Phytoestrogen-derived multifunctional ligands for targeted therapy of breast cancer

Nano-targeted delivery systems have been widely used for breast tumor drug delivery.Estrogen receptors are considered to be significant drug delivery target receptors due to their overexpression in a variety of tumor cells.However,targeted ligands have a significant impact on the safety and effectiveness of active delivery systems,limiting the clinical transformation of nanoparticles.Phytoestrogens have shown good biosafety characteristics and some affinity with the estrogen receptor.In the present study,molecular docking was used to select tanshinone IIA(Tan IIA)among phytoestrogens as a target ligand to be used in nanodelivery systems with somemodifications.Modified Tan IIA(Tan-NH2)showed a good biosafety profile and demonstrated tumor-targeting,anti-tumor and anti-tumor metastasis effects.Moreover,the ligand was utilized with the anti-tumor drug Dox-loaded mesoporous silica nanoparticles via chemical modification to generate a nanocomposite Tan-Dox-MSN.Tan-Dox-MSN had a uniform particle size,good dispersibility and high drug loading capacity.Validation experiments in vivo and in vitro showed that it also had a better targeting ability,anti-tumor effect and lower toxicity in normal organs.These results supported the idea that phytoestrogens with high affinity for the estrogen receptor could improve the therapeutic efficacy of nano-targeted delivery systems in breast tumors.

Recombinant adenovirus containing hyper-interleukin-6 and hepatocyte growth factor ameliorates acute-on-chronic liver failure in rats

AIM: To investigate the protective efficacy of recombinant adenovirus containing hyper-interleukin-6(HyperIL-6, HIL-6) and hepatocyte growth factor(HGF)(AdHGF-HIL-6) compared to that of recombinant adenovirus containing either HIL-6 or HGF(Ad-HIL-6 or Ad-HGF) in rats with acute-on-chronic liver failure(ACLF).METHODS: The recombinant adenoviruses containing HIL-6 and/or HGF were constructed. We established an ACLF model, and rats were randomly assigned to control, model, Ad-GFP, Ad-HIL-6, Ad-HGF or AdHGF-HIL-6 group. We collected serum and liver tissue samples to test pathological changes, biochemical indexes and molecular biological indexes.RESULTS: Attenuated alanine aminotransferase, prothrombin time, high-mobility group box 1(HMGB1), endotoxin, tumour necrosis factor(TNF)-α and interferon-γ were observed in the Ad-HGF-, Ad-HIL-6- and Ad-HGFHIL-6-treated rats with ACLF. Likewise, reduced hepaticdamage and apoptotic activity, as well as reduced HMGB1 and Bax proteins, but raised expression of Ki67 and Bcl-2 proteins and Bcl-2/Bax ratio were also observed in the Ad-HGF-, Ad-HIL-6- and Ad-HGF-HIL-6-treated rats with ACLF. More significant changes were observed in the Ad-HGF-HIL-6 treatment group without obvious side effects. Furthermore, caspase-3 at the protein level decreased in the Ad-HIL-6 and Ad-HGFHIL-6 treatment groups, more predominantly in the latter group.CONCLUSION: This study identifies that the protective efficacy of Ad-HGF-HIL-6 is more potent than that of Ad-HGF or Ad-HIL-6 in ACLF rats, with no significant side effects.

Dynamic Mechanical Characteristics and Damage Evolution Model of Granite

By using the technique of the split Hopkinson pressure bar（ SHPB）,impact tests at different stress wavelengths（ 0. 8-2. 0 m） and strain rates（ 20-120 s^（-1）） were conducted to study the dynamic mechanical properties and damage accumulation evolution lawof granite. Test results showthat the dynamic compressive strength and strain rate of granite have a significantly exponential correlation;the relationship between peak strain and strain rate is approximately linear,and the increase of wavelengths generally makes the level of peak strain uplift. The multiple-impacts test at a lowstrain rate indicates that at the same wavelength,the cumulative damage of granite shows an exponential increasing form with the increase of strain rate; when keeping the increase of strain rate constant and increasing the stress wavelength,the damage accumulation effect of granite is intensified and still shows an exponential increasing form; under the effect of multiple impacts,the damage development trend of granite is similar overall,but the increase rate is accelerating. Therefore the damage evolution model was established on the basis of the exponential function while the physical meaning of parameters in the model was determined. The model can reflect the effect of the wave parameters and multiple impacts. The validity of the model and the physical meaning of the parameters were verified by the test,which further offer a reference for correlational research and engineering application for the granite.

The anti-pulmonary fibrosis of Salvia miltiorrhiza Bunge: A systematic review

The characteristics of PF are diffuse alveolitis and disruption of alveolar structure leading to pulmonary interstitial fibrosis.At the same time,pulmonary fibrosis reduces lung volume and restricts ventilation,ultimately leading to hypoxemia and respiratory failure.In clinical guidelines,Nintedanib or Pirfenidone is often used for treatment.However,the two drugs,although they may slow the progression of the disease,cannot stop,or reverse fibrosis and generally result in a variety of toxic side effects.In 184-220 A.D.,it was already recorded in Supplementary Records of Famous Physicians that the function of SMB was to invigorate blood circulation and disperse blood stasis.In modern medical research,the active ingredients of SMB have likewise been found to be used in treatments such as anti-fibrosis,anti-inflammatory,antithrombotic,antioxidant,microcirculatory improvement,and antineoplastic.In this review,a comprehensive search of the former literature on SMB and pulmonary fibers was conducted using databases including PubMed,CNKI,the National Science and Technology Library,Hindawi,Chinese Science and Technology Journal Database,and the Scientific Network Database.Meanwhile,this review presents the mechanisms of the active ingredients in SMB which have anti-pulmonary fibrosis effects through the signal pathways,cytokines,inflammation response,oxidative stress,apoptosis,and matrix metalloproteinases.SMB could offer a direction for therapy for pulmonary fibrosis by identifying the possible active components and exploring the potential mechanisms.Those could provide a reference for further research and application of SMB in the treatment of pulmonary fibrosis.

Risk factors for surgical-site infections after radical gastrectomy for gastric cancer:a study in China

Background:About 10%of patients get a surgical-site infection(SSI)after radical gastrectomy for gastric cancer,but SSI remains controversial among surgeons.The aim of this study was to explore the risk factors for SSIs after radical gastrectomy in patients with gastric cancer to guide clinical therapies and reduce the incidence of SSI.Methods:The study was a retrospective cohort study in patients who underwent radical gastrectomy for gastric cancer.SSI was defined in accordance with the National Nosocomial Infection Surveillance System.We evaluated patient-related and peri-operative variables that could be risk factors for SSIs.The Chi-squared test and logistic regression analysis were used to assess the association between these risk factors and SSI.Results:Among the 590 patients,386 were men and 204 were women.The mean age was 56.6(28-82)years and 14.2%(84/590)of these patients had an SSI.Among them,incisional SSI was observed in 23 patients(3.9%)and organ/space SSI in 61 patients(10.3%).Multivariate logistic regression analysis identified sex(odds ratios[ORs]=2.548,and 95%confidence interval[CI]:1.268-5.122,P=0.009),total gastrectomy(OR=2.327,95%CI:1.352-4.004,P=0.002),albumin level(day 3 after surgery)<30 g/L(OR=1.868,95%CI:1.066-3.274,P=0.029),and post-operative total parenteral nutrition(OR=2.318,95%CI:1.026-5.237,P=0.043)as independent risk factors for SSI.Conclusions:SSI was common among patients after radical gastrectomy for gastric cancer.The method supporting post-operative nutrition and the duration of prophylactic antibiotics may be important modifiable influencing factors for SSI.

绘制小鼠牙胚发育的单细胞图谱并揭示间充质的诱导成牙关键细胞群(CD24^(+)和Plac8^(+)细胞群)

研究人员对牙发育过程中的高分辨时-空关系仍然知之甚少.该文通过高通量(92,688个细胞)单细胞RNA测序追踪牙胚发育过程的细胞轨迹,并结合ATAC测序技术,明确牙胚间充质细胞具显著区分牙齿类型的特异性特征.该文同时发掘起源于间充质细胞的牙本质和牙髓形成中的关键基因调控网络,并绘制具有成牙潜能的间充质细胞空间模式图.在此基础上,该文发现了分别分布于发育晚期牙乳头上半部和预成牙本质细胞层的两个牙胚间充质细胞群,即CD24^(+)和Plac8^(+)细胞,并解析了这两群细胞均可高效诱导非牙源性上皮细胞共同成牙的生理功能.值得关注的是其中的Plac8^(+)组织是迄今为止被证实能在体外诱导再生牙形成的含细胞数量最少且异质性最低的间充质组织模块.综上,该文的工作揭示了牙胚发育过程中由结构和功能决定的时空模式和细胞异质性,为基于干细胞的再生牙构建提供重要的理论基础.

Recognition of H3K9me1 by maize RNA-directed DNA methylation factor SHH2

RNA-directed DNA methylation(Rd DM) is a plant-specific de novo DNA methylation pathway,which has extensive cross-talk with histone modifications. Here, we report that the maize RdDM regulator SAWADEE HOMEODOMAIN HOMOLOG 2(SHH2) is an H3 K9 me1 reader. Our structural studies reveal that H3 K9 me1 recognition is achieved by recognition of the methyl group via a classic aromatic cage and hydrogen-bonding and salt-bridge interactions with the free protons of the mono-methyllysine. The di-and tri-methylation states disrupt the polar interactions, decreasing the binding affinity. Our study reveals a monomethyllysine recognition mechanism which potentially links RdDM to H3 K9 me1 in maize.

Efficient induction of neural progenitor cells from human ESC/iPSCs on Type I Collagen

A stable,rapid and effective neural differentiation method is essential for the clinical applications of human embryonic stem cells(ESCs)or induced pluripotent stem cells(iPSCs)in treating neurological disorders and diseases.Herein,we established a novel and robust monolayer differentiation method to produce functional neural progenitor cells(NPCs)from human ESC/iPSCs on Type I Collagen.The derived cells not only displayed the requisite markers,but also behaved similarly to classic NPCs both in vitro and in vivo.Upon transplantation into traumatic brain injury model,the derived NPCs facilitated recovery from injury.We also found that SMAD signaling stayed down throughout the differentiation process on Type I Collagen,and the pluripotent signals were rapidly downregulated along with raising up of neural early markers on the third day.Meanwhile,ATAC-seq data showed the related mediation of distinct transcriptome and global chromatin dynamics during NPC induction.Totally,our results thus provide a convenient way to generate NPCs from human ESC/iPSCs for neural diseases’treatment.

Low molecular weight protein phosphatase APH mediates tyrosine dephosphorylation and ABA response in Arabidopsis.

Low molecular weight protein tyrosine phosphatase(LWM-PTP),also known as acid phosphatase,is a highly conserved tyrosine phosphatase in living organisms.However,the function of LWM-PTP homolog has not been reported yet in plants.Here,we revealed a homolog of acid phosphatase,APH,in Arabidopsis plants,is a functional protein tyrosine phosphatase.The aph mutants are hyposensitive to ABA in post-germination growth.We performed an anti-phosphotyrosine antibody-based quantitative phosphoproteomics in wild-type and aph mutant and identified hundreds of putative targets of APH,including multiple splicing factors and other transcriptional regulators.Consistently,RNA-seq analysis revealed that the expression of ABA-highly-responsive genes is suppressed in aph mutants.Thus,APH regulates the ABA-responsive gene expressions by regulating the tyrosine phosphorylation of multiple splicing factors and other post-transcriptional regulators.We also revealed that Tyr383 in RAF9,a member of B2 and B3 RAF kinases that phosphorylate and activate SnRK2s in the ABA signaling pathway,is a direct target site of APH.Phosphorylation of Tyr383 is essential for RAF9 activity.Our results uncovered a crucial function of APH in ABA-induced tyrosine phosphorylation in Arabidopsis.

Efficacy of Nonsteroidal Anti-inflammatory Drugs for Treatment of Uncomplicated Lower Urinary Tract Infections in Women:A Meta-analysis

Urinary tract infections(UTIs)are among the most frequent causes for antibiotic prescription and;therefore,alternative treatment options for UTIs can potentially reduce antibiotic usage and development of resistance.To evaluate the efficacy of nonsteroidal antiinflammatory drugs(NSAIDS)for the treatment of uncomplicated lower UTIs in women,this study implemented a meta-analytic approach to evaluate the results of available randomized clinical studies from online databases.A total of four trials involving 1144 patients with uncomplicated lower UTIs were included in the final evaluation.Results showed that symptom resolution at Day 3-4 in the NSAIDs group was significantly lower than that in the antibiotics group[pooled odds ratio(OR)=0.41,95%confidence interval(CI):0.23-0.74,P<0.05].However,there was no significant difference between the NSAIDs and antibiotics groups in symptom resolution at Day 7(pooled OR=0.43,95%CI:0.17-1.06,P=0.07),secondary antibiotic treatment rate at Day 28-30(pooled OR=1.15,95%CI:0.16-7.98,P=0.89)and adverse events rate(pooled OR=1.09,95%CI:0.61-1.96,P=0.77).Therefore,this metaanalysis suggests that,although inferior to antibiotics in fast symptom resolution,symptomatic treatment with NSAIDs can be considered as an alternative treatment option for uncomplicated lower UTIs in women.However,given the low number of randomized controlled trials that met inclusion criteria in this meta-analysis,efficacy of NSAIDs for treatment of uncomplicated lower UTIs should be further evaluated in more comprehensive clinical studies.

Granulicatella adiacens Infective Endocarditis Treated With Teicoplanin and Ceftriaxone:A Case Report

We describe a case of infective endocarditis(IE)caused by Granulicatella adiacens in a patient who had fever for 4months before admission.He had a complex medical history of active hyperthyroidism and schizophrenia,which might have misled the clinician in ignoring the existence of a serious infection like IE.A history of splenectomy and the likelihood of congenital cardiac valve deficiency were the possible underlying risk factors.His persistent leukocytosis perplexed our judgement in terms of resolution of infection and treatment efficacy,which was probably due to his splenectomy.C-reactive protein was the alternative laboratory indicator.Clinical and Laboratory Standards Institute criteria have not been established for the fastidious G.adiacens.Therefore,we referred to the viridans group streptococci and literature to evaluate antimicrobial susceptibility testing.We suggest that teicoplanin combined with ceftriaxone could serve as an effective therapy for IE caused by G.adiacens.