inflammatory cytokines are involved in not only the inflammatory responses but also the development and progression of multiple digestive system diseases. Therefore， the NLRP3 inflammasome can serve as an ideal target for disease treatment. The future rediscovery and in-depth studies of multiple inflammasomes will shed new light on the treatment of multiple digestive system diseases.

Research progress of Mycobacterium abscessus complex diseases / 中华临床感染病杂志

Mycobacterium abscessus complex (MABC), a rapidly growing nontuberculous mycobacterium, has received increasing attention worldwide due to its rising isolation rate. The similarity of symptoms between MABC pulmonary disease and tuberculosis, different treatment methods required by different subtypes, as well as high levels of innate, adaptive and acquired antibiotic resistance, make MABC treatment more difficult and lead to unfavorable clinical outcomes of patients. This article reviews the basic characteristics, common antibiotic resistance mechanisms, as well as diagnosis and treatment of MABC, to provide reference for future research and clinical treatment of MABC lung disease.

Correlation analysis of BRAF V600E mutation with clinical pathological features and prognosis of differentiated thyroid cancer patients with different risk stratification / 中华核医学与分子影像杂志

Objective:To explore the relationship between B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation and clinical pathological features in patients with differentiated thyroid cancer (DTC), and to evaluate the value of BRAF V600E mutation in predicting the efficacy and follow-up of 131I treatment in DTC patients with different risk stratification. Methods:From January 2018 to June 2022, 893 DTC patients (205 males, 688 females, age (42.3±11.9) years) treated with 131I after total thyroidectomy in the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. Patients were divided into BRAF V600E mutation group ( n=729) and wild-type group ( n=164). According to the 2015 American Thyroid Association (ATA) guidelines, patients were divided into low-risk (39 cases), medium-risk (498 cases) and high-risk (356 cases), and the curative effect was divided into excellent response (ER) and non-excellent response (NER). The χ2 test, independent-sample t test and Mann-Whitney U test were used to compare differences between the two groups. Logistic regression analysis was performed to predict the influencing factors of treatment effect in DTC patients with different risk stratification. Results:The differences in age≥45 years, N stage, unilateral or bilateral DTC, multifocus, mode of operation, number and size of metastatic lymph nodes were statistically significant between BRAF V600E mutation group and wild-type group ( χ2 values: 4.45-17.40, t=-4.08, z=-3.08, all P<0.05). In medium- and high-risk stratification, the stimulated thyroglobulin (sTg) levels before and after 131I treatment were slightly higher in the BRAF V600E mutation group, while significantly sharp decreased of sTg and thyroglobulin antibody (TgAb) in wild-type group ( z value: from -9.30 to -2.65, all P<0.05). In medium- and high-risk stratification, 69.0%(60/87) and 64.3%(45/70) of BRAF V600E wild-type patients reached ER after 131I treatment, which were higher than those of mutant patients (57.4%(236/411) and 45.8%(131/286); χ2 values: 3.96, 7.39, P values: 0.046, 0.007). BRAF V600E mutation was the independent predictor affecting the efficacy of 131I treatment in DTC patients with medium- and high-risk stratification (odds ratio ( OR): 0.411 (95% CI: 0.196-0.864), 0.192 (95% CI: 0.096-0.384), P values: 0.019, <0.001). Conclusions:DTC patients with BRAF V600E mutation are related to the high invasiveness, and show poor improvement in biochemical indicators after initial 131I treatment. In addition, BRAF V600E mutation is an important factor in predicting the therapeutic effect of 131I in DTC patients with medium- and high-risk stratification.

Predictive value of metabolic tumor volume and total lesion glycolysis in 18F-FDG PET/CT imaging for prognosis in patients with extensive-stage small cell lung cancer / 中华核医学与分子影像杂志

Objective:To investigate the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with extensive-stage small cell lung cancer (ES-SCLC).Methods:From March 2019 to June 2020, 69 patients (55 males, 14 females, age: 38-87 years) with ES-SCLC who underwent pretreatment 18F-FDG PET/CT in First Affiliated Hospital of Zhengzhou University were retrospectively enrolled. The variables including gender, age, smoking, weight loss, liver metastasis, bone metastasis, malignant effusion, SUV max of the primary tumor, whole-body MTV (wbMTV) and whole-body TLG (wbTLG) (including wbMTV 40%, wbTLG 40%, wbMTV 2.5 and wbTLG 2.5) were analyzed. The predictors of overall survival (OS) were analyzed by using Kaplan-Meier method (log-rank test). Results:Of 69 ES-SCLC patients, 43(62%) died and 26(38%) were still alive by the end of follow-up, with a median survival time of 15.0(95% CI: 11.7-18.3) months. Univariate analysis revealed that age ( χ2=4.53, P=0.033), bone metastasis ( χ2=18.05, P<0.001), liver metastasis ( χ2=27.94, P<0.001), wbMTV 2.5 ( χ2=3.98, P=0.046), and wbTLG 2.5( χ2=5.80, P=0.016) were significant predictors of OS. Conclusion:wbMTV 2.5 and wbTLG 2.5 are assosciated with OS and may provide some reference value for predicting the prognosis of ES-SCLC patients.

Effect of normal iodized salt diet on urinary iodine concentration and iodine uptake rate in patients with differentiated thyroid cancer before 131I treatment / 中华核医学与分子影像杂志

Objective:To investigate the effects of normal iodized salt diet on urinary iodine concentration and iodine uptake rate in patients with differentiated thyroid cancer (DTC) before 131I treatment. Methods:A prospective study was conducted on patients with DTC (59 male patients and 130 female patients, age (43.7±12.2) years) who received 131I treatment for the first time after total thyroidectomy in the First Affiliated Hospital of Zhengzhou University between January 2021 and April 2022. Patients were divided into normal iodized salt diet group and limited iodized salt diet group according to whether iodized salt diet was administered 4 weeks before 131I treatment. The age, gender, urinary iodine concentration, iodine uptake rate and tumor risk stratification of the two groups were compared by independent-sample t test or χ2 test. In addition, according to the concentration of urinary iodine, patients were divided into group a1 (urinary iodine <200 μg/L) and group a2 (urinary iodine ≥200 μg/L). Logistic regression analysis was used to analyze the factors affecting urinary iodine concentration. Results:The urinary iodine concentration of normal iodized salt diet group was not significantly different from that of non-iodized salt diet group ((140.53±76.66) vs (121.74±74.64) μg/L; t=1.67, P=0.489). The iodine uptake rates at 2 h, 4 h and 24 h in the 2 groups were (3.77±1.06)% vs (3.42±0.97)%, (3.33±1.07)% vs (3.21±1.15)%, (2.90±2.60)% vs (3.23±2.94)%, respectively ( t values: 2.33, 0.68, -0.81, all P>0.05). There were no significant differences in age ( t=0.56, P=0.889), gender ( χ2=1.33, P=0.250) and tumor risk stratification ( χ2=0.14, P=0.709) between the two groups. Logistic regression analysis showed that tumor risk stratification was associated with urinary iodine concentration (odds ratio ( OR)=3.914, 95% CI: 1.505-10.176; P=0.005). Conclusion:Normal iodized salt diet may have no effect on urinary iodine concentration and iodine uptake rate of patients with DTC before 131I treatment.

Preparation of 89Zr-labeled mesenchymal stem cells and PET monitoring in mice with systemic lupus erythematosus / 中华核医学与分子影像杂志

Objective:To label mesenchymal stem cells (MSCs) with 89Zr-oxine complex, and assess its characteristics of PET imaging in systemic lupus erythematosus (SLE) model (MRL/lpr mice). Methods:SLE mice were screened by 18F-FDG PET imaging. 89Zr-oxine was prepared and used for labeling MSCs (10 6 MSCs and 1 MBq 89Zr-oxine). 89Zr-oxine-labeled MSCs (0.2 MBq) were injected into MRL/lpr mice and BALB/c mice (each n=5) via tail vein at a dose of 1.2×10 6 cells per mouse, and followed with microPET imaging in vivo at 2 h, 6 h, 1 d, 3 d, 7 d, 10 d and 14 d after injection. The percentage activity of injection dose per gram of tissue (%ID/g) was calculated. Independent-sample t test was used to analyze the data. Results:MSCs was successfully labeled with 89Zr-oxine, with the labeling efficiency of 20% and cell viability >90%. MicroPET imaging showed that MSCs were mainly distributed in lungs and the liver sites at 2 h after injection. The number of MSCs homing to kidneys of MRL/lpr mice ( n=5) increased significantly 24 h after the injection, and the renal uptake of MSCs in MRL/lpr mice was much higher than that in BALB/c mice ((8.28±1.27) vs (4.33±0.94) %ID/g; t=3.54, P=0.024). The renal uptake increased firstly and then decreased and then leveled off, indicating MSCs homing to kidneys. Conclusions:A method for 89Zr-oxine labeling of MSCs is successfully established. 89Zr-labeled MSCs can home to kidneys of SLE mice. PET imaging of 89Zr-labeled MSCs can be effectively used to explore the in vivo distribution and migration behavior of transplanted MSCs during the treatment of diseases such as SLE.

Study on the medication law and mechanism of treatment of lumbar disc herniation by national Traditional Chinese Medicine master Liu Bailing based on data mining and network pharmacology / 国际中医中药杂志

Objective:To explore the core prescriptions and mechanism of national TCM master Liu Bailing in the treatment of lumbar disc herniation (LDH) based on data mining and network pharmacology methods; To provide the clinical reference for the treatment of LDH.Methods:The cases of LDH treated by Professor Liu in Affiliated Hospital of Changchun University of Chinese Medicine, from January 1, 2011 to December 31, 2019 were collected and analyzed. Hierarchical clustering and association rules were used to analyze the medication rules and core prescriptions. TCMSP, GeneCards, ETCM, SymMap, DAVID, etc. were used to analyze the network pharmacology of the core compounds in treating LDH and symptoms, and reveal the mechanism.Results:A total of 1 334 prescriptions were included, involving 201 kinds of Chinese materia medica, among which the medicinal property was mainly warm, the flavor was mainly sweet and the meridians were mainly liver meridian and kidney meridian; the core medicines for the treatment of LDH included Aconiti Lateralis Radix Praeparata, Spatholobi Caulis, Cinnamomi Cortex, Corydalis Rhizoma, Eucommiae Cortex, Paederia Foetida and Amomi Fructus, reflecting that Professor Liu Bailing often treats LDH from the perspective of kidney deficiency, and commonly uses the treatment methods of dispelling wind, relieving pain, warming yang and benefiting the kidney. The core prescriptions mainly participated in three pathways of cancer, immunity and cell metabolism, including PI3K-Akt signaling pathway, TNF signaling pathway and FoxO signaling pathway. Conclusion:Professor Liu Bailing's treatment of LDH focuses on overall dialectical treatment, which mainly dispels wind, relieves pain, warms yang and benefits the kidney and the mechanism of the core prescriptions may lie in diminishing the inflammatory response. The core prescriptions may treat LDH by regulating the immune response and cellular physiological functions.

Investigation of occupational hazard emergencies in power grid enterprises in three regions from 2018 to 2020 / 中国职业医学

Objective: To analyze the occurrence and risk factors of various occupational hazard incidents in China's power grid enterprises. Methods: A total of 4 191 workers from eight power grid enterprises in Jilin Province, Shandong Province, and Chongqing City were selected using a convenience sampling method. Their exposure in workplace and the occurrence of various occupational hazard incidents from 2018 to 2020 were investigated. Results: Among the participants, 71.7% were engaged in outdoor operations. The incidence rates of occupational hazard emergency, ranking from high to low, were electric ophthalmia, acute mountain sickness, heatstroke, electro-flash dermatitis, sunburn, cold injury, solar ophthalmia, and gas poisoning in confined space, with the rate of 42.3%, 42.3%, 38.1%, 24.3%, 17.4%, 16.5%, 10.0%, and 1.3%, respectively (P<0.01). The results of multivariate logistic regression analysis showed that workers in Jilin Province had a higher risk of cold injury compared to those in Shandong Province and Chongqing City (all P<0.01). Workers in Chongqing City had a higher risk of solar ophthalmia than those in Jilin Province (P<0.01). Workers in inspection and maintenance positions had a higher risk of heatstroke and sunburn compared to those in substation positions (all P<0.05). Power grid workers with protective systems in enterprises had a lower risk of sunburn and solar ophthalmia compared to those without protective systems (all P<0.01). The risks of sunburn and solar ophthalmia among power grid workers increased with age and daily outdoor working time (all P<0.05). Taking protective measures was a protective factor against heatstroke and cold injury (all P<0.01). Conclusion: Power grid workers face the risk of various occupational hazard incidents. Relevant organizations should conduct targeted preventive measures based on regional and worker characteristics, and ensure the implementation of protective systems in different work environments.

Improvement effect of crocin on cognitive impairment of Alzheimer's disease rats through DKK3 regulation of GSK-3 β/β-Catenin pathway / 中国临床药理学与治疗学

AIM: To explore the improvement effect and mechanism of crocin on cognitive impairmrnt of Alzheimer's disease (AD) rats. METHODS: The hippocampus of SD rats were injected with Aβ 25-35 to establish AD model, then rats were randomly divided into AD group, AD + low, medium, high dose of crocin groups (10, 20, 40 mg/kg) and AD + donepezil group (1 mg/kg), intraperitoneal injection treatment for 4 weeks, set sham group. Dark avoidance test and water maze test were used to evaluate the learning and memory abilities of rats, ELISA was used to detect serum Aβ content, HE staining and Tunel staining were used to determine pathological changes and neuronal apoptosis of hippocampus of rats, immunohistochemistry was used to detect the expression of Brdu, Dcx and NeuN in hippocampus of rats, and Western blot was used to detect the protein expression of Aβ, DKK3, β-catenin, p-GSK-3β/GSK-3β, Caspase-3, Bax, Bcl-2 in hippocampus of rats. RESULTS: Compared to sham group, the learning and memory abilities of AD group rats were decreased, serum Aβ content increased, the pathological change in hippocampus was serious, neuronal apoptosis was increased, the expression of Brdu, Dcx, NeuN were decreased, the protein expression of Aβ, DKK3, p-GSK-3β/GSK-3β, Caspase-3, Bax were increased, protein expression of β-catenin, Bcl-2 were decreased (P<0.01). Compared to AD group, after the treatment of doses of crocin and donepezil, the learning and memory abilities of AD rats were improved, serum Aβ content were increased, and the pathological change in hippocampus were alleviated, neuronal apoptosis were reduced, the expression of Brdu, Dcx, NeuN were decreased, the protein expression of Aβ, DKK3, p-GSK-3β/ GSK-3β, Caspase-3, Bax were decreased, the protein expression of β-catenin, Bcl-2 were increased, notely, dose-dependent effect of crocin was significant. CONCLUSION: Crocin reduced neuronal apoptosis and mediated DKK3 to regulate GSK-3β/ β-catenin pathway to improve the cognitive impairment of AD rats.

Study of the improvement effect of "DuZhong-DangGui" on osteoarthritis rats via regulating NLPR3 inflammasome / 中国临床药理学与治疗学

AIM: To investigate the protective effect of "DuZhong-DangGui" (DZ-DG) on the knee tissue of rats with osteoarthritis (OA) and its regulation role on NLPR3 inflammasome. METHODS: Twenty-four SPF male SD rats, eighteen rats were randomly selected to establish OA model by anteri- or cruciate ligament amputation (ACLT) method, and rats were divided into control group, OA model group, DZ-DG group and positive drug group, 6 in each group, treatment for 8 weeks. The peripheral blood were collected, ELISA was used to detect the levels of IL-1β, IL-6, IL-18, and TNF-α; cartilage tissue of knee joint were collected, HE staining was used to observe pathology changes, OARSI staining was used to observe cartilage calcification and preform quantitative OARSI scoring; immunohistochemistry and TUNEL staining were used to detect the contents of Caspase1 and Collagen II and the number of apoptosis in the tissue, respectively, and western blot was used to detect the protein expressions of matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), p53, p21, NLPR3, apoptosis-associated speck-like protein containing a CARD (ASC) and Pro-Caspase-1. RESULTS: Compared to control group, OA model group rats serum levels of IL-1β, IL-6, IL-18, and TNF - α significantly increased (P<0.01), OARSI scores significantly increased (P<0.01), chondrocyte apoptosis was increased (P<0.01), Caspase-1 content and MMP-13, p53, p21, NLPR3, ASC, Pro-Caspase-1 protein expressions significantly increased (P <0.01), while Collagen II content and TIMP-1 protein expression significantly decreased (P<0.01). Compared with the OA model group, DZ-DG group and positive drug group rats serum levels of IL-1β, IL-6, IL -18 and TNF - α significantly decreased (P< 0.05), chondrocyte apoptosis were significantly decreased (P<0.01), Caspase1 content, MMP-13, p53, NLPR3, Pro-Caspase-1 significantly decreased (P< 0.05), Collagen Ⅱ content and TIMP- 1 protein expression (P<0.01); DZ-DG group rats protein expression of p21 and ASC were decreased (P<0.01). CONCLUSION: The DZ-DG have protection role on cartilage of OA rats, its effect may related to mediation of NLPR3/ASC/Pro-Caspase-1 pathway, to decrease of IL-1β, and inhibition of cell apoptosis.

Adjuvant chemotherapy versus adjuvant concurrent chemoradiotherapy after radical surgery for early-stage cervical cancer: a randomized, non-inferiority, multicenter trial / 医学前沿

We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB-IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant chemotherapy group and 164 in the adjuvant CCRT group. The median follow-up was 72.1 months. The three-year PFS rates were both 91.9%, and the five-year OS was 90.6% versus 90.0% in adjuvant chemotherapy and CCRT groups, respectively. No significant differences were observed in the PFS or OS between groups. The adjusted HR for PFS was 0.854 (95% confidence interval 0.415-1.757; P = 0.667) favoring adjuvant chemotherapy, excluding the predefined non-inferiority boundary of 1.9. The chemotherapy group showed a tendency toward good quality of life. In comparison with post-operative adjuvant CCRT, adjuvant chemotherapy treatment showed non-inferior efficacy in patients with early-stage cervical cancer having pathological risk factors. Adjuvant chemotherapy alone is a favorable alternative post-operative treatment.

AAZ2 induces mitochondrial-dependent apoptosis by targeting PDK1 in gastric cancer / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-‍(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.

Establishment of Reference Values for Early Auditory Preverbal Skills of Children with Cochlear Implants.

Auditory and verbal abilities of children with early cochlear implant (CI) surgery usually take some time to develop, and a reference index of early development for horizontal comparisons is urgently needed to guide the mapping process and adjust rehabilitation programs. Therefore, the aim of this study was to establish a reference value for early auditory preverbal skills development in children with CI and investigate the developmental curve and influencing factors for these children. The LittlEARS® Auditory Questionnaire (LEAQ) scores of 287 eligible Chinese participants were obtained at 1, 2, 3, 6, 9, 12, 18, 24, 28, and 36 months interval after CI activation. The median and standard deviation of the LEAQ score of each hearing stage for these children with different activation ages were calculated to establish the reference values. Quadratic regression was conducted to fit the expected developmental curve of the LEAQ score (y=-0.057x2+2.55x+5.45 [0 to 20 months]). With a linear mixed-effects model, we found that the receptive auditory behavior increased rapidly after CI activation, while expressive language skills developed at a steady rate. We also found that the following factors all significantly influenced the LEAQ: the duration of CI use, the development quotient, age of implantation and activation, and the presence of large vestibular aqueduct syndrome or auditory neuropathy spectrum disorder. The reference values and the expected developmental curve for the LEAQ in children with CI established by the present study provides guidance to clinicians and parents as well as realistic expectations regarding language and speech outcomes.

Comparison of foramen magnum decompression with and without duraplasty in the treatment of adult Chiari malformation Type I: a meta-analysis and systematic review.

AIM: Some meta-analyses have focused on foramen magnum decompression with duraplasty (PFDD) and without duraplasty (PFD) in paediatric or mixed populations. Nevertheless, no meta-analysis has evaluated adults only. This study aimed to include new relevant findings in a systematic review to provide the first comparison of PFDD and PFD in adult CM-I. MATERIAL AND METHODS: We retrospectively searched Web of Science, PubMed, Embase and ClinicalTrials.gov to summarize all relevant published papers on adults. A systemic review was adopted to evaluate clinical or radiological improvement, surgical complications, and reoperation rates between the PFD and PFDD groups. RESULTS: Nine papers containing information on 497 adult participants met the criteria. PFDD was related to a lower revision rate (RR=2.96, 95% CI: 1.34-6.51, P=0.007) but a higher complication rate (RR=0.35, 95% CI: 0.22-0.55, P 0.00001). No significant difference was noted between PFD and PFDD in terms of overall symptom improvement (RR=0.93, 95% CI: 0.84-1.03, P = 0.17) or syringomyelia reduction (RR=0.84, 95% CI: 0.63-1.12, P = 0.24). No significant difference in symptom improvement was observed between patients with syringomyelia (RR=0.86, 95% CI: 0.69-1.08, P = 0.20) and patients without syringomyelia (RR=0.94, 95% CI: 0.68-1.30, P = 0.73). CONCLUSION: This systematic review of observational studies reveals that PFDD may provide lower revision rates but pose a higher risk than PFD in the management of CM-I in adults. However, PFD is similar to PFDD in clinical and radiological improvements.

Amentoflavone attenuates Listeria monocytogenes pathogenicity through an LLO-dependent mechanism.

BACKGROUND AND PURPOSE: L. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved in diverse pathogenic mechanisms of L. monocytogenes infection, represents a promising therapeutic target. In this study, we sought to identify an effective inhibitor of LLO pore formation and its mechanism of action in the treatment of L. monocytogenes infection. EXPERIMENTAL APPROACH: Haemolysis assays were carried out to screen an effective LLO inhibitor. The interaction between candidate and LLO was investigated using surface plasmon resonance and molecular docking. The effect of candidate on LLO-mediated cytotoxicity, barrier disruption and immune response were investigated. Finally, the in vivo effect of candidate on mice challenged with L. monocytogenes was examined. KEY RESULTS: Amentoflavone, a natural flavone present in traditional Chinese herbs, effectively inhibited LLO pore formation by engaging the residues Lys93, Asp416, Tyr469 and Lys505 in LLO. Amentoflavone dose-dependently reduced L. monocytogenes-induced cell injury in an LLO-dependent manner. In the Caco-2 monolayer model, amentoflavone maintained the integrity of the epithelial barrier exposed to LLO. Amentoflavone inhibited the inflammatory response evoked by L. monocytogenes in an LLO-dependent manner, and inhibition was attributed to ability to block perforation-associated K+ efflux and Ca2+ influx. In the mouse infection model, amentoflavone treatment significantly reduced bacterial burden and pathological lesions in target organs, with a significant increase in survival rate. CONCLUSIONS AND IMPLICATIONS: Amentoflavone reduced the pathogenicity of L. monocytogenes by specifically inhibiting LLO pore formation, and this may represent a potential treatment for L. monocytogenes infection.