Activation of STAT3 signaling in human stomach adenocarcinoma drug-resistant cell line and its relationship with expression of vascular endothelial growth factor

AIM: To investigate the difference in activation of STAT3 signaling between two human stomach adenocarcinoma cell lines: 5-fluorouracil resistant cell line and its parental cell line, and to evaluate its relationship with the expression of vascular endothelial growth factor (VEGF). METHODS: Western blot and electrophoretic mobility shift assay (EMSA) were used to detect the expression of phospho-STAT3 protein and constitutive activation of STAT3 in two human stomach adenocarcinoma cell lines, 5-fluorouracil resistant cell line SGC7901/R and its parental cell line SGC7901, respectively. The mRNA expression of VEGF was analysed by semi-quantitative RT-PCR. The expressive intensity of VEGF protein was measured by immunocytochemistry. RESULTS: The expressions of phospho-STATS protein and constitutive activation of STAT3 between two human stomach adenocarcinoma cell lines were different. Compared with the parental cell line SGC7901, the STAT3DNA binding activity and the expressive intensity of phospho-STAT3 protein were lower in the drug-resistant cell line SGC7901/R. The expression levels of VEGF mRNA and its encoded protein were also decreased in drugresistant cell line. CONCLUSION: Over-expression of VEGF may be correlated with elevated STAT3 activation in parental cell line. Lower VEGF expression may be correlated with decreased STAT3 activation in resistant cell line, which may have resulted from negative feedback regulation of STAT signaling.

Effects of San Qi on Gastric Secretion and Protective Factors of Gastric Mucosa in the Rat with Precancerous Lesion of Stomach

In the model rat with precancerous lesion of stomach induced by the combined method of insertion of a spring into the pylorus and high salt hot paste,effects of San Qi (三七 Radix Notoginseng) on gastric secretion and protective factors of stomach were investigated.The results indicated that gastric secretion,gastric mucosal blood flow (GMBF) and aminohexose content lowered significantly,and malondialdehyde (MDA) increased significantly (P<0.01) in the model group as compared with the normal group;after treatment with San Qi Powder for 12 weeks,both gastric secresion and GMBF increased,and MDA content decreased as compared with the negative control group (P<0.01),with no significant increase of aminohexose content.It is suggested that San Qi (三七 Radix Notoginseng) may improve gastric secretion,and that increase of GMBF and antagonism against the lesion of oxygen free radicals are possibly one of its mechanisms.

Experimental study on effect of recombinant human growth hormone combined with chemotherapy on stomach neoplasms implanted in nude mice

Objective: To investigate the effect of different doses of recombined growth hormone (rhGH) on stomach neo- plasms implanted in nude mice, and its efficacy in combining with chemotherapy (flurouracil, 5-FU). Methods: Human stom- ach neoplasms model was established in nude mice. The nude mice were divided into control group, moderate-dose of rhGH group, low-dose rhGH group, 5-FU group, moderate-dose rhGH/5-FU group, and low-dose rhGH/5-FU group. The results of each group were observed after ten days. Results: After therapy, the body mass of rhGH groups was significantly increased compared with control group (P<0.05), the body mass of rhGH/5-FU groups was significantly increased compared with 5-FU group (P<0.05), but it was no significant difference between rhGH/5-FU groups and control group (P>0.05). The average tumor mass and volume of rhGH groups were not significantly increased compared with control group (P>0.05), but they were significantly reduced in 5-FU group and rhGH/5-FU groups (P<0.05). They were no significant difference between rhGH/5- FU groups and 5-FU group (P>0.05). After treatment, the percentages of S, G0/G1 and G2/M phases and proliferation index (PI) were not significantly changed in rhGH groups compared with control group (P>0.05), and the same with rhGH/5-FU groups compared with 5-FU group (P>0.05). The difference caused by dose of rhGH was not significant. Conclusion: rhGH enhances body mass, does not stimulate tumor growth, and has no adverse effects on tumor bearing nude mice. Combined with flurouracil, rhGH does not influence the efficacy of chemotherapy, and has no effect on tumor cell cycle kinetics.

THE EFFECTS OF CHINESE DRUGS FOR SUPPORTING HEALTHY ENERGY AND REMOVING BLOOD STASIS ON POSTOPERATIVE METASTASIS OF GASTRIC CARCINOMA AND ORNITHINE DECARBOXYLASE

32 postoperative cases of gastric carcinoma were treated by traditional Chinese medicine (TCM) drugs for supporting healthy energy and removing blood stasis, and their therapeutic results were compared with those in the control group treated by western medicine. After 6 months of treatment, in the TCM group, the rate of metastatic recurrence was significantly reduced, and the level of ornithine decarboxylase was also markedly lowered. Therefore, it is considered that the action of anti-metastatic recurrence of TCM drugs in postoperative cases of gastric carcinoma is probably related to the lowered activity of ornithine decarboxylase.

从补中益气汤管窥李东垣脾胃观之阴火论

“阴火”即内伤之火,其实质为脾胃亏虚,元气虚损所生之内热。“阴火”理论是李东垣提出并应用于临床阐明病机、诊治疾病、遣方用药的重要学说。其产生机制复杂,涵盖内容广泛,自古存在诸多争议,至今未有定论,临床价值尚未完全体现。补中益气汤既是东垣脾胃内伤学说的核心方,也是理解其内伤发热之“阴火”理论的关键。文章将通过探讨李东垣脾胃内伤理论体系中最重要的方剂“补中益气汤”的药物配伍特点及其理论基础,阐述李东垣脾胃观之“阴火”论的学术思想,以及“益气升阳”“甘温除热”的制方思想,浅析“阴火”理论的学术渊源,总结后世医家基于“阴火”理论的临床诊疗应用思路,以期为日后临床工作者应用“阴火”理论临床辨证论治、组方加减提供理论依据。

西藏自治区人民医院实施国家重点监控药品干预成效分析

目的:评价西藏自治区人民医院对重点监控药品进行重点干预的成效,为优化重点监控药品干预策略、促进临床合理用药提供参考。方法:西藏自治区人民医院于2020年制订《西藏自治区人民医院重点监控药品管理规定》,建立《西藏自治区人民医院重点监控药品目录》,同时开展重点监控药品处方及医嘱专项点评、采取点评结果公示及绩效考核挂钩等目标性干预措施,对比西藏自治区人民医院2019年4月-2020年3月(干预前)与2020年4月-2021年3月(干预后第一年)及2021年4月-2022年3月(干预后第二年)重点监控药品临床使用数据变化,评价重点干预措施对该类药品的管理成效及临床使用的影响。结果:该院干预后第一年及第二年的重点监控药品销售金额分别为1427.01万元、1388.12万元,低于干预前的2004.29万元;干预后重点监控药品销售金额占药品总销售金额比例分别为8.33%、7.47%,低于干预前的10.11%。重点监控药品各品种的DDC普遍较高,患者的经济负担较重。结论:西藏自治区人民医院重点监控药品的干预取得了一定成效,但医院应在此基础上采取有力措施,提高重点监控药品合理使用,进一步减轻患者经济负担。

李东垣内伤病辨治思路探析及思辨

《内外伤辨惑论》为金元四大家李东垣著作之一,其卷中部分主要论述了内伤病的病机证治等内容。李东垣所论内伤病是由脾胃受损所导致的一种不足之病,生理基础主要与脾胃的生成和布散精微功能有关,核心病机为脾胃受损所导致的精气不足及阴火上冲,时令主气也会改变内伤病的主要矛盾。针对不断变化的病机,李东垣立甘温除热、补气升阳等法,又有补中益气汤、参术调中汤等方随于后,形成了完整的内伤病辨治体系。李东垣理法十分精妙,多脱胎于先贤经典,笔者在文献梳理的基础上,选甘温除热、按而收之、风药升阳三点,思辨推敲其本义,以便灵活运用于临床。

GLI1表达与肿瘤免疫浸润及胃癌临床预后的关系

目的:探讨胃癌中胶质瘤相关癌基因1(GLI1)的表达与免疫浸润相关性,及其与临床预后的相关性。研究GLI1的表达对胃癌化疗药物耐药性的影响。方法:运用TCGA数据库分析GLI1在胃癌和正常组织中的表达差异,分析胃癌患者临床特征和GLI1基因表达水平对患者预后的影响;分析胃癌组织中GLI1基因表达与肿瘤免疫细胞浸润的相关性,探究其对化疗药物及靶向药物耐药性的影响。收集临床标本,分析GLI1在胃癌和癌旁组织中的表达差异。结果:胃癌组织中GLI1高表达是正常组织的1.7倍,其高表达患者总生存期、无病生存期较低表达患者更短(P<0.05)。胃癌组织中GLI1的高表达组间质评分、免疫评分、免疫浸润细胞丰度更高,GLI1高表达对药物敏感性降低并且和免疫检查点标志物PDCD1表达呈正相关(P<0.05)。GLI1在低分化胃癌患者中表达明显升高(P<0.05)。结论:GLI1表达与胃癌患者预后及免疫浸润相关,并且其可能通过调节化疗耐药而导致患者的不良预后,可能是胃癌潜在的治疗靶点和分子标志物。

应用失效模式与效应分析法提高药房盘点质量探索

目的:优化现代化门诊药房药品盘点过程以提升盘点质量。方法:通过文献检索、头脑风暴等方法绘制药品盘点流程图并收集每个子流程的潜在失效模式及失效原因,应用失效模式与效应分析法(Failure Mode and Effect Analysis,FMEA)对各失效模式发生的可能性、严重性和可侦测度进行评分及风险优先值(RPN)计算,量化并确定高风险失效模式,制定改进措施并实施,分析改善效果。结果:确定了盘点的3个主流程和12个子流程,以及各子流程相关的21项失效模式和38项失效原因,高风险因素共15项,制定针对性改进措施28项。干预改进后,各高风险失效模式RPN值均显著降低,其中最高的4项由392、288、280、280分别降至42、48、56、63,均处于相对低风险区域;干预管理前后复盘相符率由82.4%上涨至96.2%,盘存时长由180.2 min降至155.3 min。结论:FMEA法在药品盘点过程存在问题分析改进中的价值是肯定的,制定的各项改进措施,尤其是针对现代化药房自动化设备盘存模块的相关措施,以及低代码平台在智能化盘点中的应用等对于盘点质量的提升作用非常显著,值得借鉴并推广运用来提升药品经济和质量管理。

Advances in the study of gastric organoids as disease models

Gastric organoids are models created in the laboratory using stem cells and sophisticated three-dimensional cell culture techniques.These models have shown great promise in providing valuable insights into gastric physiology and advanced disease research.This review comprehensively summarizes and analyzes the research advances in culture methods and techniques for adult stem cells and induced pluripotent stem cell-derived organoids,and patient-derived organoids.The potential value of gastric organoids in studying the pathogenesis of stomach-related diseases and facilitating drug screening is initially discussed.The construction of gastric organoids involves several key steps,including cell extraction and culture,three-dimensional structure formation,and functional expression.Simulating the structure and function of the human stomach by disease modeling with gastric organoids provides a platform to study the mechanism of gastric cancer induction by Helicobacter pylori.In addition,in drug screening and development,gastric organoids can be used as a key tool to evaluate drug efficacy and toxicity in preclinical trials.They can also be used for precision medicine according to the specific conditions of patients with gastric cancer,to assess drug resistance,and to predict the possibility of adverse reactions.However,despite the impressive progress in the field of gastric organoids,there are still many unknowns that need to be addressed,especially in the field of regenerative medicine.Meanwhile,the reproducibility and consistency of organoid cultures are major challenges that must be overcome.These challenges have had a significant impact on the development of gastric organoids.Nonetheless,as technology continues to advance,we can foresee more comprehensive research in the construction of gastric organoids.Such research will provide better solutions for the treatment of stomach-related diseases and personalized medicine.

胃类器官:迟来者的崛起

胃类器官是利用干细胞技术和组织工程,在体外培养出具有胃肠道器官结构和功能特征的三维细胞聚集体,较传统模型更能模拟真实组织的结构和功能.自2009年首次培育出肠道类器官以来,类器官技术在动物模型和人类干细胞上取得了重要进展.胃类器官在多个领域具有应用潜力,包括研究胃肠道发育和分化机制、模拟和治疗胃肠道疾病、药物筛选和评价、再生医学和个性化治疗.但胃类器官面临的挑战包括其发育与分化过程的复杂性,以及其结构、功能、疾病和癌变的多层次复杂性.尽管存在局限性和挑战,胃类器官仍是生物医学领域的重要研究工具,为胃疾病研究和应用提供了新机遇.

从胃心痛论治冠心病PCI术后胃黏膜损伤的诊疗经验

冠心病患者在行PCI术后需长期服用抗血小板药物治疗,但长期服用抗血小板药物易致胃黏膜损伤,而单纯使用抑酸、护胃药物来治疗此类疾病,副作用多而收效不明显,且最新研究表明单纯使用PPI预防再次消化道出血时可能会增加心血管病患者心血管事件的发生率。因此,龙云主任从中医整体观念出发,从胃心痛角度来辨证论治本病,收效显著,可为临床治疗抗血小板药物致冠心病胃黏膜损伤患者提供新思路。

脾胃病科患者出院带药特征及不合理情况分析

目的通过分析某院脾胃病科患者出院带药特征及不合理情况,为出院带药的合理性管理提供参考。方法选择2021年1月1日~2022年12月31日某院脾胃病科出院患者,通过Excel表格录入患者的基本信息、住院天数、出院时的中医和西医诊断、出院带药药品分类及用法用量、疗程及合理性。结果共纳入1239例患者,有基础病的1213例,平均住院(7.85±4.84)d;平均每例出院带药(2.17±1.23)种;患者出院带药中脾胃病用药前三名分别是质子泵抑制剂、铝镁加混悬液、复方谷氨酰胺肠溶胶囊,非脾胃病用药前三名分别是心脑血管系统用药、非脾胃病用中成药和精神病类用药;出院带药药物疗程最长的是甲状腺病用药,平均(78.50±49.58)d;最少的是除质子泵抑制剂之外的脾胃病用药以及非脾胃病用中成药,平均疗程分别为(11.50±6.62)d、(10.69±6.19)d。结论首先,脾胃病科患者出院带药主要集中在消化内科用药和心脑血管系统用药、中成药、精神类疾病用药;其次,不合理出院带药主要为消化内科用药、前列腺病用药等;最后,出院带药缺乏用药交代,且疗程偏长。

甘温除热法治疗乳腺癌化疗后并发症

乳腺癌的发病以气郁、痰凝、血瘀为因,患之日久,积聚为核,囿于乳络,终耗气伤血,应用化疗药物后,毒邪进入体内最先伤及脾胃,脾胃受损则气血生化无本,输布无源,进而影响其他脏腑生理功能,致正气虚损、气血耗伤。甘温除热法可扶正祛邪、调畅气机、补益气血、安和诸脏,病及于心可用泻火升阳汤,病及于肝可用补中益气汤,病及于肺可用升阳益胃汤,病及于肾可用神圣复气汤。临证时需把握甘温除热法对应证的病机变化,选用方除李东垣著作中所载方外,亦可选黄芪建中汤、人参养荣汤、十全大补汤、七味白术散等符合甘温除热思想之方。

抗体药物偶联物在人表皮生长因子受体2低表达胃癌中的应用研究进展

胃癌(GC)是极具异质性和侵袭性的消化系统恶性肿瘤之一,传统化疗药物及曲妥珠单抗等人表皮生长因子受体2(HER2)靶向药物在GC的治疗过程中仍然存在耐药性发生率高、毒副作用大、患者耐受差等缺点。因此,研发更为有效的抗GC药物势在必行。目前针对HER2的新型靶向药层出不穷,但在某些情况下无效或产生耐药,这与HER2在某些GC细胞中低表达有关,HER2低表达(HER2 IHC1+或IHC2+/ISH-)约占全部类型的40%~60%,但在临床实践中,这类患者仍被报告为HER2阴性GC。因此准确检测HER2表达状态对于确定可能受益于曲妥珠单抗治疗的患者至关重要。抗体药物偶联物(ADC)的出现为HER2阳性GC提供了新的治疗选择,凭借其精准高效的抗肿瘤作用,有望在未来替代传统GC化学疗法。近期有研究发现ADC可能在HER2低表达GC中具有潜在抗肿瘤活性,相关临床研究正在评估其在HER2低表达GC治疗中的有效性和安全性。本文就靶向治疗时代ADC在HER2低表达GC患者中的应用和最新研究进展作一综述,并讨论HER2靶向ADC在应用和研发过程中面临的挑战。

Suppression of P-gp induced multiple drug resistance in a drug resistant gastric cancer cell line by overexpression of Fas

AIM To observe the drug sensitizing effect andrelated mechanisms of fas gene transduction onhuman drug-resistant gastric cancer cellSGC7901/VCR(resistant to Vincristine).METHODS The cell cycle alteration wasobserved by FACS.The sensitivity of gastriccancer cells to apoptosis was determined by invitro apoptosis assay.The drug sensitization ofcells to several anti-tumor drugs was observedby MTT assay.Immunochemical method wasused to show expression of P-gp and Topo Ⅱ ingastric cancer cells.RESULTS Comparing to SGC7901 and pBK-SGC7901/VCR,fas-SGC7901/VCR showeddecreasing G2 cells and increasing S cells,theG2 phase fraction of pBK-SGC7901/VCR wasabout 3.0 times that of fas-SGC7901/VCR,but Sphase fraction of fas-SGC7901/VCR was about1.9 times that of pBK-SGC7901/VCR,indicatingS phase arrest of fas-SGC7901/VCR.FACS alsosuggested apoptosis of fas-SGC7901/VCR,fas-SGC7901/VCR was more sensitive to apoptosisinducing agent VM-26 than pBK-SGC7901/VCR.MTT assay showed increased sensitization offas-SGC7901/VCR to DDP,MMC and 5-FU,butsame sensitization to VCR according to pBK-SGC7901/VCR.SGC7901,pBK-SGC7901/ VCRand fas-SGC7901/VCR had positively stainedTopo Ⅱ equally.P-gp staining in pBK- SGC7901/VCR was stronger than in SG07901,but there was little staining of P-gp in fas.SGC7901/VCR.CONCLUSION fas gene transduction couldreverse the MDR of human drug-resistant gastriccancer cell SGC7901/VCR to a degree,possiblybecause of higher sensitization to apoptosis anddecreased expression of P-gp.

Transduction of Fas gene or Bcl-2 antisense RNA sensitizes cultured drug resistant gastric cancer cells to chemotherapeutic drugs

AIM To compare the expression level of Fas gene and Bcl-2 gene in gastric cancer cells SGC7901 and gastric cancer MDR (multidrug resistant) cells SGC7901/VCR, to transduce Fas cDNA and Bcl-2 antisense nucleic acid into SGC7901/VCR cells respectively, and to observe the expression of two genes in transfectants and non-transfectants as well as their drug sensitivity.METHODS Eukaryotic expression vector pBK-Fas cDNA and pDOR-anti Bcl-2 were constructed and transfected into SGC7901/VCR cells by lipofectamine, respectively. Northern blot and Western blot were used to detect the expression of mRNA and protein in SGC7901/VCR and SGC7901 cells and transfectants, and drug sensitivity of transfectants for VCR, CDDP and 5-FU was analyzed with MTT assay.RESULTS After gene transfection, 80 for Fas and 120 for antisense Bcl-2 drug-resistant clones were selected from 2×105 cells, transfection rate being 0.04% and 0.06%. Two clones of SGC7901 Fas/VCR cells and SGC7901 anti Bcl-2/VCR cells were randomly selected for further incubation. Hybridization results showed that the expression level of Fas mRNA and protein in SGC7901/VCR cells was much lower, but that of Bcl-2 mRNA and protein was higher than that in SGC7901 cells. The expression of Fas mRNA and protein in SGC7901 Fas/VCR cells was higher, and of Bcl-2 mRNA and protein was lower in SGC7901 anti Bcl-2/VCR cells than that in non-transfectants. MTT assay showed that transfectants were more sensitive to VCR, CDDP, 5-FU than non-transfectants.CONCLUSION Bcl-2 gene displayed high expression while Fas gene had low expression in drug resistant gastric cancer cells. Expression of Bcl-2 protein was effectively blocked in SGC7901 anti Bcl-2/VCR cells by gene transfection. In contrast, the expression of Fas mRNA and protein in SGC7901 Fas/VCR cells increased. Fas gene and Bcl-2 antisense nucleic acid transfection sensitized drug resistant gastric cancer cells to chemotherapeutic drugs. These results suggest cell apoptosis plays an important role in the mechanism of MDR, and enhancing apoptosis might reverse MDR.

The effect pathway of retinoic acid through regulation of retinoic acid receptor α in gastric cancer cells

AIM To evaluate the role of RARα gone in mediating the growth inhibitory effect of all-trans retinoic acid(ATRA) on gastric cancer cells. METHODS The expression levels of retinoic acid receptors(PARs)in gastric cancer cells were detected by Northern blot.Transient transfection and chlorophenicol acetyl transferase(CAT)assay were used to show the transcriptional activity of β retinoic acid response element (βPARE)and AP-1 activity.Cell growth inhibition was determined by MTT assay and anchorage-independent growth assay,respectively.Stable transfection was performed by the method of Lipofectamine,and the cells were screened by G418. RESULTS ATRA could induce expression level of RARα in MGC80-3,BGC-823 and SGC-7901 cells obviously, resulting in growth inhibition of these cell lines.After sense RARα gone was transfected into MKN-45 cells that expressed rather low level of RARα and could not be induced by ATPA,the cell growth was inhibited by ATPA markedly.In contrast,when antisense RARα gone was transfected into BGC-823 cells,a little inhibitory effect by ATPA was seen,compared with the parallel BGC-823 cells.In transient transfection assay,ATPA effectively induced transcriptional activity of βRARE in MGC80-3, BGC-823,SGC-7902 and MKN/RARα cell lines,but not in MKN-45 and BGC/aRARα cell lines.Similar results were observed in measuring anti-AP-1 activity by ATPA in these cancer cell lines. CONCLUSION ATRA inhibits the growth of gastric cancer cells by up-regulating the level of RARα; RARα is the major mediator of ATRA action in gastric cancer cells;and adequate level of RARα is required for ATRA effect on gastric cancer cells.

Formulation and evaluation of novel stomach specific floating microspheres bearing famotidine for treatment of gastric ulcer and their radiographic study

Objective:To develop and characterize multiple-unit-type oral floating microsphere of famotidine to prolong gastric residence time and to target stomach ulcer.Methods:The floating microspheres were prepared by modified solvent evaporation method,Eudragil S-100 was used as polymer.Microspheres were characterized for the micromeritic properties,floating behavior,entrapment efficiency and scanning electron microscopy.The invitro release studies and floating behavior were studied in simulated gastric fluid at pH 1.2.Different drug release kinetics models were also applied for all the batches.Selected formulations were also subjected for X-ray radiographic study.Results:Floating microspheres were successfully prepared by modified solvent evaporation technique.Microspheres showed passable flow properties.The maximum yield of microspheres was up to(95.11±0.35)%.On the basis of optical microscopy particle size range was found to be ranging from(52.18±182.00) to(91.64±5.16) μm.Scanning electron microscopy showed their spherical size,perforated smooth surface and a cavity inside microspheres.Microspheres were capable to float up to 20 h in simulated gastric fluid.X-ray radiographic studies also proved its better retention in the stomach.Conclusions:On the basis of the results,such dosage forms may be a good candidate for stomach targeting and may be dispensed in hard gelatin capsules.

Effect of garlic on micronucleus frequency of peripheral blood lymphocytes in MNNG-induced gastric carcinoma and precancerous lesion in rats

IM To investigate the effects of garlic on micronuclei frequency (MNF) of peripheral blood lymphocytes (PBL) in gastric carcinoma (GC) and precancerous lesion (PL) in Wistar rats induced by NmethylN′nitroNnitrosoguanidine (MNNG). METHODS Gastric carcinoma and precancerous lesions were induced by MNNG 125mg/5ml per day for 10 months. 10% garlic 10ml per day were given to the experimental group, and running water to control group. MNF of PBL in the control CG (n=16), MNNG (n=30), prevention (n=30) and treatment groups (n=20) were detected at 10 and 16 months by the technic of micronucleus cell culture. RESULTS MNF of MNNG group at the 10th and 16th month was similar; that of MNNG, GC and PL was remarkably higher than the control group (P<001), respectively; and that of PL was lower than GC (P<001). MNF of prevention and treatment groups was decreased, with significant difference from MNNG group (P<001). MNF of the prevention group at the 16th month was lower than that at the 10th month (P<001), the difference between the prevention and treatment groups was not significant. CONCLUSION MNNG was a continuous mutagenicity and carcinogenicity, and garlic has a remarkable antimutagenic and anticarcinogenic effect. The micronucleus frequency of PBL may be a new marker of earlystage gastric carcinogenesis.