Apatinib reduces liver cancer cell multidrug resistance by modulating NF-κB signaling pathway

Objectives:This investigation aimed to elucidate the inhibitory impact of apatinib on the multidrug resistance of liver cancer both in vivo and in vitro.Methods:To establish a Hep3B/5-Fu resistant cell line,5-Fu concentrations were gradually increased in the culture media.Hep3B/5-Fu cells drug resistance and its alleviation by apatinib were confirmed via flow cytometry and Cell Counting Kit 8(CCK8)test.Further,Nuclear factor kappa B(NF-κB)siRNA was transfected into Hep3B/5-Fu cells to assess alterations in the expression of multidrug resistance(MDR)-related genes and proteins.Nude mice were injected with Hep3B/5-Fu cells to establish subcutaneous xenograft tumors and then categorized into 8 treatment groups.The treatments included oxaliplatin,5-Fu,and apatinib.In the tumor tissues,the expression of MDRrelated genes was elucidated via qRT-PCR,immunohistochemistry,and Western blot analyses.Results:The apatinibtreated mice indicated slower tumor growth with smaller size compared to the control group.Both the in vivo and in vitro investigations revealed that the apatinib-treated groups had reduced expression of MDR genes GST-pi,LRP,MDR1,and p-p65.Conclusions:Apatinib effectively suppresses MDR in human hepatic cancer cells by modulating the expression of genes related to MDR,potentially by suppressing the NF-κB signaling pathway.

Identification of FDA-Approved Drugs as Modulators of Multidrug Resistance Protein 2 (MRP2/ABCC2) Expression Levels in MRP2-Overexpressing Cells: Preliminary Data

Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have shown that MRP2 can significantly affect the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of many therapeutic drugs and chemicals found in the environment and diet. This transporter can also efflux newly developed anticancer agents that target specific signaling pathways and are major clinical markers associated with multidrug resistance (MDR) of several types of cancers. MDR remains a major limitation to the advancement of the combinatorial chemotherapy regimen in cancer treatment. In addition to anticancer agents, MRP2 reduces the efficacy of various drug classes such as antivirals, antimalarials, and antibiotics. The unique role of MRP2 and its contribution to MDR makes it essential to profile drug-transporter interactions for all new and promising drugs. Thus, this current research seeks to identify modulators of MRP2 protein expression levels using cell-based assays. A unique recently approved FDA library (372 drugs) was screened using a high-throughput In-Cell ELISA assay to determine the effect of these therapeutic agents on protein expression levels of MRP2. A total of 49 FDA drugs altered MRP2 protein expression levels by more than 50% representing 13.17% of the compounds screened. Among the identified hits, thirty-nine (39) drugs increased protein expression levels whereas 10 drugs lowered protein expression levels of MRP2 after drug treatment. Our findings from this initial drug screening showed that modulators of MRP2 peregrinate multiple drug families and signify the importance of profiling drug interactions with this transporter. Data from this study provides essential information to improve combinatorial drug therapy and precision medicine as well as reduce the drug toxicity of various cancer chemotherapies.

The Activity of Erianin and Chrysotoxine from Dendrobium chrysotoxum to Reverse Multidrug Resistance in B16/h MDR-1 Cells

The ability of two dihydrostilbene derivatives erianin and chrysotoxine from Dendrobium chrysotoxum to reverse multidrug resistant (MDR) cells was investigated using murine B16 melanoma cells transfected with the human MDR 1 gene and crossresistant to vinblastine and adriamycin (B16/h MDR 1 cells). Both of the two compounds were shown to increase the accumulation of adriamycin, the P glycoprotein (P gp) substrate, in B16/h MDR 1 transfectants.

Reversing multidrug resistance by RNA interference through the suppression of MDR1 gene in human hepatoma cells

AIM： To reverse the multidrug resistance （MDR） by RNA interference （RNAi）-mediated MDRI suppression in heparoma cells.METHODS： For reversing MDR by RNAi technology, two different short hairpin RNAs （shRNAs） were designed and constructed into pGenSil-1 plasmid, respectively. They were then transfected into a highly adriarnycin-resistant HepG2 hepatorna cell line （HepG2/ADM）. The RNAi effect on MDR was evaluated by real-time PCR, cell cytotoxicity assay and rhodarnine 123 （Rh123） efflux assy. RESULTS： The stably-transfected clones showed various degrees of reversal of MDR phenotype. Surprisingly, the MDR phenotype was completely reversed in two transfected clones. CONCLUSION： MDR can be reversed by the shRNAmediated MDRI suppression in HepG2/ADM cells, which provides a valuable clue to make multidrug-resistant hepatoma cells sensitive to anti-cancer drugs.

REVERSAL EFFECTS OF MIFEPRISTONE ON MULTIDRUG RESISTANCE(MDR) IN DRUG-RESISTANT BREAST CANCER CELL LINE MCF7/ADR IN VITRO AND IN VIVO

To explore the reversal effect of mifepristone on multidrug resistance (MDR) in drug-resistant human breast cancer cell line MCF7/ADR and its mechanisms. Methods: Expression of MDR1 and MDR-associated protein(MRP) mRNA in MCF7/ADR cells was detected using reverse transcription- polymerase chain reaction(RT-PCR). Western blotting was used to assay the protein levels of P-glycoprotein (P-gp) and MRP. Intracellular rhodamine 123 retention and [3H]vincristine (VCR) accumulation were measured by flow cytometry and liquid scintillation counter, respectively. MTT reduction assay was used to determine the sensitivity of cells to the anticancer agent, adriamycin (ADR). Additionally, a MCF7/ADR cell xenograft model was established to assess the reversal effect of mifeprisone on MDR in MCF7/ADR cells in vivo. Results: Miferpristone dose-dependently down- regulated the expression of MDR1 and MRP mRNA in MCF7/ADR cells, accompanied by a significant decrease in the protein levels of P-gp and MRP. After exposure to 5, 10, and 20 mmol/L mifepristone, MCF7/ADR cells showed a 3.87-, 5.81-, and 7.40-fold increase in the accumulation of intracellular VCR(a known substrate of MRP), and a 2.14-, 4.39-, and 5.53-fold increase in the retention of intracellular rhodamine 123(an indicator of P-gp function), respectively. MTT analysis showed that the sensitivity of MCF7/ADR cells to ADR was enhanced by 7.23-, 13.62-, and 20.96-fold after incubation with mifepristone as above-mentioned doses for 96 h. In vivo, mifepristone effectively restored the chemosensitivity of MCF7/ADR cells to ADR. After 8 weeks of administration with ADR(2 mg穔g-1穌-1) alone or in combination with mifepristone(50 mg穔g-1穌-1), the growth inhibitory rate of xenografted tumors in nude mice was 8.08% and 37.25%, respectively. Conclusion: Mifepristone exerts potent reversal effects on MDR in MCF7/ADR cells in vitro and in vivo through down- regulation of MDR1/P-gp and MRP expression and inhibition of P-gp- and MRP-dependent drug efflux, thus increasing the sensitivity to anticancer drug.

Genotyping Characteristics of Human Fecal Escherichia coli and Their Association with Multidrug Resistance in Miyun District, Beijing

Objective To explore the genotyping characteristics of human fecal Escherichia coli(E. coli) and the relationships between antibiotic resistance genes(ARGs) and multidrug resistance(MDR) of E. coli in Miyun District, Beijing, an area with high incidence of infectious diarrheal cases but no related data.Methods Over a period of 3 years, 94 E. coli strains were isolated from fecal samples collected from Miyun District Hospital, a surveillance hospital of the National Pathogen Identification Network. The antibiotic susceptibility of the isolates was determined by the broth microdilution method. ARGs,multilocus sequence typing(MLST), and polymorphism trees were analyzed using whole-genome sequencing data(WGS).Results This study revealed that 68.09% of the isolates had MDR, prevalent and distributed in different clades, with a relatively high rate and low pathogenicity. There was no difference in MDR between the diarrheal(49/70) and healthy groups(15/24).Conclusion We developed a random forest(RF) prediction model of TEM.1 + baeR + mphA + mphB +QnrS1 + AAC.3-IId to identify MDR status, highlighting its potential for early resistance identification. The causes of MDR are likely mobile units transmitting the ARGs. In the future, we will continue to strengthen the monitoring of ARGs and MDR, and increase the number of strains to further verify the accuracy of the MDR markers.

MDRO肺炎感染患者SAA、PCT、Treg细胞及有关因子表达水平

目的探讨血清淀粉样蛋白A(serum amyloid A protein,SAA)、降钙素原(procalcitonin,PCT)、Treg细胞及有关因子在多重耐药菌(multidrug-resisitant organism,MDRO)肺炎感染患者中的表达水平及其与疗效的关联性。方法选取97例MDRO肺炎感染患者为研究对象,根据治疗14 d后的治疗效果分为有效组(73例)和无效组(24例),根据入院时肺炎严重指数(PSI)分为低危(34例)、中危(49例)、高危(14例)三个亚组。比较2组治疗前、治疗7 d后、治疗14 d后SAA、PCT、Treg细胞、超敏C反应蛋白(hs-CRP)、肿瘤坏死因子-α(TNF-α)水平,比较治疗前低危、中危、高危患者血清各指标水平及PSI评分,分析血清各指标水平与PSI评分的相关性。结果与无效组比较,治疗7、14 d后有效组SAA、PCT、hs-CRP、TNF-α水平较低,Treg细胞数较高,差异有统计学意义(P<0.05);治疗前,低危患者SAA、PCT、hs-CRP、TNF-α及PSI评分<中危患者<高危患者,Treg细胞数>中危患者>高危患者,差异有统计学意义(P<0.05);治疗前,SAA、PCT、hs-CRP、TNF-α水平与PSI评分呈正相关,Treg细胞数与PSI评分呈负相关(P<0.05);受试者操作特征(ROC)曲线显示治疗前SAA、PCT、Treg细胞、hs-CRP、TNF-α联合预测治疗无效的AUC大于各指标单独预测。结论MDRO肺炎感染患者SAA、PCT、hs-CRP、TNF-α、Treg细胞数量呈异常表达,且表达水平对预后具有重要影响,临床可监测其水平变化,联合预测预后的价值较高。

Efficacy and Safety of Combined Bedaquiline and Delamanid Use among Patients with Multidrug-Resistant Tuberculosis in Beijing,China

Objectives The combined use of bedaquiline and delamanid(BDQ-DLM)is limited by an increased risk of prolonging the QTc interval.We retrospectively evaluated patients who received DLM/BDQcontaining regimens at a TB-specialized hospital.We aimed to present clinical efficacy and safety data for Chinese patients.Methods This case-control study included patients with multidrug-resistant tuberculosis(MDR-TB)treated with BDQ alone or BDQ plus DLM.Results A total of 96 patients were included in this analysis:64 in the BDQ group and 32 in the BDQ+DLM group.Among the 96 patients with positive sputum culture at the initiation of BDQ alone or BDQ combined with DLM,46 patients(71.9%)in the BDQ group and 29(90.6%)in the BDQ-DLM group achieved sputum culture conversion during treatment.The rate of sputum culture conversion did not differ between the two groups.The time to sputum culture conversion was significantly shorter in the BDQ-DLM group than in the BDQ group.The most frequent adverse event was QTc interval prolongation;however,the frequency of adverse events did not differ between the groups.Conclusion In conclusion,our results demonstrate that the combined use of BDQ and DLM is efficacious and tolerable in Chinese patients infected with MDR-TB.Patients in the BDQ-DLM group achieved sputum culture conversion sooner than those in the BDQ group.

Five-year analysis of isolated pathogens and antibiotic resistance of ocular infections from two large tertiary comprehensive hospitals in east China

AIM:To analyze the spectrum of isolated pathogens and antibiotic resistance for ocular infections within 5y at two tertiary hospitals in east China.METHODS:Ocular specimen data were collected from January 2019 to October 2023.The pathogen spectrum and positive culture rate for different infection location,such as keratitis,endophthalmitis,and periocular infections,along with antibiotic resistance were analyzed.RESULTS:We included 2727 specimens,including 827(30.33%)positive cultures.A total of 871 strains were isolated,530(60.85%)bacterial and 341(39.15%)fungal strains were isolated.Gram-positive cocci(GPC)were the most common ocular pathogens.The most common bacterial isolates were Staphylococcus epidermidis(25.03%),Staphylococcus aureus(7.46%),Streptococcus pneumoniae(4.59%),Corynebacterium macginleyi(3.44%),and Pseudomonas aeruginosa(3.33%).The most common fungal genera were Fusarium spp.(12.74%),Aspergillus spp.(6.54%),and Scedosporium spp.(5.74%).Staphylococcus epidermidis strains showed more than 50%resistance to fluoroquinolones.Streptococcus pneumoniae and Corynebacterium macginleyi showed more than 90%resistance to erythromycin.The percentage of bacteria showing multidrug resistance(MDR)significantly decreased(χ^(2)=17.44,P=0.002).CONCLUSION:GPC are the most common ocular pathogens.Corynebacterium macginleyi,as the fourth common bacterium,may currently be the local microbiological feature of east China.Fusarium spp.is the most common fungus.More than 50%of the GPC are resistant to fluoroquinolones,penicillins,and macrolides.However,the proportion of MDR strains has been reduced over time.

Diarrheal Diseases: A Review on Gastroenteritis Bacteria Global Burden and Alternative Control of Multidrug-Resistant Strains

Diarrheal diseases represent a significant and pervasive health challenge for humanity. The aetiology of diarrheal diseases is typically associated with the presence of enteropathogens, including viruses, bacteria and parasites. The implementation of preventive measures, including the maintenance of good food hygiene, effective water sanitation, and the development of rotavirus vaccines, has resulted in a notable reduction in the prevalence of the disease. However, the emergence of bacterial multidrug resistance due to the past or present inappropriate use of antibiotics has rendered bacterial infections a significant challenge. The objective of this review is threefold: firstly, to provide an overview of diarrheal diseases associated with bacteria;secondly, to offer a concise analysis of bacterial multidrug resistance on a global scale;and thirdly, to present the potential of filamentous fungi as an alternative solution to the challenge posed by multidrug-resistant strains. Campylobacter spp. is the most dangerous bacteria, followed by Shigella spp. and Vibrio cholerae in all age groups combined. However, Shigella spp. was the deadliest in children under five years of age and, together with E. coli, are the most antibiotic-resistant bacteria. With their highly developed secondary metabolism, fungi are a reservoir of natural bioactive compounds.

In Vitro Study of Ultrasound on Multidrug Resistance in MDR Human Hepatoma HepG_2 Cells

OBJECTIVE The aim of the study was to examine the reversal effects of ultrasound （US） on the MDR in HepG2/ADM, a HepG2 cell line resistant to Adriamycin （ADM）, and to study the mechanism of US action.METHODS Using the MTT assay, the effects of US on MDR in HepG2/ADR cells were studied. Before and after the treatment with 0.5 W/cm^2 low intensity ultrasound （LIUS）, the expression of the MDR-related genes, mdrl, mrp and lrp was assayed with the reverse transcriptase polymerase chain reaction （RT-PCR） and the levels of their respective protein expression determined by flow cytometry. By using confocal laser scanning microscopy （CLSM）, we examined the intracellular daunorubicin （DNR） distribution, and the effects on the cells of treatment with US or DNR.RESULTS LIUS significantly reversed MDR in HepG2/ADR cells. After treatment with LIUS at 0.5 W/cm^2, chemosensitivity to ADM and DNR increased 3.35-fold and 2.81-fold, respectively. The reversal activity by LIUS plus verapamil （VER） was stronger than with either US or VER alone. After treatment with 0.5 W/cm^2, the expression of both the MDR1 and the MRP mRNA genes began to decline （P 〈 0.01 and P 〈 0.05, respectively）; the expression of LRP showed no significant changes. Changes in the expression of the P-glycoprotein （P-gp） and MRP were similar to those of their mRNA expressions. Results of the CLSM showed that administration of US （0. 5 W/cm^2） or VER （15.7 uM） with DNR to HepGa/ADM cells showed a significant change in the distribution of DNR in the cells.CONCLUSION Our results show that LIUS can reverse MDR. The reversal effects are stronger than those of either US or VER alone, when combined with VER administration. As LIUS is noninvasive causing no toxicity, it might have potential for clinical application. The reversal mechanism needs further study.

米诺环素联合头孢哌酮舒巴坦对MDR-AB感染重症肺炎患者肺功能及炎性因子的影响

目的 观察米诺环素联合头孢哌酮舒巴坦对多重耐药鲍曼不动杆菌(MDR-AB)感染重症肺炎患者肺功能及炎性因子的影响。方法 选取2020年1月—2023年6月武夷山市立医院收治的MDR-AB感染重症肺炎患者135例,根据随机数字表法分为联合组(68例)和对照组(67例)。在常规治疗基础上,对照组予头孢哌酮舒巴坦治疗,联合组在对照组基础上予米诺环素治疗,2组均治疗2周。比较2组疗效、细菌清除率,治疗前后肺功能[第1秒用力呼气容积(FEV_(1))、用力肺活量(FVC)、FEV_(1)/FVC]、炎性因子[白介素-8(IL-8)、C反应蛋白(CRP)、降钙素原(PCT)]及不良反应。结果 联合组总有效率为97.06%,高于对照组的86.57%(χ^(2)=4.964,P=0.026);联合组细菌总清除率为73.53%,高于对照组的56.72%(χ^(2)=4.204,P=0.040)。治疗2周后,2组FEV_(1)、FVC、FEV_(1)/FVC高于治疗前,且联合组高于对照组(P<0.05或P<0.01);2组IL-8、CRP、PCT水平低于治疗前,且联合组低于对照组(P<0.05或P<0.01)。联合组与对照组不良反应总发生率比较差异无统计学意义(14.71%vs.10.45%,χ^(2)=0.556,P=0.456)。结论 米诺环素联合头孢哌酮舒巴坦治疗MDR-AB感染重症肺炎疗效显著,可促进细菌清除,改善患者肺功能,减轻炎性反应,且安全性较高。

MDR-PTB患者CT征象及治疗转归的危险因素分析

目的分析耐多药肺结核(MDR-PTB)患者的计算机断层扫描(CT)征象及治疗转归的危险因素。方法回顾性分析2019年2月至2022年3月在陕西省结核病防治院接受治疗的84例MDR-PTB患者临床资料,其中男53例,女31例,年龄(38.52±6.707)岁。经标准化学治疗24个月后按临床治疗转归分为治疗有效组(完成治疗、治愈,57例)与治疗无效组(治疗失败,27例),同期选择84例非MDR-PTB患者为参照组。采用t检验对比参照组与MDR-PTB组治疗前的CT征象,采用χ^(2)检验对比MDR-PTB治疗有效组与治疗无效组临床资料,采用多因素logistic回归分析MDR-PTB患者治疗转归的影响因素。结果MDR-PTB组厚壁空洞、多发空洞、肺损毁、胸膜增厚、肺内播散、肺实变、钙化影、条索影、全肺受累发生率分别为53.57%(45/84)、57.14%(48/84)、9.52%(8/84)、66.67%(56/84)、72.62%(61/84)、58.33%(49/84)、59.52%(50/84)、53.57%(45/84)、29.76%(25/84),参照组分别为19.05%(16/84)、15.48%(13/84)、1.19%(1/84)、16.67%(14/84)、50.00%(42/84)、30.95%(26/84)、17.86%(15/84)、23.81%(20/84)、7.14%(6/84),差异均有统计学意义(均P<0.05);MDR-PTB组斑片影、间质病变及胸腔积液发生率分别为69.05%(58/84)、11.90%(10/84)、60.71%(51/84),参照组分别为61.90%(52/84)、9.52%(8/84)、55.95%(47/84),差异均无统计学意义(均P>0.05)。治疗有效组年龄<60岁、初治、初始痰涂片细菌等级≤2+、初始痰培养细菌等级≤2+、规范用药、治疗6个月后痰培养阴性、无多发空洞、无厚壁空洞、无全肺受累、无胸膜增厚、无肺实变、无钙化影率分别为61.40%(35/57)、66.67%(38/57)、70.18%(40/57)、73.68%(42/57)、78.95%(45/57)、71.93%(41/57)、52.63%(30/57)、56.14%(32/57)、87.72%(50/57)、40.35%(23/57)、49.12%(28/57)、49.12%(28/57),治疗无效组分别为25.93%(7/27)、37.04%(10/27)、44.44%(12/27)、33.33%(9/27)、48.15%(13/27)、40.74%(11/27)、22.22%(6/27)、25.93%(7/27)、33.33%(9/27)、15.52%(5/27)、25.93%(7/27)、22.22%(6/27),差异均有统计学意义(均P<0.05)。logistic回归分析结果显示,年龄、复治、初始痰培养细菌等级3级及以上、多发空洞、厚壁空洞、全肺受累均是MDR-PTB患者治疗转归的危险因素(均P<0.05),治疗6个月后痰培养阴性、规范用药均是患者治疗转归的保护因素(均P<0.05)。结论MDR-PTB患者CT征象具有病灶分布广、形态多样性等特点,其治疗转归受到多种因素的影响,临床应重视对相关因素的干预,改善患者的治疗转归。

利奈唑胺联合多黏菌素B、亚胺培南治疗老年MDR-AB肺炎患者的效果

目的:观察利奈唑胺联合多黏菌素B、亚胺培南治疗老年多重耐药鲍氏不动杆菌(MDR-AB)肺炎患者的效果。方法:选取2022年1月至2023年1月该院收治的120例老年MDR-AB肺炎患者进行前瞻性研究,按照随机数字表法分为观察组与对照组各60例。对照组采用多黏菌素B联合亚胺培南治疗,观察组在对照组基础上加用利奈唑胺葡萄糖注射液治疗,比较两组治疗总有效率、血清炎性因子[白细胞介素(IL)-6、IL-8、肿瘤坏死因子(TNF-α)]水平、外周血T细胞亚群指标(CD3^(+)、CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))水平、肺功能指标[用力肺活量(FVC)、最大呼气中段流量(MMF)、呼气峰流速(PEF)]水平和不良反应发生率。结果:观察组治疗总有效率为95.00%,明显高于对照组的83.33%,差异有统计学意义(P<0.05);治疗后,观察组FVC、MMF、PEF、CD3^(+)、CD4^(+)和CD4^(+)/CD8^(+)水平高于对照组,IL-6、IL-8、TNF-α和CD8^(+)水平低于对照组,差异均有统计学意义(P<0.05);两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论:利奈唑胺联合多黏菌素B、亚胺培南治疗老年MDR-AB肺炎患者可提高治疗总有效率和肺功能指标水平,改善T细胞亚群指标水平,以及降低炎性因子水平,效果优于多黏菌素B联合亚胺培南治疗。

Multidrug-Resistant of Escherichia coli and Salmonella spp. Strains in Chicken Feces Intended for Consumption in Open Spaces of Ouagadougou, Burkina Faso

Resistant bacteria can be transmitted to humans through feces or contaminated meat from local chickens. Bacterial strains were isolated from the intestinal contents of 400 local chicken samples from various sales sites. These strains were then characterized using bacteriological and biochemical methods to identify resistant strains. In a study conducted in Ouagadougou, we systematically collected chicken fecal samples from 20 locations across the city, followed by isolation and identification of Salmonella spp. using specific enrichment and culture methods, as well as Escherichia coli. Bacterial strains were characterized using antibiotic resistance profiles were determined through agar diffusion tests, revealing sensitivity or resistance to a range of antibiotics based on established scientific criteria. The results showed that out of the 400 samples collected, 81.25% and 63.5% were contaminated by Escherichia coli and Salmonella spp., respectively. Among these, 86.15% of identified Escherichia coli and 50.78% of Salmonella spp. displayed resistance to at least one tested antibiotic. Among 280 Escherichia coli isolates identified resistant to at least one antibiotic, 31.07% were resistant to cefotaxime (CTX), 20.35% to ceftazidime (CAZ), 21.07% to ceftriaxone (CTR), 75% to amoxicillin clavulanic acid (AMC), 23.57% aztreoname (ATM) and 27.14% were resistant to imipenem (IMP). In the case of the 129 Salmonella spp. isolates resistant to at least one tested antibiotic, 34.88% were resistant to CTX;41.08% to CAZ;35.65% to CTR, 92% to AMC, 39.53% to ATM and finally 47.28% were resistant to IMP. Our study revealed high prevalence of resistance in bacterial strains isolated from local chickens sold outdoors in Ouagadougou. These findings raise significant public health concerns, due to the possible transmission of these resistant strains to humans through the consumption of contaminated meat, thus complicating the treatment of bacterial infections.

Survey of Multidrug Resistance and Class I Integron Prevalence in Chicken-derived Salmonella

[Objective] This study aimed to investigate the multidrug resistance and prevalence of class I integrons in Salmonel a. [Method] Salmonel a strains were isolated from chicken farms in Shandong Province. Kauffmann-White classification method was employed to analyze the serotypes of Salmonel a strains. Minimum in-hibition concentration （MIC） of Salmonel a strains against 19 common antimicrobial drugs was analyzed determined with microdilution method. The class I integrons and carried drug resistance gene cassettes were detected by PCR. [Result] A total of 311 Salmonel a strains were isolated and classified into two serotypes, including 133 Salmonel a Indiana strains and 178 Salmonel a Enteritidis strains. Drug sensitivity test showed that the isolated Salmonel a strains were general y resistant to sulfadiazine, sulfamethoxazole, nalidixic acid, ampicil in, tetracycline, doxycycline and trimethoprim, with a multidrug resistance rate of 91.0% （283/311）; 99% strains were sensitive to amikacin and colistin. PCR assay indicated that the detection rate of class I integrons was 65.0% （202/311）; the positive rate of class I integrons in Salmonel a strains with multidrug resistance was 92.6%; among 202 positive strains, six strains carried gene cassette dfr17-aadA5. [Conclusion] According to the above results, class I integrons exist general y in Salmonel a and are closely associated with the multidrug resistance of Salmonel a strains.

Structure-activity Relationship of Phenothiazines for Inhibition of Protein Kinase C and Reversal of Multidrug Resistance

Studies on structure-activity relationship of phenothiazines (PTZs) forinhibition of protein kinase C (PKC) and reversal of multidrug resistance (MDR) has been made invitro. The results showed that the order of potency of reversal effect of PTZs on MDR is as follows:2-COC_3 H_7 > 2-CF_3 > 2-COCH_3 > H. The type of piperazinyl substitution also significantlyaffected potency against MDR. The results show the order: CH_3 > COOC_2 H_5 > C_2 H_4 OH. Inaddition, PKC plays a marked role in diverse cellular process including MDR. Some derivatives of PTZwas tested for inhibition of PKC, of which PTZ11 showed the highest inhibitory effect of MDR andPKC, implying a potential reversal agent of MDR for tumor therapy in the future. We also tried toexplore the possible binding model of PTZs to PKC. Our molecular-modeling study preliminarilysuggests how these PTZs bind to PKC and provides a structural basis for the design of high affinityPKC-modulator. The infor-mation may be used in the rational design of more effective drugs.

Reversal of Multidrug Resistance by Neferine in Adriamycin Resistant Human Breast Cancer Cell Line MCF-7/ADM

Objective: To study the reversal effect of neferine on adriamycin (ADM) resistant human breast cancer cell line MCF-7/ADM. Methods: The cytotoxic effect of Nef or ADM was determined by 3-[4, 5-dimethylthiazol-2.-yl], 5-diphenyl tetraxolium bromid (MTT) assay. Apoptosis and the expression of P-glycoprotein (P-gp) were detected by flow cytometry (FCM). The intracellular ADM concentration was measured by HPLC. Results: Nef at 1, 5, 10 mol/L decreased the IC50 of ADM to MCF-7/ADM from 11.63 g/mL to 4.59, 2.44, 0.27 g/mL respectively. MCF-7/ADM could resist the apoptosis induced by ADM while Nef (1-10 mol/L) could augment ADR-mediated apoptosis. Nef (10 mol/L) increased the accumulation of ADM up to 2.88 fold in MCF-7/ADM but not in sensitive cells MCF-7/S and reduced the expression of P-gp in MCF-7/ADM cells. Conclusion: Nef can circumvent multidrug resistance (MDR) of MCF-7/ADM cells and the mechanism was associated with the increase of intracellular accumulation of ADM and the reduced expression of P-gp in MCF-7/ADM cells.

Antimicrobial peptides: new hope in the war against multidrug resistance

The discovery of antibiotics marked a golden age in the revolution of human medicine. However,decades later, bacterial infections remain a global healthcare threat, and a return to the pre-antibiotic era seems inevitable if stringent measures are not adopted to curb the rapid emergence and spread of multidrug resistance and the indiscriminate use of antibiotics. In hospital settings, multidrug resistant(MDR) pathogens, including carbapenem-resistant Pseudomonas aeruginosa, vancomycin-resistant enterococci(VRE), methicillin-resistant Staphylococcus aureus(MRSA), and extendedspectrum β-lactamases(ESBL) bearing Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae are amongst the most problematic due to the paucity of treatment options,increased hospital stay, and exorbitant medical costs. Antimicrobial peptides(AMPs) provide an excellent potential strategy for combating these threats. Compared to empirical antibiotics, they show low tendency to select for resistance, rapid killing action, broad-spectrum activity, and extraordinary clinical efficacy against several MDR strains. Therefore, this review highlights multidrug resistance among nosocomial bacterial pathogens and its implications and reiterates the importance of AMPs as next-generation antibiotics for combating MDR superbugs.

Inhibitory effects of emodin, baicalin, schizandrin and berberine on hef A gene: Treatment of Helicobacter pylori-induced multidrug resistance

AIM: To investigate the inhibitory effects of emodin, baicalin, etc.on the hefA gene of multidrug resistance(MDR) in Helicobacter pylori(H.pylori).METHODS: The double dilution method was used to screen MDR H.pylori strains and determine the minimum inhibitory concentrations(MICs) of emodin, baicalin, schizandrin, berberine, clarithromycin, metronidazole, tetracycline, amoxicillin and levofloxacin against H.pylori strains.After the screened MDR stains were treated with emodin, baicalin, schizandrin or berberine at a 1/2 MIC concentration for 48 h, changes in MICs of amoxicillin, tetracycline, levofloxacin, metronidazole and clarithromycin were determined.MDR strains with reduced MICs of amoxicillin were selected to detect the hefA mR NA expression by realtime quantitative PCR.RESULTS: A total of four MDR H.pylori strains were screened.Treatment with emodin, baicalin, schizandrin and berberine significantly decreased the MICs of amoxicillin and tetracycline against some strains, decreased by 1 to 2 times, but did not significantly change the MICs of clarithromycin, levofloxacin, and metronidazole against MDR strains.In the majority of strains with reduced MICs of amoxicillin, hef A m RNA expression was decreased; one-way ANOVA(SPSS 12.0) used for comparative analysis, P < 0.05.CONCLUSION: Emodin, baicalin, schizandrin and berberine significantly decreased the MICs of amoxicillin and tetracycline against some H.pylori strains, possibly by mechanisms associated with decreasing hefA mR NA expression.