Urinary tract infections(UTIs)are among the most prevalent pediatric bacterial infections,and undertreated episodes may lead to renal scarring,hypertension,or chronic kidney disease.Multidrug-resistant(MDR)Enterobacte...Urinary tract infections(UTIs)are among the most prevalent pediatric bacterial infections,and undertreated episodes may lead to renal scarring,hypertension,or chronic kidney disease.Multidrug-resistant(MDR)Enterobacterales have been increasingly reported in children,with higher rates in Asian and Middle Eastern settings than in high-income countries[1,2].展开更多
In this paper,we analyze the article published by El Labban et al,which explores the impact of cirrhosis on patients with necrotizing fasciitis.The authors conclude that cirrhosis is a significant risk factor for incr...In this paper,we analyze the article published by El Labban et al,which explores the impact of cirrhosis on patients with necrotizing fasciitis.The authors conclude that cirrhosis is a significant risk factor for increased in-hospital morbidity and mortality in this patient population.Building upon their final observation regarding the importance of understanding this association,we will delve into the topic of infections in patients with liver cirrhosis.These patients exhibit intrinsic characteristics that make them particularly susceptible to infections,both bacterial and fungal.This heightened risk not only increases the likelihood of severe infections but also makes them a common trigger for acute decompensations,including the development of acute-on-chronic liver failure,which markedly worsens prognosis and mortality.Infections in patients with cirrhosis often require a more aggressive and rapid diagnostic and therapeutic approach due to the higher risk of nosocomial infections,multidrug-resistant organisms,and atypical clinical presentations.Delayed or inadequate management can lead to unfavorable outcomes,further complicating the course of their underlying liver disease.The aim of this article is to emphasize the importance of early and appropriate management in patients with cirrhosis with infections.Evidence supports that timely and tailored interventions not only improve clinical outcomes but also reduce mortality.By raising awareness among clinicians about the complexity of these cases,we hope to contribute to optimizing the care of this high-risk population.展开更多
Recent studies have shown a noticeable increase in global Helicobacter pylori(H.pylori)resistance,with clarithromycin resistance surpassing 15%in various areas.However,inadequate epidemiological monitoring,especially ...Recent studies have shown a noticeable increase in global Helicobacter pylori(H.pylori)resistance,with clarithromycin resistance surpassing 15%in various areas.However,inadequate epidemiological monitoring,especially in developing countries,and the absence of uniform testing methods lead to discrepancies between regions and a possible underestimation of resistance levels.The complexity of treating H.pylori is driven by its highly dynamic genome,which is prone to frequent mutations contributing to phenotypical resistance.The usual course of action in empirical treatment involves using a combination of various drugs simultaneously,leading to significant resistance selection pressure and potential side effects.The emergence of H.pylori strains resistant to multiple drugs is closely tied to failures in first-line treatment,highlighting the need to prevent further resistance by using optimal initial empirical therapy or regimens guided by antibiotic susceptibility testing,requiring a collection of mixed samples and multiple isolates for accurate assessment.The emergence of new treatments like potassium-competitive acid blockers offers a hopeful approach to decrease antimicrobial usage while still ensuring effectiveness in comparison to traditional therapies with proton pump inhibitors.Additionally,the use of probiotics is under investigation to identify specific strains and formulations that may mitigate therapy-associated adverse effects.展开更多
Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This s...Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This study demonstrates that tenacissoside I(TI),a compound isolated from Marsdenia tenacissima(Roxb.)Wight et Arn,traditionally used in clinical practice as an ethnic medicine for cancer treatment,exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells.TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin(DOX)and paclitaxel(PAC)by downregulating ABCB1 expression and reducing ABCB1 drug transport function.Mechanistically,protein arginine methyltransferase 1(PRMT1),whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues,was differentially expressed in TI-treated SW620/AD300 cells.SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine(aDMA)and enhanced PRMT1-EGFR interaction compared to their parental cells.Moreover,TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR,PRMT1-EGFR interaction,and EGFR downstream signaling in SW620/AD300 and KBV200 cells.These effects were significantly reversed by PRMT1 overexpression.Additionally,TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities.This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR,suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.展开更多
Tumors,due to their diversity and heterogeneity,pose a significant threat to human health.Multidrug resistance is a prevalent and grave issue in clinical treatment,resulting in treatment failure and cancer recurrence....Tumors,due to their diversity and heterogeneity,pose a significant threat to human health.Multidrug resistance is a prevalent and grave issue in clinical treatment,resulting in treatment failure and cancer recurrence.This resistance renders conventional drug therapies ineffective,presenting a substantial challenge to human health and medical care.Exploring natural products as potential sources for anti-cancer drugs could lead to the development of innovative and efficacious cancer treatments.This article aims to investigate the health implications of natural products(such as paclitaxel,podophyllotoxin,homoharringtonine,camptothecin,and vinblastine)in the discovery of anti-cancer drugs while discussing the methods and progress made in researching novel anti-cancer drugs derived from natural products.The paper discusses the diversity,intricate structures,and target affinity of natural products along with their structural modification techniques,combination therapies utilization possibilities with prodrugs or nanoparticles.Additionally,considering the escalating multidrug resistance observed in tumors nowadays;certain natural products offer new insights and approaches for discovering effective anti-tumor drugs that are crucial for addressing global public health challenges.The challenges faced by natural products during drug development including issues related to bioavailability toxicity concerns as well as limited resources are examined thoroughly.Potential opportunities current issues along with future challenges are highlighted aiming at facilitating the clinical translation of original anti-cancer drugs using natural products.展开更多
Developing novel anti-infective drugs is essential to combat antimicrobial resistance,address emerging pathogens,and safeguard global health against evolving infectious threats.A recent publication in the esteemed jou...Developing novel anti-infective drugs is essential to combat antimicrobial resistance,address emerging pathogens,and safeguard global health against evolving infectious threats.A recent publication in the esteemed journal Nature by Qisen Deng et al.reported on the comprehensive evaluation of the therapeutic efficacy of mandimycin against multidrug-resistant(MDR)fungal pathogens.The polyene macrolide antifungal antibiotic,mandimycin,was discovered using a phylogeny-guided natural-product discovery platform.Authors utilized various in vivo mouse models such as systemic and soft-tissue infections to assess the antifungal activity of mandimycin.The efficacy was measured by quantifying the fungal burden in major organs and assessing survival rates.In systemic infections,mandimycin demonstrated significant dose-dependent antifungal efficacy,as compared to amphotericin B,particularly in cases where the latter was ineffective against MDR C.auris.Furthermore,mandimycin showed a favorable safety profile,with low toxicity and no observed side effects at effective doses.The study's findings contribute valuable insights into the potential of mandimycin as a novel antifungal agent,offering hope for improved treatment options against challenging fungal infections.The results pave the way for further research and clinical applications in the fight against antifungal resistance.展开更多
The treatment of Acinetobacter baumannii(A.baumannii)poses significant clinical challenges due to its multidrug/pan-drug resistance.In this study,we isolated a broad-spectrum lytic A.baumannii phage,named P425,from me...The treatment of Acinetobacter baumannii(A.baumannii)poses significant clinical challenges due to its multidrug/pan-drug resistance.In this study,we isolated a broad-spectrum lytic A.baumannii phage,named P425,from medical wastewater,targeting nine multidrug-resistant A.baumannii(MDRAB)with diverse capsular types.Biological characterization revealed that P425 maintains activity at pH range of 3–12 and temperature range of 4–50℃.It resists UV irradiation for 20 minutes,and had an optimal multiplicity of infection(OMOI)is 0.00001.The adsorption kinetics showed that P425 achieves>90%within 10 minutes of incubation,and the one-step growth curve indicated a 10-min latent period,with a burst size of 184 PFU/cell.The genome sequencing results indicated that it harbors a double-stranded DNA genome of 40,583 bp with a GC content of 39.39%.Intergenomic similarity analysis classified it as a novel species within the Friunavirus genus,while electron microscopy results showed that it belongs to the Podoviridae family.Notably,P425 exhibits potent 24-h in vitro inhibitory activity against MDRAB,and demonstrates synergistic effect at an MOI of 0.001 when combined with five classes of antibiotics targeting distinct antimicrobial mechanisms.Safety evaluations confirmed the absence of cytotoxicity,hemolytic activity,or systemic toxicity both in vitro and in vivo.In mouse infection models,P425 can significantly improve the survival rates of mice infected with Ab25(ST1791/KL101).When co-administered with levofloxacin,it achieved 100%protection against mortality and promoted immune recovery.Collectively,P425 is a prospective lytic phage that could offer novel strategies for combating MDRAB infections.展开更多
Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.Howe...Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.However,emerging evidence indicates that unintended pro-metastatic effects may offset the therapeutic benefits of HDACis.Chen et al elucidate this paradox,demonstrating that TSA-induced hyperacetylation activates the BRD4/c-Myc/ER-stress axis,thereby promoting epithelial-mesenchymal transition and metastasis in esophageal squamous cell carcinoma(ESCC).Furthermore,they clarify the clinical significance of histone acetylation in the prognostic evaluation of ESCC.Their findings underscore the complexity of epigenetic therapies and highlight the necessity of reevaluating the associated risks and combinatorial therapeutic strategies with HDACi-based treatments.Here,we summarize the potential risks of HDACis therapy and discuss feasible combination therapeutic strategies.展开更多
The efficacy of conventional antibiotics against multidrug-resistant pathogenic fungi is markedly limited.A study published in Nature by Wang et al.introduced mandimycin,a novel antifungal agent with a distinct mechan...The efficacy of conventional antibiotics against multidrug-resistant pathogenic fungi is markedly limited.A study published in Nature by Wang et al.introduced mandimycin,a novel antifungal agent with a distinct mechanism of action,diverging from established polyene macrolide antibiotics that target ergosterol.The emergence of multidrug-resistant fungal pathogens poses substantial risks to patient health,healthcare infrastructures,and public health at large.The alarming increase in these pathogens is attributed to their capability to withstand numerous antifungal treatments,resulting in escalated morbidity and mortality rates among affected patients.The strategies employed by these pathogens to compromise patient health include modifications at drug target sites,improved efflux mechanisms,and biofilm formation,all of which complicate treatment protocols and extend hospital stays[1].This concerning trend accentuates the urgent need for ongoing monitoring and investigation into innovative antifungal agents and therapeutic approaches to address these resilient pathogens.展开更多
[Objective]To screen sensitive drugs and their combinations against biofilm formation of Escherichia coli isolated from Tibetan pigs and Tibetan chickens.[Method]Semi-quantitative modified crystal violet staining and ...[Objective]To screen sensitive drugs and their combinations against biofilm formation of Escherichia coli isolated from Tibetan pigs and Tibetan chickens.[Method]Semi-quantitative modified crystal violet staining and the micro broth dilution method were employed to assess the biofilm-forming capacities of 152 E.coli,and their susceptibility to 12 commonly used antibiotics.Meanwhile,the checkerboard testing method was employed to evaluate the combined antibacterial activity of the sequential solvent fractions(methanol,dichloromethane,ethyl acetate,and petroleum ether)from four Tibetan veterinary medicinal plants(Spenceria ramalana Trimen,Thalictrum delawayi Franch.,Gentiana sino-ornata Balf.f.,Lonicera rupicola Hook.f.&Thomson),the ethyl acetate extract of two Enterococcus faecium and antibiotics with high resistance rates[chloramphenicol(CHL),oxytetracycline(OTC),ampicillin(AMP),and sulfamethoxazole(SMZ)]against ten selected multi-drug resistant E.coli(designated E1-E10).Lastly,the biofilm eradication of drug combinations on biofilms of E.coli E6 was examined.[Result]Most of the 152 E.coli exhibited moderate and no biofilm-forming capacities.The resistance rates to CHL,sulfamethazine(SM2),OTC,AMP,and SMZ exceeded 90%.In contrast,the resistance rates to difloxacin(DIF),ciprofloxacin(CIP),amikacin(AMK),ceftiofur(EFT),tobramycin(TOB),and ceftriaxone(CTR)were below 50%.Notably,the strains demonstrated a higher susceptibility to amikacin,with a drug resistance rate of only 19.90%.The MIC values for the E.coli E1-E10 were observed to range from 3.93 to 15.63 mg/mL for the methanol extract of S.ramalana,3.93 to 31.52 mg/mL for the ethyl acetate extract of T.delavayi,7.81 to 15.63 mg/mL for the methanol extract of G.sino-ornata,and 7.81 to 31.52 mg/mL for the ethyl acetate extract of L.rupicola.The ethyl acetate extracts from E.aecium S16 and S17 exhibited MIC values ranging from 0.42 to 13.38 mg/mL and from 0.45 to 3.63 mg/mL,respectively.The combinations of sequential solvent fractions derived from four Tibetan veterinary medicinal plants,the ethyl acetate extract of E.faecium,and antibiotics exhibiting high resistance rates demonstrated varying effects.At the MIC,all drug combinations showed a significant biofilm eradication effect compared to their single applications.The ethyl acetate extracts of L.rupicola and T.delavayi,combined with OTC and AMP,demonstrated a stronger inhibitory effect on E.coli E6 biofilm compared to other combinations.Specifically,the ethyl acetate extracts of L.rupicola and T.delavayi inhibited E.coli E6 biofilm by 48.92%and 42.58%in the presence of OTC,and by 48.58%and 47.84%in the presence of AMP,respectively.[Conclusion]The combined application of four selected Tibetan medicinal plants,probiotics,and antibacterial agents may offer a potential solution to address drug resistance and biofilm formation in E.coli isolated from Tibetan pigs and Tibetan chickens.展开更多
Tumor microenvironment-responsive drug self-delivery systems utilize tumor microenvironment-responsive chemical bonds to link anti-tumor drugs,exploiting the hydrophilic and hydrophobic properties of different drugs t...Tumor microenvironment-responsive drug self-delivery systems utilize tumor microenvironment-responsive chemical bonds to link anti-tumor drugs,exploiting the hydrophilic and hydrophobic properties of different drugs to form amphiphilic prodrug molecules with self-assembly characteristics.Upon stimulation by specific factors in the tumor microenvironment,these amphiphilic prodrug molecules can release drugs at precise sites within the tumor.These strategies significantly increase the drug concentration at the tumor site while effectively reducing the damage of anti-cancer drugs to normal tissues.Owing to the advanced delivery strategies such as synergistic administration and controlled drug release,tumor microenvironment-responsive drug self-delivery systems hold great potential for treating malignant tumors with multidrug resistance(MDR).At the same time,the stimulus-reactivity of metal complexes provides an important opportunity to design site-specific prodrugs that can maximize therapeutic efficacy while minimizing adverse side effects of metal drugs.This innovative drug design complements the tumor microenvironment-responsive self-delivery system,providing more feasible therapeutic strategies and possibilities in the field of cancer therapy and drug delivery.This work provides a comprehensive review of recent advancements in drug self-delivery systems,offering insights into their potential applications in cancer therapy and MDR reversal.展开更多
Acinetobacter(A.)baumannii is a Gram-negative,non-fermenting opportunistic pathogen increasingly implicated in nosocomial infections,particularly in intensive care units(ICUs).Its ability to acquire multidrug resistan...Acinetobacter(A.)baumannii is a Gram-negative,non-fermenting opportunistic pathogen increasingly implicated in nosocomial infections,particularly in intensive care units(ICUs).Its ability to acquire multidrug resistance(MDR),including to carbapenems,poses a major public health threat.Infections caused by A.baumannii-ranging from pneumonia to bloodstream and wound infections-are difficult to treat and associated with high mortality,especially in critically ill patients[1].展开更多
BACKGROUND ATP-binding cassette subfamily B member 4(ABCB4)deficiency is associated with cholestatic liver disease primarily because of missense mutations,and many variants remain unidentified.Here,we validate the pat...BACKGROUND ATP-binding cassette subfamily B member 4(ABCB4)deficiency is associated with cholestatic liver disease primarily because of missense mutations,and many variants remain unidentified.Here,we validate the pathogenicity and mechanism of ABCB4 variants in clinical and in vitro trials,hypothesizing that these variants are responsible for impaired biliary function and contribute to the development of cholestatic liver diseases.AIM To clarify the functional features and pathogenicity of ABCB4 variants.METHODS Clinical data were collected from five patients with cholestatic liver disease that was initially not detected by routine examinations.Later,whole-exome sequencing confirmed ABCB4 variants and the patients were treated from January 2017 to December 2023.Pathogenic mechanisms were analyzed using bioinformatics tools,and a cell model in vitro was established to investigate ABCB4 mRNA expression,multidrug resistance protein 3(MDR3)expression,cellular localization,and phosphatidylcholine secretion.Results were compared using Student's t-tests.RESULTS Five missense variants(c.1757T>A,c.1865G>A,c.2362C>T,c.2777C>T and c.3250C>T),one intron variant(c.537-32G>T),and one synonymous(c.C504T)variant were identified.Three of the five patients had various degrees of cholestasis,two presented with liver cirrhosis,and all had elevated gamma-glutamyl transferase.Three of the four patients who underwent a liver biopsy had bile duct dilation,and one had gallstones.Two of the four patients had normal and reduced MDR3 immunohistochemical levels.Bioinformatic analysis indicated that these variants were likely pathogenic except c.C504T variant.None of the missense variants influenced subcellular MDR3 Localization in vitro.However,the c.1865G>A variant significantly decreased ABCB4 mRNA values,and all missense variants down-regulated phosphatidylcholine secretion.CONCLUSION This study uncovered new ABCB4 variants and emphasized the pathogenic potential of specific variants.The findings from five patients provided insight into the pathogenic mechanisms underlying ABCB4-related diseases.展开更多
Objective： To investigate whether the change of drug resistance degree could be evaluated by apoptotic rate in ovarian cancer cell lines. Methods： Human epithelia ovarian cancer cell line A2780 and its platinum （DD...Objective： To investigate whether the change of drug resistance degree could be evaluated by apoptotic rate in ovarian cancer cell lines. Methods： Human epithelia ovarian cancer cell line A2780 and its platinum （DDP） resistance cell line AD4 were used. They were divided into 4 groups respectively （A2780-DDP group, A2780-DDP＋VRM group, AD4-DDP group and AD4-DDP＋VRM group）. 3-（4, 5- dimethylthiazol-2-yl）-2, 5-diphenyl-2H-tetrazolium bromide （MTT） was used to measure the multiple of drug resistance. The expression of drug-resistance genes （mdrl, TopoⅡα and GSTπ） was detected by using reverse transcription polymerase chain reaction （RT-PCR）. Semi-quantity assay was proceed by rate the of multidrug resistance genes to G3 PDH gene. Apoptosis was measured by DNA gel electrophoresis and flow cytometry respectively. The advantages and disadvantage of evaluating drug-resistance with these three methods were analyzed. Results： The 50% inhibition concentration （IC50） of A2780 and AD4 was 19.2 μg/mL and 66 μg/mL respectively, and the resistance fold of the AD4 was 3.4. Some drug-resistance genes could be detected by RT-PCR in A2780 and AD4 cell lines. The expression of mdrl was only （0.09±0.03）×10^-2 ： 1 and （0.10±0.02） × 10^-2：1 respectively （rate to G3 PDH gene） with the difference being not significant between them. The expression of TopoⅡα in the A2780 cells was （2.60±0.12）×10^-2：1 and （0.11±0.03）× 10^-2：1 in the AD4 cells respectively with the difference between them being significant. On the contrary, the expression of GSTπ in A2780 cells was lower than in AD4 cells, and the ratio was （0.11±0.03）×10^-2：1 and （3.13±0.14）×10^-2：1 respectively with tile difference being significant between them. There was no significant difference among the genes expression after the drugs were given for 6 h, 12 h and 24 h. couldn＇t reflect the change of drug-resistance timely. DNA gel electrophoresis used to detect apoptosis was only a qualitative analysis. Different drug resistance degrees may be detected by flow cytometry as early as few hours after drugs were given, which realized the earlier and quantities detection of drug resistance. Conclusion： Detection of apoptosis with flow cytometry may not be affected by the variety of drug-resistance genes, suggested this was a general, quantitative and objective method to reflect drug resistance.展开更多
To study the effects of hypoxia on the expression of P-gp and mutltidrug resistance protein in human lung adenocarcinoma A549 cell line, and to explore the probable mechanism of hypoxia in tumor cell of MDR. The expre...To study the effects of hypoxia on the expression of P-gp and mutltidrug resistance protein in human lung adenocarcinoma A549 cell line, and to explore the probable mechanism of hypoxia in tumor cell of MDR. The expression of hypoxia inducible factor-1α, P-gp and mutltidrug resistance protein was immunohistochemically detected by culturing human lung adenocarcinoma A549 cell under hypoxia (2 % O_2) for 24 h. After interaction with adriamycin or cisplatin under hypoxia (2 % O_2) for 24 h, the cell survival rate was detected by MTT. Our results showed that the expression of hypoxia inducible factor-1α, P-gp and mutltidrug resistance protein under hypoxia were higher than the expression under normoxia, and correlations between the expression of HIF-1α and P-gp or multidrug resistance-associated protein was observed (P<0.05). The resistance of adriamycin of A549 cell was enhanced under hypoxia. It is concluded that the resistance of tumor chemotherapy is enhanced in hypoxia. The expression of HIF-1α is obviously correlated with the expression of P-gp and mutltidrug resistance protein.展开更多
[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-Whi...[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.展开更多
In this study, two kinds of docetaxel （DTX）-loaded mixed micelles, composed of Solutol HS15 （HS 15）/Pluronic F127 （F 127） or folate-conjugated F127, （SF-DTX and FSF-DTX）, were prepared by the thin-film hydrati...In this study, two kinds of docetaxel （DTX）-loaded mixed micelles, composed of Solutol HS15 （HS 15）/Pluronic F127 （F 127） or folate-conjugated F127, （SF-DTX and FSF-DTX）, were prepared by the thin-film hydration method and evaluated in vitro. Both SF-DTX and FSF-DTX were spherical with diameter close to 23 nm. They had high encapsulating efficiency （99.05% and 90.28% for SF-DTX and FSF-DTX, respectively） and sustained-release property. SF and FSF were able to enhance the cellular accumulation of DTX in KBv cells and reduce ATP content in A-549 cells. They also were able to reverse multidrug resistance （MDR）. In vitro cytotoxicity and cellular accumulation of DTX suggested an active targeting of FSF-DTX. It could be concluded from the results that the novel F 127/HS 15 system could serve as a potential nanocarrier with the ability of overcoming MDR, and folate-conjugated F 127/HS 15 might achieve active targeting at the same time.展开更多
Silver nitrate could inhibit the clinical multidrug resistant isolates at high concentrations（with minimal inhibitory concentrations（MICs） from 32 μM to 64 μM）. The activities of amikacin in the presence of sub-...Silver nitrate could inhibit the clinical multidrug resistant isolates at high concentrations（with minimal inhibitory concentrations（MICs） from 32 μM to 64 μM）. The activities of amikacin in the presence of sub-lethal silver nitrate（15 μM） were tested for the combinational effects against multidrug resistant clinical isolates in vitro. Silver nitrate restored the susceptibility of drug-resistant Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus to amikacin. It lowered the MICs of amikacin from 〉128 μg/mL to（2–16） μg/mL and 32 μg/mL, respectively, and lowered the MICs of amikacin on extended spectrum β-lactamase-producing Pseudomonas aeruginosa and Escherichia coli from（16–32） μg/mL and 16 μg/mL to（〈1–4） μg/mL and 〈1 μg/mL, respectively.展开更多
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 potenc...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.展开更多
文摘Urinary tract infections(UTIs)are among the most prevalent pediatric bacterial infections,and undertreated episodes may lead to renal scarring,hypertension,or chronic kidney disease.Multidrug-resistant(MDR)Enterobacterales have been increasingly reported in children,with higher rates in Asian and Middle Eastern settings than in high-income countries[1,2].
文摘In this paper,we analyze the article published by El Labban et al,which explores the impact of cirrhosis on patients with necrotizing fasciitis.The authors conclude that cirrhosis is a significant risk factor for increased in-hospital morbidity and mortality in this patient population.Building upon their final observation regarding the importance of understanding this association,we will delve into the topic of infections in patients with liver cirrhosis.These patients exhibit intrinsic characteristics that make them particularly susceptible to infections,both bacterial and fungal.This heightened risk not only increases the likelihood of severe infections but also makes them a common trigger for acute decompensations,including the development of acute-on-chronic liver failure,which markedly worsens prognosis and mortality.Infections in patients with cirrhosis often require a more aggressive and rapid diagnostic and therapeutic approach due to the higher risk of nosocomial infections,multidrug-resistant organisms,and atypical clinical presentations.Delayed or inadequate management can lead to unfavorable outcomes,further complicating the course of their underlying liver disease.The aim of this article is to emphasize the importance of early and appropriate management in patients with cirrhosis with infections.Evidence supports that timely and tailored interventions not only improve clinical outcomes but also reduce mortality.By raising awareness among clinicians about the complexity of these cases,we hope to contribute to optimizing the care of this high-risk population.
基金Supported by the Industrial Technological Initiation Scholarship of National Council for Scientific and Technological Development,CNPq,Brazil,No.0932204294929829 and No.7414780530977345the Scientific Initiation Scholarship Programme(PIBIC)of National Council for Scientific and Technological Development,CNPq,Brazil,No.5763023359532159,No.6472982965854452,and No.7340128440641417+2 种基金the Scientific Initiation Scholarship Programme(PIBIC)of Bahia State Research Support Foundation,FAPESB,Brazil,No.19.573.301.5418the PERMANECER Programme of Pro-Rectory of Student Assistance at Federal University of Bahia,No.R8EZ-4V4W-6LQX-5LC8the CNPq Research Productivity Fellow,No.4357511882624145.
文摘Recent studies have shown a noticeable increase in global Helicobacter pylori(H.pylori)resistance,with clarithromycin resistance surpassing 15%in various areas.However,inadequate epidemiological monitoring,especially in developing countries,and the absence of uniform testing methods lead to discrepancies between regions and a possible underestimation of resistance levels.The complexity of treating H.pylori is driven by its highly dynamic genome,which is prone to frequent mutations contributing to phenotypical resistance.The usual course of action in empirical treatment involves using a combination of various drugs simultaneously,leading to significant resistance selection pressure and potential side effects.The emergence of H.pylori strains resistant to multiple drugs is closely tied to failures in first-line treatment,highlighting the need to prevent further resistance by using optimal initial empirical therapy or regimens guided by antibiotic susceptibility testing,requiring a collection of mixed samples and multiple isolates for accurate assessment.The emergence of new treatments like potassium-competitive acid blockers offers a hopeful approach to decrease antimicrobial usage while still ensuring effectiveness in comparison to traditional therapies with proton pump inhibitors.Additionally,the use of probiotics is under investigation to identify specific strains and formulations that may mitigate therapy-associated adverse effects.
基金supported by the National Natural Science Foundation of China(Nos.82274211 and 82474190)the Natural Science Foundation of Tianjin(Nos.24JCZDJC00120 and 24PTLYHZ00280)Liaoning Provincial Department of Education Basic Research Projects for Higher Education Institutions(No.LJ212510163021)。
文摘Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This study demonstrates that tenacissoside I(TI),a compound isolated from Marsdenia tenacissima(Roxb.)Wight et Arn,traditionally used in clinical practice as an ethnic medicine for cancer treatment,exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells.TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin(DOX)and paclitaxel(PAC)by downregulating ABCB1 expression and reducing ABCB1 drug transport function.Mechanistically,protein arginine methyltransferase 1(PRMT1),whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues,was differentially expressed in TI-treated SW620/AD300 cells.SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine(aDMA)and enhanced PRMT1-EGFR interaction compared to their parental cells.Moreover,TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR,PRMT1-EGFR interaction,and EGFR downstream signaling in SW620/AD300 and KBV200 cells.These effects were significantly reversed by PRMT1 overexpression.Additionally,TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities.This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR,suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.
基金supported by the National Natural Science Foundation of China(grant number 22309103)Natural Science Foundation of Shandong Province(grant numbers ZR2022MH162,ZR2022QE202)+1 种基金PhD Research Start-up Foundation of Qufu Normal University(grant numbers 614901,615201)the project of introduction and cultivation for young innovation talents in the colleges and universities of Shandong Province(grant number 614202).
文摘Tumors,due to their diversity and heterogeneity,pose a significant threat to human health.Multidrug resistance is a prevalent and grave issue in clinical treatment,resulting in treatment failure and cancer recurrence.This resistance renders conventional drug therapies ineffective,presenting a substantial challenge to human health and medical care.Exploring natural products as potential sources for anti-cancer drugs could lead to the development of innovative and efficacious cancer treatments.This article aims to investigate the health implications of natural products(such as paclitaxel,podophyllotoxin,homoharringtonine,camptothecin,and vinblastine)in the discovery of anti-cancer drugs while discussing the methods and progress made in researching novel anti-cancer drugs derived from natural products.The paper discusses the diversity,intricate structures,and target affinity of natural products along with their structural modification techniques,combination therapies utilization possibilities with prodrugs or nanoparticles.Additionally,considering the escalating multidrug resistance observed in tumors nowadays;certain natural products offer new insights and approaches for discovering effective anti-tumor drugs that are crucial for addressing global public health challenges.The challenges faced by natural products during drug development including issues related to bioavailability toxicity concerns as well as limited resources are examined thoroughly.Potential opportunities current issues along with future challenges are highlighted aiming at facilitating the clinical translation of original anti-cancer drugs using natural products.
基金the National Key Research and Development Program of China(2023YFD1700500)the College Student Research Training Program(202110307002T)Bayer Grants4Ag Initiative for their support.
文摘Developing novel anti-infective drugs is essential to combat antimicrobial resistance,address emerging pathogens,and safeguard global health against evolving infectious threats.A recent publication in the esteemed journal Nature by Qisen Deng et al.reported on the comprehensive evaluation of the therapeutic efficacy of mandimycin against multidrug-resistant(MDR)fungal pathogens.The polyene macrolide antifungal antibiotic,mandimycin,was discovered using a phylogeny-guided natural-product discovery platform.Authors utilized various in vivo mouse models such as systemic and soft-tissue infections to assess the antifungal activity of mandimycin.The efficacy was measured by quantifying the fungal burden in major organs and assessing survival rates.In systemic infections,mandimycin demonstrated significant dose-dependent antifungal efficacy,as compared to amphotericin B,particularly in cases where the latter was ineffective against MDR C.auris.Furthermore,mandimycin showed a favorable safety profile,with low toxicity and no observed side effects at effective doses.The study's findings contribute valuable insights into the potential of mandimycin as a novel antifungal agent,offering hope for improved treatment options against challenging fungal infections.The results pave the way for further research and clinical applications in the fight against antifungal resistance.
基金supported by the Nanjing Infectious Disease Clinical Medical Center,Innovation center for infectious disease of Jiangsu Province(NO.CXZX202232)the Leading Talent Project of Jiangsu Province Traditional Chinese Medicine(NO.SLJ0216)+4 种基金the Nanjing Health science and Technology Development Special fund Project(NO.YKK20102)the General Program of Jiangsu Commission of Health(NO.M2021088)the Nanjing Health science and Technology Development General Project(NO.YKK21121)the 2023 Nanjing Second Hospital Talent Support Project Grant(RCZD23003)the Jiangsu Province Postgraduate Research and Practice Innovation Program(KYCX24_2176).
文摘The treatment of Acinetobacter baumannii(A.baumannii)poses significant clinical challenges due to its multidrug/pan-drug resistance.In this study,we isolated a broad-spectrum lytic A.baumannii phage,named P425,from medical wastewater,targeting nine multidrug-resistant A.baumannii(MDRAB)with diverse capsular types.Biological characterization revealed that P425 maintains activity at pH range of 3–12 and temperature range of 4–50℃.It resists UV irradiation for 20 minutes,and had an optimal multiplicity of infection(OMOI)is 0.00001.The adsorption kinetics showed that P425 achieves>90%within 10 minutes of incubation,and the one-step growth curve indicated a 10-min latent period,with a burst size of 184 PFU/cell.The genome sequencing results indicated that it harbors a double-stranded DNA genome of 40,583 bp with a GC content of 39.39%.Intergenomic similarity analysis classified it as a novel species within the Friunavirus genus,while electron microscopy results showed that it belongs to the Podoviridae family.Notably,P425 exhibits potent 24-h in vitro inhibitory activity against MDRAB,and demonstrates synergistic effect at an MOI of 0.001 when combined with five classes of antibiotics targeting distinct antimicrobial mechanisms.Safety evaluations confirmed the absence of cytotoxicity,hemolytic activity,or systemic toxicity both in vitro and in vivo.In mouse infection models,P425 can significantly improve the survival rates of mice infected with Ab25(ST1791/KL101).When co-administered with levofloxacin,it achieved 100%protection against mortality and promoted immune recovery.Collectively,P425 is a prospective lytic phage that could offer novel strategies for combating MDRAB infections.
基金Supported by National Natural Science Foundation of China,No.32270768,No.82273970,No.32070726 and No.82370715Hubei Natural Science Foundation of China,No.2024AFB218+1 种基金National Key R&D Program of China,No.2023YFC2507904Doctoral Startup Foundation of Hubei University of Technology,No.XJ2022003901.
文摘Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.However,emerging evidence indicates that unintended pro-metastatic effects may offset the therapeutic benefits of HDACis.Chen et al elucidate this paradox,demonstrating that TSA-induced hyperacetylation activates the BRD4/c-Myc/ER-stress axis,thereby promoting epithelial-mesenchymal transition and metastasis in esophageal squamous cell carcinoma(ESCC).Furthermore,they clarify the clinical significance of histone acetylation in the prognostic evaluation of ESCC.Their findings underscore the complexity of epigenetic therapies and highlight the necessity of reevaluating the associated risks and combinatorial therapeutic strategies with HDACi-based treatments.Here,we summarize the potential risks of HDACis therapy and discuss feasible combination therapeutic strategies.
基金supported by the National Natural Science Foundation of China(82460111)the The First People’s Hospital of Yunnan Province Talent Project program(No.KHBS-2022013,KHYJ-2025-04-02,2022-KHRCBZ-B03)+4 种基金the Kunming Medical University Joint Special Project on Applied Basic Research(202301AY070001-210)Yunnan Provincial Key Laboratory of Clinical Virology(No.2023A4010403-04)Yunnan Foundmental basical research project(202301AT070034)the Yunnan Provincial Key Laboratory of Birth Defects and Genetic Diseases(No.2022ZDKFKT001)the Open Project of Yunnan Provincial Clinical Medical Research Center for Elderly Diseases(No.:2023YJZX-LN03/13 of 202102AA3100692023).
文摘The efficacy of conventional antibiotics against multidrug-resistant pathogenic fungi is markedly limited.A study published in Nature by Wang et al.introduced mandimycin,a novel antifungal agent with a distinct mechanism of action,diverging from established polyene macrolide antibiotics that target ergosterol.The emergence of multidrug-resistant fungal pathogens poses substantial risks to patient health,healthcare infrastructures,and public health at large.The alarming increase in these pathogens is attributed to their capability to withstand numerous antifungal treatments,resulting in escalated morbidity and mortality rates among affected patients.The strategies employed by these pathogens to compromise patient health include modifications at drug target sites,improved efflux mechanisms,and biofilm formation,all of which complicate treatment protocols and extend hospital stays[1].This concerning trend accentuates the urgent need for ongoing monitoring and investigation into innovative antifungal agents and therapeutic approaches to address these resilient pathogens.
基金Supported by Project of Sichuan Provincial Department of Science and Technology(2016KZ0007)Science and Technology Project of Sichuan Province(2022JDRC0121)+1 种基金Innovative Research Projects for Postgraduate at Southwest Minzu University(CX2020SZ49)Sichuan Provincial Department of Science and Technology(2023NSFSC0179)。
文摘[Objective]To screen sensitive drugs and their combinations against biofilm formation of Escherichia coli isolated from Tibetan pigs and Tibetan chickens.[Method]Semi-quantitative modified crystal violet staining and the micro broth dilution method were employed to assess the biofilm-forming capacities of 152 E.coli,and their susceptibility to 12 commonly used antibiotics.Meanwhile,the checkerboard testing method was employed to evaluate the combined antibacterial activity of the sequential solvent fractions(methanol,dichloromethane,ethyl acetate,and petroleum ether)from four Tibetan veterinary medicinal plants(Spenceria ramalana Trimen,Thalictrum delawayi Franch.,Gentiana sino-ornata Balf.f.,Lonicera rupicola Hook.f.&Thomson),the ethyl acetate extract of two Enterococcus faecium and antibiotics with high resistance rates[chloramphenicol(CHL),oxytetracycline(OTC),ampicillin(AMP),and sulfamethoxazole(SMZ)]against ten selected multi-drug resistant E.coli(designated E1-E10).Lastly,the biofilm eradication of drug combinations on biofilms of E.coli E6 was examined.[Result]Most of the 152 E.coli exhibited moderate and no biofilm-forming capacities.The resistance rates to CHL,sulfamethazine(SM2),OTC,AMP,and SMZ exceeded 90%.In contrast,the resistance rates to difloxacin(DIF),ciprofloxacin(CIP),amikacin(AMK),ceftiofur(EFT),tobramycin(TOB),and ceftriaxone(CTR)were below 50%.Notably,the strains demonstrated a higher susceptibility to amikacin,with a drug resistance rate of only 19.90%.The MIC values for the E.coli E1-E10 were observed to range from 3.93 to 15.63 mg/mL for the methanol extract of S.ramalana,3.93 to 31.52 mg/mL for the ethyl acetate extract of T.delavayi,7.81 to 15.63 mg/mL for the methanol extract of G.sino-ornata,and 7.81 to 31.52 mg/mL for the ethyl acetate extract of L.rupicola.The ethyl acetate extracts from E.aecium S16 and S17 exhibited MIC values ranging from 0.42 to 13.38 mg/mL and from 0.45 to 3.63 mg/mL,respectively.The combinations of sequential solvent fractions derived from four Tibetan veterinary medicinal plants,the ethyl acetate extract of E.faecium,and antibiotics exhibiting high resistance rates demonstrated varying effects.At the MIC,all drug combinations showed a significant biofilm eradication effect compared to their single applications.The ethyl acetate extracts of L.rupicola and T.delavayi,combined with OTC and AMP,demonstrated a stronger inhibitory effect on E.coli E6 biofilm compared to other combinations.Specifically,the ethyl acetate extracts of L.rupicola and T.delavayi inhibited E.coli E6 biofilm by 48.92%and 42.58%in the presence of OTC,and by 48.58%and 47.84%in the presence of AMP,respectively.[Conclusion]The combined application of four selected Tibetan medicinal plants,probiotics,and antibacterial agents may offer a potential solution to address drug resistance and biofilm formation in E.coli isolated from Tibetan pigs and Tibetan chickens.
基金supported by the National Natural Science Foundation of China(No.21907059)Shandong Province Chinese Medicine Science and Technology Development Project(No.M-2022258)+1 种基金the Young Scientist Development Foundation of Shandong First Medical University(No.202201-002)the Academic Promotion Program of Shandong First Medical University(Nos.2019LJ003 and 2019QL011).
文摘Tumor microenvironment-responsive drug self-delivery systems utilize tumor microenvironment-responsive chemical bonds to link anti-tumor drugs,exploiting the hydrophilic and hydrophobic properties of different drugs to form amphiphilic prodrug molecules with self-assembly characteristics.Upon stimulation by specific factors in the tumor microenvironment,these amphiphilic prodrug molecules can release drugs at precise sites within the tumor.These strategies significantly increase the drug concentration at the tumor site while effectively reducing the damage of anti-cancer drugs to normal tissues.Owing to the advanced delivery strategies such as synergistic administration and controlled drug release,tumor microenvironment-responsive drug self-delivery systems hold great potential for treating malignant tumors with multidrug resistance(MDR).At the same time,the stimulus-reactivity of metal complexes provides an important opportunity to design site-specific prodrugs that can maximize therapeutic efficacy while minimizing adverse side effects of metal drugs.This innovative drug design complements the tumor microenvironment-responsive self-delivery system,providing more feasible therapeutic strategies and possibilities in the field of cancer therapy and drug delivery.This work provides a comprehensive review of recent advancements in drug self-delivery systems,offering insights into their potential applications in cancer therapy and MDR reversal.
基金supported by ICMR-RMRC intramural fund(RMRC/IM/2022/26).
文摘Acinetobacter(A.)baumannii is a Gram-negative,non-fermenting opportunistic pathogen increasingly implicated in nosocomial infections,particularly in intensive care units(ICUs).Its ability to acquire multidrug resistance(MDR),including to carbapenems,poses a major public health threat.Infections caused by A.baumannii-ranging from pneumonia to bloodstream and wound infections-are difficult to treat and associated with high mortality,especially in critically ill patients[1].
基金Supported by the National Natural Science Foundation of China,No.81970454.
文摘BACKGROUND ATP-binding cassette subfamily B member 4(ABCB4)deficiency is associated with cholestatic liver disease primarily because of missense mutations,and many variants remain unidentified.Here,we validate the pathogenicity and mechanism of ABCB4 variants in clinical and in vitro trials,hypothesizing that these variants are responsible for impaired biliary function and contribute to the development of cholestatic liver diseases.AIM To clarify the functional features and pathogenicity of ABCB4 variants.METHODS Clinical data were collected from five patients with cholestatic liver disease that was initially not detected by routine examinations.Later,whole-exome sequencing confirmed ABCB4 variants and the patients were treated from January 2017 to December 2023.Pathogenic mechanisms were analyzed using bioinformatics tools,and a cell model in vitro was established to investigate ABCB4 mRNA expression,multidrug resistance protein 3(MDR3)expression,cellular localization,and phosphatidylcholine secretion.Results were compared using Student's t-tests.RESULTS Five missense variants(c.1757T>A,c.1865G>A,c.2362C>T,c.2777C>T and c.3250C>T),one intron variant(c.537-32G>T),and one synonymous(c.C504T)variant were identified.Three of the five patients had various degrees of cholestasis,two presented with liver cirrhosis,and all had elevated gamma-glutamyl transferase.Three of the four patients who underwent a liver biopsy had bile duct dilation,and one had gallstones.Two of the four patients had normal and reduced MDR3 immunohistochemical levels.Bioinformatic analysis indicated that these variants were likely pathogenic except c.C504T variant.None of the missense variants influenced subcellular MDR3 Localization in vitro.However,the c.1865G>A variant significantly decreased ABCB4 mRNA values,and all missense variants down-regulated phosphatidylcholine secretion.CONCLUSION This study uncovered new ABCB4 variants and emphasized the pathogenic potential of specific variants.The findings from five patients provided insight into the pathogenic mechanisms underlying ABCB4-related diseases.
基金This work was supported by a grant from National Natural Sciences Foundation of China (No. 30070786).
文摘Objective： To investigate whether the change of drug resistance degree could be evaluated by apoptotic rate in ovarian cancer cell lines. Methods： Human epithelia ovarian cancer cell line A2780 and its platinum （DDP） resistance cell line AD4 were used. They were divided into 4 groups respectively （A2780-DDP group, A2780-DDP＋VRM group, AD4-DDP group and AD4-DDP＋VRM group）. 3-（4, 5- dimethylthiazol-2-yl）-2, 5-diphenyl-2H-tetrazolium bromide （MTT） was used to measure the multiple of drug resistance. The expression of drug-resistance genes （mdrl, TopoⅡα and GSTπ） was detected by using reverse transcription polymerase chain reaction （RT-PCR）. Semi-quantity assay was proceed by rate the of multidrug resistance genes to G3 PDH gene. Apoptosis was measured by DNA gel electrophoresis and flow cytometry respectively. The advantages and disadvantage of evaluating drug-resistance with these three methods were analyzed. Results： The 50% inhibition concentration （IC50） of A2780 and AD4 was 19.2 μg/mL and 66 μg/mL respectively, and the resistance fold of the AD4 was 3.4. Some drug-resistance genes could be detected by RT-PCR in A2780 and AD4 cell lines. The expression of mdrl was only （0.09±0.03）×10^-2 ： 1 and （0.10±0.02） × 10^-2：1 respectively （rate to G3 PDH gene） with the difference being not significant between them. The expression of TopoⅡα in the A2780 cells was （2.60±0.12）×10^-2：1 and （0.11±0.03）× 10^-2：1 in the AD4 cells respectively with the difference between them being significant. On the contrary, the expression of GSTπ in A2780 cells was lower than in AD4 cells, and the ratio was （0.11±0.03）×10^-2：1 and （3.13±0.14）×10^-2：1 respectively with tile difference being significant between them. There was no significant difference among the genes expression after the drugs were given for 6 h, 12 h and 24 h. couldn＇t reflect the change of drug-resistance timely. DNA gel electrophoresis used to detect apoptosis was only a qualitative analysis. Different drug resistance degrees may be detected by flow cytometry as early as few hours after drugs were given, which realized the earlier and quantities detection of drug resistance. Conclusion： Detection of apoptosis with flow cytometry may not be affected by the variety of drug-resistance genes, suggested this was a general, quantitative and objective method to reflect drug resistance.
文摘To study the effects of hypoxia on the expression of P-gp and mutltidrug resistance protein in human lung adenocarcinoma A549 cell line, and to explore the probable mechanism of hypoxia in tumor cell of MDR. The expression of hypoxia inducible factor-1α, P-gp and mutltidrug resistance protein was immunohistochemically detected by culturing human lung adenocarcinoma A549 cell under hypoxia (2 % O_2) for 24 h. After interaction with adriamycin or cisplatin under hypoxia (2 % O_2) for 24 h, the cell survival rate was detected by MTT. Our results showed that the expression of hypoxia inducible factor-1α, P-gp and mutltidrug resistance protein under hypoxia were higher than the expression under normoxia, and correlations between the expression of HIF-1α and P-gp or multidrug resistance-associated protein was observed (P<0.05). The resistance of adriamycin of A549 cell was enhanced under hypoxia. It is concluded that the resistance of tumor chemotherapy is enhanced in hypoxia. The expression of HIF-1α is obviously correlated with the expression of P-gp and mutltidrug resistance protein.
基金Supported by National Natural Science Foundation of China(31201949,31172362)~~
文摘[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.
基金The Key Disciplines Research Funds for the Young Teachers(Grant No.2013jzzdxk038)
文摘In this study, two kinds of docetaxel （DTX）-loaded mixed micelles, composed of Solutol HS15 （HS 15）/Pluronic F127 （F 127） or folate-conjugated F127, （SF-DTX and FSF-DTX）, were prepared by the thin-film hydration method and evaluated in vitro. Both SF-DTX and FSF-DTX were spherical with diameter close to 23 nm. They had high encapsulating efficiency （99.05% and 90.28% for SF-DTX and FSF-DTX, respectively） and sustained-release property. SF and FSF were able to enhance the cellular accumulation of DTX in KBv cells and reduce ATP content in A-549 cells. They also were able to reverse multidrug resistance （MDR）. In vitro cytotoxicity and cellular accumulation of DTX suggested an active targeting of FSF-DTX. It could be concluded from the results that the novel F 127/HS 15 system could serve as a potential nanocarrier with the ability of overcoming MDR, and folate-conjugated F 127/HS 15 might achieve active targeting at the same time.
基金Peking Union Medical College(PUMC)Youth Fund and the Fundamental Research Funds for the Central Universities,China(Grant No.333203084)
文摘Silver nitrate could inhibit the clinical multidrug resistant isolates at high concentrations（with minimal inhibitory concentrations（MICs） from 32 μM to 64 μM）. The activities of amikacin in the presence of sub-lethal silver nitrate（15 μM） were tested for the combinational effects against multidrug resistant clinical isolates in vitro. Silver nitrate restored the susceptibility of drug-resistant Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus to amikacin. It lowered the MICs of amikacin from 〉128 μg/mL to（2–16） μg/mL and 32 μg/mL, respectively, and lowered the MICs of amikacin on extended spectrum β-lactamase-producing Pseudomonas aeruginosa and Escherichia coli from（16–32） μg/mL and 16 μg/mL to（〈1–4） μg/mL and 〈1 μg/mL, respectively.
文摘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.
