MicroRNA-630 alleviates inflammatory reactions in rats with diabetic kidney disease by targeting toll-like receptor 4

BACKGROUND Diabetic kidney disease(DKD)is a major complication of diabetes mellitus.Renal tubular epithelial cell(TEC)damage,which is strongly associated with the inflammatory response and mesenchymal trans-differentiation,plays a significant role in DKD;However,the precise molecular mechanism is unknown.The recently identified microRNA-630(miR-630)has been hypothesized to be closely associated with cell migration,apoptosis,and autophagy.However,the association between miR-630 and DKD and the underlying mechanism remain unknown.AIM To investigate how miR-630 affects TEC injury and the inflammatory response in DKD rats.METHODS Streptozotocin was administered to six-week-old male rats to create a hypergly cemic diabetic model.In the second week of modeling,the rats were divided into control,DKD,negative control of lentivirus,and miR-630 overexpression groups.After 8 wk,urine and blood samples were collected for the kidney injury assays,and renal tissues were removed for further molecular assays.The target gene for miR-630 was predicted using bioinformatics,and the association between miR-630 and toll-like receptor 4(TLR4)was confirmed using in vitro investigations and double luciferase reporter gene assays.Overexpression of miR-630 in DKD rats led to changes in body weight,renal weight index,basic blood parameters and histopathological changes.RESULTS The expression level of miR-630 was reduced in the kidney tissue of rats with DKD(P<0.05).The miR-630 and TLR4 expressions in rat renal TECs(NRK-52E)were measured using quantitative reverse transcription polymerase chain reaction.The mRNA expression level of miR-630 was significantly lower in the high-glucose(HG)and HG+mimic negative control(NC)groups than in the normal glucose(NG)group(P<0.05).In contrast,the mRNA expression level of TLR4 was significantly higher in these groups(P<0.05).However,miR-630 mRNA expression increased and TLR4 mRNA expression significantly decreased in the HG+miR-630 mimic group than in the HG+mimic NC group(P<0.05).Furthermore,the levels of tumor necrosis factor-alpha(TNF-α),interleukin-1β(IL-1β),and IL-6 were significantly higher in the HG and HG+mimic NC groups than in NG group(P<0.05).However,the levels of these cytokines were significantly lower in the HG+miR-630 mimic group than in the HG+mimic NC group(P<0.05).Notably,changes in protein expression were observed.The HG and HG+mimic NC groups showed a significant decrease in E-cadherin protein expression,whereas TLR4,α-smooth muscle actin(SMA),and collagen IV protein expression increased(P<0.05).Conversely,the HG+miR-630 mimic group exhibited a significant increase in E-cadherin protein expression and a notable decrease in TLR4,α-SMA,and collagen IV protein expression than in the HG+mimic NC group(P<0.05).The miR-630 targets TLR4 gene expression.In vivo experiments demonstrated that DKD rats treated with miR-630 agomir exhibited significantly higher miR-630 mRNA expression than DKD rats injected with agomir NC.Additionally,rats treated with miR-630 agomir showed significant reductions in urinary albumin,blood glucose,TLR4,and proinflammatory markers(TNF-α,IL-1β,and IL-6)expression levels(P<0.05).Moreover,these rats exhibited fewer kidney lesions and reduced infiltration of inflammatory cells.CONCLUSION MiR-630 may inhibit the inflammatory reaction of DKD by targeting TLR4,and has a protective effect on DKD.

Design of N-11-Azaartemisinins Potentially Active against Plasmodium falciparum by Combined Molecular Electrostatic Potential, Ligand-Receptor Interaction and Models Built with Supervised Machine Learning Methods

N-11-azaartemisinins potentially active against Plasmodium falciparum are designed by combining molecular electrostatic potential (MEP), ligand-receptor interaction, and models built with supervised machine learning methods (PCA, HCA, KNN, SIMCA, and SDA). The optimization of molecular structures was performed using the B3LYP/6-31G* approach. MEP maps and ligand-receptor interactions were used to investigate key structural features required for biological activities and likely interactions between N-11-azaartemisinins and heme, respectively. The supervised machine learning methods allowed the separation of the investigated compounds into two classes: cha and cla, with the properties εLUMO+1 (one level above lowest unoccupied molecular orbital energy), d(C6-C5) (distance between C6 and C5 atoms in ligands), and TSA (total surface area) responsible for the classification. The insights extracted from the investigation developed and the chemical intuition enabled the design of sixteen new N-11-azaartemisinins (prediction set), moreover, models built with supervised machine learning methods were applied to this prediction set. The result of this application showed twelve new promising N-11-azaartemisinins for synthesis and biological evaluation.

Impact of Probiotics on Toll-like Receptor 4 Expression in an Experimental Model of Ulcerative Colitis

Toll-like receptors （TLRs） are key components of the innate immune system which trigger antimicrobial host defense responses. This study aimed to investigate the impact of probiotics （Lactoba- cillus, Bifiidobacterium） on the expression of TLR4 and tumor necrosis factor-alpha （TNF-α in the co- lon mucosa of rat experimental ulcerative colitis model induced by trinitrobenzene sulfonic acid （TNBS）/ethanol and immune complexes. The gross and histological changes of the colonic mucosa were observed and assessed by the means-standard deviation and independent samples t-test. The pro- tein expression levels of TLR4 and TNF-α were detected by using immunohistochemistry and Westem blotting, respectively. It was revealed that there was visible infiltration of inflammatory cells, formation of crypt abscess, and the reduction of goblet cells in the colon tissue of experimental models. As com- pared with the control group, the levels of TLR4 and TNF-α protein were significantly increased in the model group （P〈0.01 for both）. No significant difference was found in the expression of TLR4 and TNF-α between the two-week probiotics treatment group and the model group （P〉0.05）, whereas sig- nificant reductions were shown in rats which were treated with probiotics for four weeks as compared with the model group （P〈0.01）. There was no significant difference between two probiotics-treated groups. Our results implied that probiotics were likely to play a key role in protecting ulcerative colitis by reducing the inflammatory factor TNF-α expression through inhibiting the TLR4 expression in the colon tissue of experimental models.

Profiles and Source Apportionment of Nonmethane Volatile Organic Compounds in Winter and Summer in Xi’an, China, based on the Hybrid Environmental Receptor Model

Summer and winter campaigns for the chemical compositions and sources of nonmethane hydrocarbons(NMHCs)and oxygenated volatile organic compounds(OVOCs)were conducted in Xi’an.Data from 57 photochemical assessment monitoring stations for NMHCs and 20 OVOC species were analyzed.Significant seasonal differences were noted for total VOC(TVOC,NMHCs and OVOCs)concentrations and compositions.The campaign-average TVOC concentrations in winter(85.3±60.6 ppbv)were almost twice those in summer(47.2±31.6 ppbv).Alkanes and OVOCs were the most abundant category in winter and summer,respectively.NMHCs,but not OVOCs,had significantly higher levels on weekends than on weekdays.Total ozone formation potential was higher in summer than in winter(by 50%)because of the high concentrations of alkenes(particularly isoprene),high temperature,and high solar radiation levels in summer.The Hybrid Environmental Receptor Model(HERM)was used to conduct source apportionment for atmospheric TVOCs in winter and summer,with excellent accuracy.HERM demonstrated its suitability in a situation where only partial source profile data were available.The HERM results indicated significantly different seasonal source contributions to TVOCs in Xi’an.In particular,coal and biomass burning had contributions greater than half in winter(53.4%),whereas traffic sources were prevalent in summer(53.1%).This study’s results highlight the need for targeted and adjustable VOC control measures that account for seasonal differences in Xi’an;such measures should target not only the severe problem with VOC pollution but also the problem of consequent secondary pollution(e.g.,from ozone and secondary organic aerosols).

The remedial effect of soluble interleukin-1 receptor type Ⅱ on endometriosis in the nude mouse model

Objective： Recent studies have shown that the local expression of soluble interleukin （IL） -1 receptor type Ⅱ （slL-1 R Ⅱ ） in endometrial tissue of women with endometriosis is decreased, and the depression of IL-1 R Ⅱ was more significant in infertile women than that in fertile women with endometriosis. In this research, we investigated the remedial effect of slL-1-R Ⅱ administration on endometriosis in the nude mouse model. Methods： Nineteen nude model mice with endometriosis were randomly divided into three groups： group A was treated by intraperitoneal administration with only slL-1 R Ⅱ for two weeks, group B was similarly treated with only IL- 1, and group C （control） was administered saline. After 2 weeks, the size of the ectopic endometrial lesions was calculated, and the expression of vascular endothelial growth factor （VEGF） and B-cell lymphoma leukemia-2 （Bcl- 2） were detected by immunohistochemistry. The IL-8 and VEGF levels in the peritoneal fluid （PF） and serum were also measured by enzyme-linked immunosorbent assay （ELISA）. Results： The mean size of ectopic endometrial lesion did not differ between the three groups （P 〉 0.05）. Compared with the control, the expression of VEGF and Bcl-2 was significantly lower in group A, and higher in group B. In the three groups, the levels of IL-8 in the PF and serum were highest in group A, and lowest in group B. Conclusion： slL-1 R Ⅱ may suppresse hyperplasia of ectopic endometriosis, perhaps by reducing the expression of certain cytokines, such as VEGF, IL-8, and Bcl-2, which could provide a new clinical strategy for the treatment of endometriosis.

Administration of soluble activin receptor 2B increases bone and muscle mass in a mouse model of osteogenesis imperfecta

Osteogenesis imperfecta（OI） comprises a group of heritable connective tissue disorders generally defined by recurrent fractures, low bone mass, short stature and skeletal fragility. Beyond the skeletal complications of OI,many patients also report intolerance to physical activity, fatigue and muscle weakness. Indeed, recent studies have demonstrated that skeletal muscle is also negatively affected by OI, both directly and indirectly. Given the well-established interdependence of bone and skeletal muscle in both physiology and pathophysiology and the observations of skeletal muscle pathology in patients with OI, we investigated the therapeutic potential of simultaneous anabolic targeting of both bone and skeletal muscle using a soluble activin receptor 2B（ACVR2B） in a mouse model of type Ⅲ OI（oim）. Treatment of 12-week-old oim mice with ACVR2 B for 4 weeks resulted in significant increases in both bone and muscle that were similar to those observed in healthy,wild-type littermates. This proof of concept study provides encouraging evidence for a holistic approach to treating the deleterious consequences of OI in the musculoskeletal system.

Expression of metabotropic glutamate receptor 1a in a rat cortical neuronal model of in vitro mechanical injury and the effects of its competitive antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid

The present study established a rat cortical neuronal model of in vitro mechanical injury. At 30 minutes after injury, the survival rate of the injured cortical neurons was decreased compared with normal neurons, and was gradually decreased with aggravated degree of injury. Reverse transcription-polymerase chain reaction results showed that at 1 hour after injury, there was increased expression of metabotropic glutamate receptor la in cortical neurons. Immunohistochemical staining results showed that at 30 minutes after injury, the number of metabotropic glutamate receptor 1a-positive cells increased compared with normal neurons. At 12 hours after injury, lactate dehydrogenase activity in the （RS）-l-aminoindan-1, 5-dicarboxylic acid （AIDA）-treated injury neurons was si[jnificantly decreased than that in the pure injury group. At 1 hour after injury, intracellular free Ca＂＋ concentration was markedly decreased in the AIDA-treated injury neurons than that in the pure injury neurons. These findings suggest that after mechanical injury to cortical neurons, metabotropic glutamate receptor la expression increased. The resulting increase in intracellular free Ca2＋ concentration was blocked by AIDA, indicating that AIDA exhibits neuroprotective effects after mechanical injury.

Source Apportionment of PM2.5 in the Metropolitan Area of Costa Rica Using Receptor Models

In this work, receptor models were used to identify the PM2.5 sources and its contribution to the air quality in residential, comercial and industrial sampling sites in the Metropolitan Area of Costa Rica. Principal component analysis with absolute principal component scores (PCA-APCS), UNIMX and positive matrix factorization (PMF) was applied to analyze the data collected during 1 year of sampling campaign (2010-2011). The PM2.5 samples were characterized through its composition looking for trace elements, inorganic ions and organic and elemental carbon. These three models identified some common sources of PM2.5: marine aerosol, crustal material, traffic, secondary aerosols (secondary sulfate and secondary nitrate resolved by PMF), a mixed source of heavy fuels combustion and biomass burning, and industrial emissions. The three models predicted that the major sources of PM2.5 in the Metropolitan Area of Costa Rica were related to anthropogenic sources (73%, 65% and 69%, respectively, for PCA-APCS, Unmix and PMF) although natural sources also contributed to PM2.5 (21%, 24% and 26%). On average, PCA and PMF methods resolved 94% and 95% of the PM2.5 mass concentrations, respectively. The results were comparable to the estimate using UNMIX.

Molecular Characterization, 3D Modeling of Grass Carp Interleukin-10 Receptor 1 (IL10R1)

Interleukin-10 (IL-10) is an important cytokine that plays a pivotal role in natural and adaptive immune systems. However, in lower vertebrates, especially in teleost the receptor of this cytokine is still largely unknown. This paper described the cloning and characterization of grass carp interleukin-10 receptor 1 (gcIL10R1) and the 3D structure of its extracellular domain was predicted. The gcIL10R1 cDNA included 180 bp5’ untranslated region (UTR), 870 bp3’ UTR and an open reading frame (ORF) of 1632 bp. The ORF was found to encode a 543 amino acid protein with a putative JAK1 binding site, one STAT3 binding site. The phylogenetic analysis clusters gcIL10R1 with other teleost IL10R1s but independently of the amphibian, avian and mammalian IL10R1s. The 3D structure of its extracellular domain was the first homology model of a fish IL10R1 that revealed a high similarity with its mammalian and avian counterparts.

Homology Model and Ligand Binding Interactions of the Extracellular Domain of the Human α4β2 Nicotinic Acetylcholine Receptor

Addiction to nicotine, and possibly other tobacco constituents, is a major factor that contributes to the difficulties smokers face when attempting to quit smoking. Amongst the various subtypes of nicotinic acetylcholine receptors (nAChRs), the α4β2 subtype plays an important role in mediating the addiction process. The characterization of human α4β2-ligand binding interactions provides a molecular framework for understanding ligand-receptor interactions, rendering insights into mechanisms of nicotine addiction and may furnish a tool for efficiently identifying ligands that can bind the nicotine receptor. Therefore, we constructed a homology model of human α4β2 nAChR and performed molecular docking and molecular dynamics (MD) simulations to elucidate the potential human α4β2-ligand binding modes for eleven compounds known to bind to this receptor. Residues V96, L97 and F151 of the α4 subunit and L111, F119 and F121 of the β2 subunit were found to be involved in hydrophobic interactions while residues S153 and W154 of the α4 subunit were involved in the formation of hydrogen bonds between the receptor and respective ligands. The homology model and its eleven ligand-bound structures will be used to develop a virtual screening program for identifying tobacco constituents that are potentially addictive.

Neuroactive alkaloids that modulate the neuronal nicotinic receptor and provide neuroprotection in an Alzheimer's disease model:the case of Teline monspessulana

Despite the advances in combinatorial or synthetic chemis- try and bioinformatics, recent literature has demonstrated the relevance of nature and biomass as a source of new molecules to treat different pathologies, i.e., bioactive com- pounds obtained from Ecteinascidia turbinate to treat some types of cancer or rapamycin from Streptomyces hygroscop- icus to prevent organ rejection after transplant. This trend will continue simply due to the fact that Mother Nature has been synthesizing molecules for millions of years. In our lab- oratory, we have characterized several compounds obtained from natural sources and that possess important neuronal effects,

Ferrets: A powerful model of SARS-CoV-2

The rapid spread of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) in recent years not only caused a global pandemic but resulted in enormous social,economic,and health burdens worldwide.Despite considerable efforts to combat coronavirus disease 2019(COVID-19),various SARS-CoV-2 variants have emerged,and their underlying mechanisms of pathogenicity remain largely unknown.Furthermore,effective therapeutic drugs are still under development.Thus,an ideal animal model is crucial for studying the pathogenesis of COVID-19 and for the preclinical evaluation of vaccines and antivirals against SARS-CoV-2 and variant infections.Currently,several animal models,including mice,hamsters,ferrets,and nonhuman primates(NHPs),have been established to study COVID-19.Among them,ferrets are naturally susceptible to SARS-CoV-2 infection and are considered suitable for COVID-19 study.Here,we summarize recent developments and application of SARS-CoV-2 ferret models in studies on pathogenesis,therapeutic agents,and vaccines,and provide a perspective on the role of these models in preventing COVID-19 spread.

Multiple templates-based homology modeling and docking analysis of angiotensin Ⅱ type 1 receptor

Using the latest reported homologous Chemokine receptors (PDB ID:3ODU,3OE0 and 3OE6) as templates,twenty models of angiotensin II (Ang II) type 1 (AT1) receptor (known as p30556) were generated by multiple templates homology modeling.According to the results of the initial validation of these twenty models,the model 0020 was finally chosen as the best one for further studies.Then,a 2 ns molecular dynamic (MD) simulation for model 0020 was conducted in normal saline (0.9%,w/V) under periodical boundary conditions,which was followed by docking studies of model 0020 with several existing AT1 receptor blockers (ARBs).The docking results reveal that model 0020 possesses good affinities with these docked ARBs which are in accordance with both the IC50 inhibitor values and their curative effects.The results also show more potent interactions between the model 0020 and its ARBs than those of ever reported results,such as hydrogen bonds,hydrophobic interactions,and especially cation-π interactions and π-π interactions which have never been reported before.This may reveal that the structure of the model 0020 is quite close to its real crystal structure and the model 0020 may have the potential to be used for structure based drug design.

铁死亡在不同细菌所致小鼠血流感染模型中的变化规律及生物学意义

背景:发现血流感染新的疾病诊断标志物、治疗疾病及减轻脏器损伤的分子靶点具有重要意义。铁死亡是新发现的一种细胞死亡形式,脓毒症动物模型中铁死亡的过度激活与炎症反应激活以及肝脏、心脏、肾脏等重要脏器的损伤有关,但铁死亡与血流感染的关系尚不十分清楚。目的:探讨铁死亡在不同细菌所致小鼠血流感染模型中的变化规律及生物学意义。方法:建立革兰阴性菌大肠埃希菌、肺炎克雷伯菌及革兰阳性菌金黄色葡萄球菌、粪肠球菌血流感染的SPF级ICR雄性小鼠模型,每组各42只。建模后0.5,1,3,6,12,24,48 h时检测肝脏、心肌、肾脏中铁死亡标志基因转铁蛋白受体1、谷胱甘肽过氧化物酶4 mRNA表达水平。另选用18只SPF级ICR雄性小鼠,随机分为二甲基亚砜(DMSO)对照组、DMSO+肺炎克雷伯菌组、铁死亡抑制剂Ferrostatin-1+肺炎克雷伯菌组,每组6只;后两组采用尾静脉注射肺炎克雷伯菌悬液的方式建立肺炎克雷伯菌血流感染模型,分别在血流感染建模前1 h给予5 mg/kg的Ferrostatin-1及等剂量DMSO腹腔注射;建模后6 h小鼠检测血清中丙氨酸氨基转移酶、天冬氨酸氨基转移酶、血肌酐、血尿素氮、磷酸肌酸激酶同工酶、乳酸脱氢酶以及各组织中铁死亡标志基因的mRNA表达水平。结果与结论:①血流感染建模后,不同细菌血流感染小鼠肝脏、心肌、肾脏中转铁蛋白受体1 mRNA表达水平先升高后降低,谷胱甘肽过氧化物酶4 mRNA表达水平先降低后升高且均在建模后6 h达到峰值;②革兰阴性菌血流感染小鼠中转铁蛋白受体1和谷胱甘肽过氧化物酶4 mRNA表达的变化较革兰阳性菌血流感染小鼠更为显著,其中以肺炎克雷伯菌血流感染小鼠中转铁蛋白受体1和谷胱甘肽过氧化物酶4 mRNA表达的变化最显著;③肺炎克雷伯菌血流感染建模后6 h时,小鼠的丙氨酸氨基转移酶、天冬氨酸氨基转移酶、血肌酐、血尿素氮、磷酸肌酸激酶同工酶、乳酸脱氢酶水平均明显升高;④建模前给予铁死亡抑制剂Ferrostatin-1干预可显著降低丙氨酸氨基转移酶、天冬氨酸氨基转移酶、血肌酐、血尿素氮、磷酸肌酸激酶同工酶、乳酸脱氢酶表达水平;⑤以上结果提示不同细菌致血流感染小鼠中铁死亡明显激活且革兰阴性菌血流感染小鼠的铁死亡激活更为显著;抑制铁死亡可明显减轻肺炎克雷伯菌血流感染小鼠的肝脏、心肌、肾脏损伤。

广州周边地区地表水稀土元素污染特征及来源解析

以广州市周边地区地表水为研究对象,测定地表水中溶解态稀土元素La、Ce、Pr、Nd、Sm、Eu、Gd、Tb、Dy、Ho、Er、Tm、Yb和Lu的浓度,采用单因子评价指数、内梅罗综合污染指数以及潜在生态风险指数对地表水中溶解态稀土元素进行污染和风险评价,通过APCS-MLR受体模型对广州市周边城区地表水中溶解态稀土元素的来源进行定量化解析,探究高度城市化的非矿区地表水中稀土元素的浓度分布特征。结果表明,研究区地表水溶解态稀土元素La、Ce、Nd、Pr、Gd、Dy、Sm、Er、Yb、Ho、Tb、Eu、Tm和Lu的平均浓度分别是背景值的6.97、5.15、4.06、4.58、1.58、1.71、1.14、1.26、1.22、1.67、1.33、0.47、0.83和0.80倍,表明广州市周边地区地表水中稀土元素可能存在富集现象,尤其是La、Ce、Nd和Pr等轻稀土元素。空间分布特征表明,稀土元素浓度较高的区域集中在位于广州市市内的石门山、黄山鲁和白云山,推断轻稀土元素浓度可能会受到城市中剧烈的人为活动影响。单因子污染指数结果表明,研究区地表水主要受轻稀土元素(La、Ce、Pr和Nd)污染;内梅罗综合污染指数分析表明,石门山、罗浮山、白云山和黄山鲁采样区地表水中稀土元素属于重度污染水平。潜在生态风险评价结果表明,轻稀土元素La、Ce、Pr和Nd为主要污染因子,石门山、白云山和黄山鲁采样区地表水中稀土元素污染属于中度风险水平;罗浮山和帽峰山属于低风险水平。皮尔逊相关性分析显示研究区地表水中稀土元素之间存在较强的相关性;由APCS-MLR受体模型分析得出2个主要污染源(源1和源2)和未解析源(源3),源1为自然源,贡献率为80.96%~99.12%,为研究区地表水稀土元素的主要来源;源2为人为源,主要由交通运输、工业活动等引起,其贡献率为0.32%~8.67%,是研究区地表水稀土元素的第二大来源。

固本安神方对围绝经期综合征模型大鼠性激素水平及卵巢雌激素受体蛋白表达水平的影响

目的 探讨固本安神方对围绝经期综合征(PMS)模型大鼠性激素水平及卵巢雌激素受体蛋白表达水平的影响。方法 选取动情周期规则的雌性SD大鼠60只,腹腔注射160 mg/kg去氧乙烯基环己烯(VCD),以复制PMS大鼠模型。造模成功后,将雌性SD大鼠随机分为模型组(B组,等体积生理盐水),中药组[C组,0.56 g/(kg·d)更年安片],西药组[D组,0.1 mg/(kg·d)戊酸雌二醇片],固本安神方高、中、低剂量组[E_(1)组、E_(2)组、E_(3)组,18.0,9.0,4.5 g/(kg·d)],各10只。另取雌性SD大鼠10只为正常组(A组,等体积生理盐水)。各组大鼠分别灌胃给药4周后,摘取其子宫、双侧卵巢,称定湿重,计算子宫指数、卵巢指数;采用酶联免疫吸附试验(ELISA)法测定血清中卵泡刺激素(FSH)、促黄体生成素(LH)、雌二醇(E_(2))的水平;采用免疫印记(Western blot)法测定卵巢组织中雌激素受体α(ERα)、雌激素受体β(ERβ)、G蛋白偶联雌激素受体1(GPER1)蛋白表达水平。结果 与B组比较,C组、D组、E_(1)组大鼠的子宫指数、卵巢指数均显著升高(P<0.01);C组、D组、E_(1)组大鼠血清中FSH和LH水平均显著降低(P<0.01),E_(2)水平均显著升高(P<0.01);C组、D组、E_(1)组大鼠卵巢组织中ERα,ERβ,GPER1蛋白表达水平均显著升高(P<0.01),E_(2)组、E_(3)组大鼠卵巢组织中ERα蛋白表达水平均显著升高(P<0.05),E_(2)组大鼠卵巢组织中GPER1蛋白表达水平显著升高(P<0.05)。结论 固本安神方治疗PMS模型大鼠的作用机制可能与影响性激素分泌及提高卵巢雌激素受体的蛋白表达水平有关。

曲妥珠单抗生物仿制药对比原研药治疗复发或转移性HER-2阳性乳腺癌的药物经济学评价

目的从卫生体系角度评估曲妥珠单抗生物仿制药(汉曲优)与原研药(赫赛汀)治疗复发或转移性人表皮生长因子受体2(HER-2)阳性乳腺癌的经济性。方法根据NCT03084237试验数据构建分区生存模型,模拟周期为3周,模拟时限为10年。以成本和质量调整生命年(QALY)为产出指标,采用成本-效用分析法评价上述2种方案的经济性。采用单因素敏感性分析和概率敏感性分析检验模型的稳健性。结果曲妥珠单抗生物仿制药组与原研药组的成本分别为111516.72、111122.30元,效用分别为1.52、1.36 QALYs,增量成本-效果比(ICER)为2465.12元/QALY,小于以3倍中国2023年人均国内生产总值(GDP)作为的意愿支付(WTP)阈值(268200元/QALY)。单因素敏感性分析结果表明,曲妥珠单抗生物仿制药费用与曲妥珠单抗原研药费用对ICER有较大影响。概率敏感性分析结果显示,当WTP阈值大于14902元/QALY时,曲妥珠单抗生物仿制药组具有经济性的概率为100%。结论当WTP阈值为3倍中国2023年人均GDP(268200元/QALY)时,与曲妥珠单抗原研药相比,曲妥珠单抗生物仿制药治疗复发或转移性HER-2阳性乳腺癌具有较好的经济性。

多肽BR0336在小鼠2型糖尿病合并非酒精性脂肪性肝炎模型上的初步药效学研究

目的研究多肽BR0336注射液在STZ-HFD诱导的雄性C57BL/6小鼠2型糖尿病(T2DM)合并非酒精性脂肪性肝炎(NASH)模型上的药效学。方法新生雄性小鼠通过链脲佐菌素诱导建立T2DM模型,从1个月龄起开始给予高脂饲料喂养,根据空腹血糖和体重随机分为模型组、替西帕肽(TZP)的0.15 mg·kg^(-1)阳性对照组和BR0336的低(0.05 mg·kg^(-1))、中(0.15 mg·kg^(-1))、高(0.5 mg·kg^(-1))剂量组,通过与正常对照组比较,考察小鼠体重、摄食量、空腹血糖、血清胰岛素、糖化血红蛋白、肝功能和血脂情况,并进行肝脏组织病理学NAS和纤维化分析。结果BR0336各剂量组能显著降低模型小鼠的体重、摄食量、空腹血糖、胰岛素和HbA1c%,减低肝脏NAS评分和纤维化率,并对模型动物的肝功能和血脂异常具有良好保护作用。与阳性对照组相比,等剂量BR0336在动物的摄食量、胰岛素、肝功能和血脂生化方面表现更优,能更有效延缓NASH和纤维化进程。结论BR0336对STZ-HFD诱导的T2DM合并NASH模型小鼠在高血糖和脂质代谢紊乱方面具有一定治疗作用。

HER2阴性乳腺癌化疗患者复发转移的影响因素及风险预测模型构建

目的探讨人表皮生长因子受体-2(HER2)阴性乳腺癌化疗患者复发转移的影响因素,并构建风险预测模型。方法回顾性分析180例接受新辅助化疗的HER2阴性乳腺癌患者病历资料和随访资料,根据2年内复发转移情况将患者分为复发转移组(35例)和未复发转移组(145例)。采用Logistic回归分析HER2阴性乳腺癌化疗患者复发转移的影响因素,依据回归分析结果构建风险预测模型,计算一致性指数(C-index)检验模型准确性。绘制受试者工作曲线(ROC),以曲线下面积(AUC)检验风险预测模型对HER2阴性乳腺癌化疗患者复发转移的预测价值。结果复发转移组和未复发转移组在月经状态、临床分期、p53蛋白、Ki-67、VEGF方面比较,差异有统计学意义(P<0.05)。Logistic回归分析显示,月经状态、临床分期、p53蛋白、Ki-67、VEGF是HER2阴性乳腺癌化疗患者复发转移的影响因素(P<0.05)。基于上述因素构建风险预测模型,结果显示该列线图模型的校准曲线和Y=X直线相近,模型校准度良好,C-index值为0.844,提示该模型具有良好区分度。绘制ROC曲线发现,列线图风险预测模型预测HER2阴性乳腺癌化疗患者复发转移的AUC为0.844。结论月经状态、临床分期、p53蛋白、Ki-67、VEGF是HER2阴性乳腺癌化疗患者复发转移的影响因素,基于上述影响因素构建的风险预测模型可有效评估患者复发转移。

基于Markov模型的胰高血糖素样肽1受体激动剂联合二甲双胍治疗2型糖尿病药物经济学评价

目的 对胰高血糖素样肽1受体激动剂(GLP-1RA)联合二甲双胍治疗2型糖尿病(T2DM)进行经济学评价。方法 从我国卫生体系角度出发,基于7项GLP-1RA联合二甲双胍治疗T2DM的随机对照试验(RCT),构建二甲双胍单药或联合GLP-1RA治疗T2DM的Markov模型,模拟治疗期间T2DM无并发症、T2DM伴并发症以及死亡3种状态的动态变化。模型以质量调整生命年(QALYs)为健康产出指标、以3倍我国2023年人均国内生产总值(GDP)为意愿支付(WTP)阈值。模型循环周期设定为1年,共计模拟20年,采用Markov模型进行队列模拟,以增量成本-效用比(ICUR)为评价指标,从而获得每种治疗策略的长期成本、效用及其经济性。通过对成本、效用及贴现的敏感性分析,检验研究结果的稳定性。结果 与二甲双胍单药治疗相比,5种GLP-1RA类药物(利拉鲁肽、度拉糖肽、艾塞那肽、聚乙二醇洛塞那肽、司美格鲁肽)联合二甲双胍治疗方案的ICUR均小于3倍我国2023年人均GDP,增加的成本可接受。敏感性分析中各参数在设定的范围内变化,或将模拟时间延长至30年或50年,对研究结论无显著影响;概率敏感性分析结果表明,WTP阈值为3倍我国2023年人均GDP值(268 074元)时,二甲双胍联合司美格鲁肽0.5 mg方案具有成本-效用优势的概率最高,约为99.7%。结论 对于T2DM患者,相比于二甲双胍单药治疗,利拉鲁肽、度拉糖肽、艾塞那肽、聚乙二醇洛塞那肽、司美格鲁肽以说明书推荐剂量联合二甲双胍治疗方案均属于优势方案,具有经济性。